Suppression of Serum TSH by Graves Ig: Evidence for a Functional Pituitary TSH Receptor
Leon J. S. Brokken, Jolanda W. C. Scheenhart, Wilmar M. Wiersinga and Mark F. Prummel
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: firstname.lastname@example.org.
Antithyroid treatment for Graves hyperthyroidism restores euthyroidism clinically within 12 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.