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Suppression of Serum TSH by Graves’ Ig: Evidence for a Functional Pituitary TSH Receptor

Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. Leon J. S. Brokken, Department of Endocrinology, F5-171, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: l.j.brokken{at}amc.uva.nl

Abstract

Antithyroid treatment for Graves’ hyperthyroidism restores euthyroidism clinically within 1–2 months, but it is well known that TSH levels can remain suppressed for many months despite normal free T₄ and T₃ levels. This has been attributed to a delayed recovery of the pituitary-thyroid axis. However, we recently showed that the pituitary contains a TSH receptor through which TSH secretion may be down-regulated via a paracrine feedback loop. In Graves’ disease, TSH receptor autoantibodies may also bind this pituitary receptor, thus causing continued TSH suppression. This hypothesis was tested in a rat model. Rat thyroids were blocked by methimazole, and the animals were supplemented with L-T₄. They were then injected with purified human IgG from Graves’ disease patients at two different titers or with IgG from a healthy control (thyroid hormone binding inhibitory Ig, 591, 127, and < 5 U/liter). Despite similar T₄ and T₃ levels, TSH levels were indeed lower in the animals treated with high TSH receptor autoantibodies containing IgGs; the 48-h mean TSH concentration (mean ± SEM; n = 8) was 11.6 ± 1.3 ng/ml compared with 16.2 ± 0.9 ng/ml in the controls (P < 0.01). The intermediate strength TSH receptor autoantibody-treated animals had levels in between the other two groups (13.5 ± 2.0 ng/ml). We conclude that TSH receptor autoantibodies can directly suppress TSH levels independently of circulating thyroid hormone levels, suggesting a functioning pituitary TSH receptor.

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