EVIDENCE FOR THE SECRETION OF THYROTROPIN WITH ENHANCED BIOACTIVITY IN SYNDROMES OF THYROID-HORMONE RESISTANCE

Resistance to thyroid hormone (RTH) is a rare genetic disorder associa ted 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, mea suring cAMP production in Chinese hamster ovary cells transfected with the recombinant human TSH receptor as well as in FRTL-5 cells. The ra tio of biologically active us. immunoreactive TSH (B/I) was significan tly 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 T SH under basal conditions. On the contrary, supraphysiological doses o f T-3 normalized the B/I ratio of circulating TSH. Concanavalin-A chro matography 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 syndrome s is enhanced and can be normalized after T-3 administration. These fi ndings may account for the occurrence of goiter and elevated thyroid h ormone levels in RTH patients despite normal serum TSH concentrations.