The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 10 4814-4817
Copyright © 2001 by The Endocrine Society
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: [email protected]
Antithyroid treatment for Graves' hyperthyroidism restores euthyroidismclinically 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 hypothesiswas tested in a rat model. Rat thyroids were blocked by methimazole,and the animals were supplemented with L-T4. They were theninjected with purified human IgG from Graves' diseasepatients at two different titers or with IgG from a healthycontrol (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 comparedwith 16.2 ± 0.9 ng/ml in the controls (P < 0.01).The intermediate strength TSH receptor autoantibody-treatedanimals 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.
GRAVES' DISEASE IS an autoimmune thyroid disorder characterizedby circulating Ig directed against the TSH receptor (TSH-R)(1, 2). The majority of these TSH-R autoantibodies (TRAb) act as agonists by mimicking TSH binding leading to Graves' hyperthyroidism and goiter. Antithyroid drug treatment usuallyrestores euthyroidism within 4-6 wk in patients with hyperthyroidism(3). However, it may take much longer for TSH values to normalize. Many treated Graves' disease patients who are clinically euthyroid and have normal T4 and T3 serum levels continue to show decreased TSH levels (4, 5).
The explanation for this continued suppression of TSH is unknown, but it is usually attributed to a delayed recovery of the pituitary-thyroid axis (6). We offer an alternative explanation, involving a direct effect of TRAb on TSH secretion by the pituitary. We have recently postulated that in addition to a negative feedback control by T4 levels, TSH secretion is influenced through a negative ultra-short-loop feedback mechanism within the pituitary. We indeed demonstrated that the TSH-R is expressed in the human anterior pituitary on folliculo-stellate (FS) cells (7). When TSH is secreted by the thyrotrophs, it can bind to this receptor on FS cells, which then signal the thyrotrophs to decrease their TSH secretion. That the FS cells are involved in this feedback control is likely, because they are well known for their paracrine regulatory capabilities (8, 9). Apart from this physiological control, the TSH-R on FS cells may also bind circulating TRAb, which, by mimicking TSH, subsequently can cause a decrease in TSH secretion independently of thyroid hormone levels. Such a mechanism may very well be responsible for the low TSH levels observed in otherwise euthyroid Graves' patients receiving antithyroid drug treatment. TRAb often remain present in patients treated for Graves' disease (10, 11) and can be responsible for the long-term suppression of TSH.
To test this hypothesis, we used a modified long-acting thyroid stimulatorbioassay in which we measured the plasma TSH response to the administrationof TRAb in rats that were unable to mount a thyroid responseto TRAb because of prior antithyroid drug treatment