Changes in the Degree of Sialylation of Carbohydrate Chains Modify the Biological Properties of Circulating Thyrotropin Isoforms in Various Physiological and Pathological States1

Variation in asparagine-linked carbohydrate chains have a major impact on TSH biological properties. In particular, highly sialylated TSH is characterized by impaired intrinsic bioactivity and prolonged half-life. The aim of the present study was to investigate the changes in the degree of sialylation of circulating TSH isoforms that may occur in several physiological and clinical situations. Bioactivity and terminal sugar residues of immunopurified TSH were studied in 26 normal adults (day- and nighttime serum pools), 2 cord serum pools from normal fetuses during the third trimester, 1 fetus with primary hypothyroidism (PH; 27th week), 1 fetus with resistance to thyroid hormone (RTH; 28th and 33rd weeks), 24 patients with PH (before and during L-T4 treatment), and 5 patients with RTH before and during triiodothyrocetic acid (TRIAC) treatment. Nighttime TSH isoforms have an increased degree of sialylation compared to daytime TSH (35.8 +/- 9.7% vs. 23.8 +/- 5.8%; P < 0.03), thus accounting for the lower bioactivity [biological/immunological TSH ratio (TSH B/I), 1.3 +/- 0.4 vs. 2.0 +/- 0.2; P < 0.0007]. In adult PH, TSH isoforms are highly sialylated (45.4 +/- 7.6%; P < 0.007), showing an impaired bioactivity (0.7 +/- 0.3; P < 0.001). L-T4 therapy was accompanied by a trend toward normalization of TSH biological properties; TSH B/I was higher (1.0 +/- 0.3; P < 0.01), and the degree of sialylation was lower (36.8 +/- 7.0%; P < 0.02). A significant inverse correlation between TSH B/I values and the degree of sialylation was observed (P < 0.001). In normal fetuses, extremely bioactive asialo-TSH isoforms are circulating during the 3rd trimester. The impaired thyroid hormone action, such as that occurring in hypothyroid or RTH fetuses, induces an early expression of alpha-2,6-sialyltransferase activity within thyrotropes and results in the secretion of high amounts of sialylated TSH isoforms (34.6% and 26.3%). A hybrid TSH with peculiar terminal sugar residues and enhanced bioactivity is circulating in patients with RTH (TSH B/I, > or = 2.2). Treatment with low doses of TRIAC can initially reduce thyroid hormone secretion in RTH, mainly through the secretion of TSH isoforms with changed terminal sugar residues and reduced bioactivity (TSH B/I, 0.9-1.7). In conclusion, changes in the terminal sialic acid residues modulate the biological properties of circulating TSH, play a relevant physiopathological role in various situations, and contribute to adjust thyroid-stimulating activity to temporary needs.