Changes in the sialylation and sulfation of secreted thyrotropin in congenital hypothyroidism.

Abstract

We have examined the oligosaccharide structure of secreted thyrotropin (TSH) in perinatal and mature rats with congenital primary hypothyroidism. Rat pituitaries from euthyroid control animals and those rendered hypothyroid by methimazole treatment were incubated with [3H1glucosamine in vitro. Secreted TSH was purified, and oligosaccharides were enzymatically released and characterized by anion-exchange HPLC. In perinatal hypothyroid animals compared with control animals, oligosaccharides from TSH a and (3 subunits contained more species with three or more negative charges. Moreover, perinatal hypothyroid animals demonstrated a dramatic increase in the ratio of sialylated to sulfated species within oligosaccharides of the same negative charge (2.9-to 7.4-fold increase for TSH-a; 15.1-to 25.5-fold increase for TSH-,B). In mature hypothyroid 9-week-old animals compared with control animals, changes were less pronounced, suggesting that endocrine regulation of oligosaccharide structure is dependent upon the maturational state of the animal. These changes were specific for TSH because glycosylation of free a subunit (synthesized by the thyrotroph and gonadotroph) and of total glycoproteins was minimally altered by hypothyroidism. Together, these data provide direct evidence and characterization of specific changes in the structure of a secreted pituitary glycoprotein hormone occurring as a result of in vivo endocrine alterations during early development. Moreover, they provide a potential structural basis to explain the delayed clearance of both TSH and the gonadotropins with end-organ deficiency, which may have important implications for the in vivo biological activities of these hormones. Specifically, such posttranslational changes may be an important adaptive response to prevent the consequences of endocrine deficiency during early development.Thyrotropin (TSH) is a glycoprotein hormone containing an a subunit with two sites of asparagine-linked glycosylation and a p subunit with one such site (1). Oligosaccharides on TSH play an important role in directing subunit combination, protecting the molecule from intracellular proteolysis, and influencing the metabolic clearance rate and biological activity of the circulating hormone (2-6).In humans and experimental animals with intact hypothalamic-pituitary regulation, serum TSH levels are elevated in primary hypothyroidism (7) at least in part because of increased TSH subunit gene transcription (8)(9)(10)(11). Moreover, measurement of TSH is used either as a primary or confirmatory screening test to detect congenital primary hypothyroidism, a preventable cause of mental retardation in children (12). However, it is not known whether structural alterations occur in TSH in congenital primary hypothyroidism or how the absence of thyroid hormone during prenatal development and early life affects the subsequent integration of the hypothalamic-pituitary-thyroid axis. The rat has proven to be an ideal animal to study TSH structure and regulation because maturation of...

Sorafenib therapy decreases the clearance of thyrotropin

“…The specific glycosylation pattern of TSH carbohydrate structures is a major determinant of its renal and hepatic metabolism, with increased sialylation associated with prolonged plasma half-life (14). Hypothyroidism was associated with increased sialylated pituitary TSH isoforms in the mammalian, including human circulation (15,16). Evidence supports the notion that slower TSH degradation could, at least partly, explain supranormal TSH levels in hypothyroid states (14,17).…”

Circulatory half-life but not interaction with the lutropin/chorionic gonadotropin receptor is modulated by sulfation of bovine lutropin oligosaccharides.

“…Gyves et al (20) recently reported that TSH from hypothyroid rats has increased levels of sialic acid-bearing oligosaccharides. Furthermore, they have found that hTSH produced in CHO cells has a longer half-life than native hTSH isolated from cadavers (21).…”

Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships

“…This mechanism provides to the pituitarythyroid balance an enormous potential to adapt to physiological needs by regulating both the quality and the amount of TSH with a combinatorial flexibility, which has not been easy to decipher experimentally. It was first observed that distribution of pituitary rat TSH was modified in primary hypothyroidism, suggesting a selective release of hormonal forms with altered glycosylation (74). In hypothyroid patients, plasma TSH glycoforms appeared mostly acidic with an increased sialic acid content due to a shift to higher glycan branching (148).…”