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Department of Medical Science University of Milan Endocrinology and Diabetology Unit Fondazione Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico 20122 Milan, Italy
Address all correspondence and requests for reprints to: Paolo Beck-Peccoz, M.D., University of Milan, Endocrinology and Diabetology Unit, Padiglione. Granelli, Via Francesco Sforza 35, 20122 Milan, Italy. E-mail: paolo.beckpeccoz{at}unimi.it.
The treatment of thyrotoxicosis has been for centuries based on the surgical removal of the thyroid. The first steps in search of a medical therapy for such a frequent thyroid disorder started at the end of 1920s when Chesney et al. (1) made the first observation that cabbage and other Brassica plants (cauliflowers and turnips) possess goitrogenic effects in animals and that these effects are preventable if cabbage and iodine were given at the same time. Nevertheless, it was only the serendipitous discovery by Richter and Clisby (2) and MacKenzie et al. (3, 4) of compounds causing goiter in animals that led Astwood (5) to introduce thiourea and thiouracil as possible medical treatment of thyrotoxicosis. Further studies prompt the synthesis of methimazole and propylthiouracil that Astwood termed antithyroid drugs. These compound act inhibiting the oxidation of iodide and iodination of mono- and diiodotyrosine as well as iodotyrosine coupling and thyroglobulin biosynthesis. Moreover, propylthiouracil prevent the conversion of T4 to T3. Both drugs are highly effective in controlling thyrotoxicosis of different origin, particularly Graves’ disease (6), but many side effects may be observed. Among them, urticaria, arthralgia, fever, and transient granulocytopenia are common (1–5% of treated patients), whereas arthritis and gastrointestinal discomfort are seen in less that 1% of patients. Rare or very rare are agranulocytosis, aplastic anemia, thrombocytopenia, toxic or cholestatic hepatitis, and systemic lupus-like syndrome (6). It is worth noting that the therapy of Graves’ disease is only symptomatic because the defects in immune surveillance pathways, and therefore an etiological therapy, still remain to be ascertained.
Treatment with the above drugs was for 65 yr the unique alternative to the gland destruction by surgery or radioiodine, which was available at the beginning of 1940s. In the present issue of Endocrinology, Neumann et al. (7) present convincing data on a newly designed drug able to antagonize TSH receptor. Compound 52 (NIDDK/CEB-52) is a low-molecular-weight antagonist synthesized by chemically modifying Org41841 that was originally identified as a partial agonist of both LH/chorionic gonadotropin and TSH receptors (8, 9). The methodological approach to discover new agonists of TSH receptor has been complex. The authors used a cyclic nucleotide gated ion channel-coupled cAMP assay (10) in a quantitative high-throughput screening of a huge number (73, 180) of compounds, which allowed them to select and identify hundreds of TSH receptor agonists, and Org41841 was the most potent among them (11). The next step was the identification of low-molecular-weight antagonists by rational design using a model of Org41841/TSH receptor complex. A three-dimensional homology model of the transmembrane region of TSH receptor was generated based on the recently solved x-ray structure of the β2-adrenergic receptor crystal structure (12, 13).
In vitro experiments have shown that Compound 52 selectively inhibits activation of TSH receptor by both TSH and thyroid-stimulating autoantibodies. Indeed, Compound 52 inhibited the regulation of thyroperoxidase mRNA transcript induced by both TSH and thyroid-stimulating autoantibodies in primary culture of human thyrocytes expressing endogenous TSH receptor, a more physiological condition compared with cell lines transfected with TSH receptor (7).
Altogether these results suggest that Compound 52 may be a useful tool in the management of TSH receptor-mediated hyperthyroidism, including Graves’ disease, TSH-secreting pituitary adenomas, and the form of thyroid hormone resistance accompanied by signs and symptoms of hyperthyroidism (14, 15, 16). In fact, TSH receptor antagonist may block thyroid stimulation by TSH receptor-stimulating autoantibodies circulating in Graves’ disease or by TSH autonomously hypersecreted by a pituitary adenoma. In thyroid hormone resistance, the antagonist may prevent thyroid stimulation by TSH molecules with enhanced biological activity (17), thus reducing thyroid hormone hyperproduction and attenuating thyroid hormone effects on some tissues less resistant to their action, such as brain, heart, and bone (18). Again, the therapeutic approach to these disorders is symptomatic and does not cure the disease. However, these low-molecular-weight compounds may have fewer side effects than methimazole and propylthiouracil. Moreover, compared with possible polypeptides with antagonistic properties, these compounds appear devoid of intrinsic immunogenicity. Furthermore, it is conceivable to foreseeing a role for antagonist compounds, ad hoc designed, in the treatment of hyperthyroidism secondary to TSH receptor activating mutations, such as those found in congenital (19, 20, 21) or acquired (22, 23) hyperthyroidism. The congenital forms are rare and thyroidectomy must be performed at a very young age because huge goiter may develop during treatment with the classical antithyroid drugs. On the contrary, the acquired forms of TSH receptor-activating mutations are very frequent in areas of even moderate iodine deficiency, accounting for more than 85% of hyperthyroid patients with uni- or multinodular toxic goiter (22). Finally, the blockade of TSH receptor on the plasma membrane of tumoral cells in differentiated thyroid carcinomas, aiming to stop cell proliferation, is another hypothetical field of application of these low-molecular-weight antagonists.
In conclusion, the discovery of TSH receptor antagonists open a new era in the treatment of TSH receptor-mediated hyperthyroidism and will probably in the future substitute the 65-yr-old antithyroid drugs. Fewer side effects of such a therapy are expected and thyrotoxicosis due to TSH-secreting pituitary adenoma or thyroid hormone resistance with signs and symptoms of hyperthyroidism will benefit much more from these drugs than from the old ones, which may block thyroid hormone secretion but not the TSH receptor-mediated proliferative effect.
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Footnotes |
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Received September 17, 2008.
Accepted for publication September 19, 2008.
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References |
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 Top References |
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mutations in toxic thyroid nodules in geographical regions with different iodine supply in Turkey. Eur J Endocrinol 155:535–545
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