Evidence for the secretion of thyrotropin with enhanced bioactivity in syndromes of thyroid hormone resistance.

Abstract

Resistance to thyroid hormone (RTH) is a rare genetic disorder associated with diverse mutations in the thyroid hormone receptor beta-gene. TSH-dependent thyroid hyperstimulation, leading to goiter and elevated thyroid hormone levels, is a characteristic feature of RTH. However, about 60% of untreated resistance patients have circulating TSH levels within the normal range, raising the possibility that the biological activity of TSH is altered. We, therefore, assayed the bioactivity of circulating TSH in 11 patients from 8 different kindreds with RTH, measuring cAMP production in Chinese hamster ovary cells transfected with the recombinant human TSH receptor as well as in FRTL-5 cells. The ratio of biologically active vs. immunoreactive TSH (B/I) was significantly higher in RTH patients than in 8 normal controls [TSH B/I, 4.2 +/- 0.9 (range, 2.2-11.9) vs. 1.3 +/- 0.2 (range, 0.6-2.1)]. TSH released in response to TRH had a bioactivity similar to that of circulating TSH under basal conditions. On the contrary, supraphysiological doses of T3 normalized the B/I ratio of circulating TSH. Concanavalin-A chromatography of TSH from RTH patients showed the presence of circulating forms with altered carbohydrate branching. Our data indicate that the bioactivity of circulating TSH in thyroid hormone resistance syndromes is enhanced and can be normalized after T3 administration. These findings may account for the occurrence of goiter and elevated thyroid hormone levels in RTH patients despite normal serum TSH concentrations.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…However, this cannot be always demonstrated by in vitro bioassay. In some instances it can be shown by isoelectric focusing, if a sufficient amount of TSH can be concentrated and developed by Western blotting or by Concanavalin-A chromatography (78). Another method is to affinity purify the TSH being tested, inject it intravenously in TSH-suppressed mice or rats (treated with high dose of T 3 ), and follow its half-life by RIA, or follow the biological activity of TSH by measuring T 4 secretion in serum.…”

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…The response of TSH to TSH-releasing hormone is normal or exaggerated, in proportion to the baseline TSH level. The relatively high TSH bioactivity explains why goiters develop despite normal levels of immunoreactive TSH [46]. Thyroidal radioiodide uptake is high and not dischargeable by perchlorate.…”

A De Novo L330S Point Mutation in Thyroid Hormone Receptor Beta Gene in a Thai Female with Resistance to Thyroid Hormone.

“…However, a number of RTH subjects still have goiter despite TSH in the normal range [1,15] . This can be partly explained by the increased biological activity of TSH from subjects with RTH compared to controls [16]. Elevated thyroid hormones and goiter have been mistakenly interpreted as hyperthyroidism and treated as such with antithyroid drug which would not ameliorate the patient's problem but might induce enlargement of the goiter as demonstrated in our patient.…”