Hypothalamic Hypothyroidism Caused by Lesions in Rat Paraventricular Nuclei Alters the Carbohydrate Structure of Secreted Thyrotropin

Taylor, Terry; Gesundheit, Neil; Gyves, Peter W.; Jacobowitz, David M.; Weintraub, Bruce D.

doi:10.1210/endo-122-1-283

Cited by 40 publications

(19 citation statements)

References 39 publications

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“…We demonstrated previously that TSH secreted in vitro by mature hypothyroid rodent pituitary explants showed small but significant increases in multiantennary (27), as well as sialylated (28) oligosaccharide structures when compared with those from control animals. Moreover, others have reported an increase in the size and charge of intrapituitary TSH in primary hypothyroidism (29) and an increase in the size of lutropin and follitropin in castrated monkeys compared with control monkeys (30,31).…”

Section: Tsh-alpha (Hypothyroid)mentioning

confidence: 79%

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

Gyves¹,

Gesundheit²,

Thotakura³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Tsh-alpha (Hypothyroid)mentioning

confidence: 79%

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

Gyves¹,

Gesundheit²,

Thotakura³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…TSH production in the thyrotroph is regulated by feedback inhibition by circulating thyroid hormone and via stimulation by hypothalamic TRH (4). There is some evidence that TRH enhances the biologic activity of TSH by modifying its glycosylation pattern (29)(30)(31). This was recently confirmed in mice with targeted ablation of the TRH gene who exhibit T 4 levels that were 50% of those in wild-type mice, despite TSH concentrations that were elevated twofold (32).…”

Section: Discussionmentioning

confidence: 89%

“…However, previous published data in rats and humans render this hypothesis plausible (29)(30)(31). Changes in the glycosylation of TSH could also impact its bioactivity.…”

Section: Figurementioning

confidence: 97%

Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin

Abel¹,

Kaulbach²,

Campos-Barros³

et al. 1999

J. Clin. Invest.

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Patients with resistance to thyroid hormone (RTH) exhibit elevated thyroid hormone levels and inappropriate thyrotropin (thyroid-stimulating hormone, or TSH) production. The molecular basis of this disorder resides in the dominant inhibition of endogenous thyroid hormone receptors (TRs) by a mutant receptor. To determine the relative contributions of pituitary versus hypothalamic resistance to the dysregulated production of thyroid hormone in these patients, we developed a transgenic mouse model with pituitary-specific expression of a mutant TR (∆337T). The equivalent mutation in humans is associated with severe generalized RTH. Transgenic mice developed profound pituitary resistance to thyroid hormone, as demonstrated by markedly elevated baseline and non-triodothyronine (T 3 )-suppressible serum TSH and pituitary TSH-β mRNA. Serum thyroxine (T 4 ) levels were only marginally elevated in transgenic mice and thyrotropin-releasing hormone (TRH) gene expression in the paraventricular hypothalamus was downregulated. After TRH administration, T 4 concentrations increased markedly in transgenic, but not in wild-type mice. Transgenic mice rendered hypothyroid exhibited a TSH response that was only 30% of the response observed in wild-type animals. These findings indicate that pituitary expression of this mutant TR impairs both T 3 -mediated suppression and T 3 -independent activation of TSH production in vivo. The discordance between basal TSH and T 4 levels and the reversal with TRH administration demonstrates that resistance at the level of both the thyrotroph and the hypothalamic TRH neurons are required to elevate thyroid hormone levels in patients with RTH.

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“…There was a 3-fold increase in TSH but normal circulating T4 suggesting the possibility of reduced TSH bioactivity. Previous studies have indicated that TRH enhances the biological activity of TSH via alteration of TSH glycosylation (Beck-Peccoz et al 1985, Taylor et al 1988, Taylor & Weintraub 1989. This concept was supported recently by Yamada et al (1997) who demonstrated that mice with a targeted ablation of TRH have T4 levels 50% lower than wild-type mice despite 2-fold elevated TSH concentrations.…”

Section: Transgenic Models Of Human Rthmentioning

confidence: 99%

Insight into the physiological actions of thyroid hormone receptors from genetically modified mice

OShea¹,

Williams²

2002

Journal of Endocrinology

195

110

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Thyroid hormones exert a range of developmental and physiological actions in all vertebrates. Serum concentrations of L-thyroxine (T4) and 3,5,3 -L-triiodothyronine (T3) are maintained by a negative feedback loop involving T3-inhibition of hypothalamic thyrotrophin releasing hormone (TRH) and pituitary thyroid stimulating hormone (TSH) secretion, and by tissue specific and hormone-regulated expression of the three iodothyronine deiodinase enzymes that activate or metabolise thyroid hormones. T3 actions are mediated by two T3-receptors, TRalpha and TRbeta, which act as hormone-inducible transcription factors. The TRalpha (NR1A1) and TRbeta (NR1A2) genes encode mRNAs that are alternatively spliced to generate 9 mRNA isoforms (TRalpha1, alpha2, alpha3, Deltaalpha1, Deltaalpha2, beta1, beta2, beta3 and Deltabeta3), of which four (TRalpha1, alpha2, beta1 and beta2) are known to be expressed at the protein level in vivo. The numerous TR mRNAs are expressed widely in tissue- and developmental stage-specific patterns, although it is important to note that levels of mRNA expression may not correlate with receptor protein concentrations in individual tissues. The TRalpha2, alpha3, Deltaalpha1 and Deltaalpha2 transcripts encode proteins that fail to bind T3 in vitro. These non-binding isoforms, in addition to TRDeltabeta3 which does bind hormone, may act as dominant negative antagonists of the true T3-binding receptors in vitro, but their physiological functions and those of the TRbeta3 isoform have not been determined. In order to obtain a new understanding of the complexities of T3 action in vivo and the role of TRs during development, many mouse models of disrupted or augmented thyroid hormone signalling have been generated. The aim of this review is to provide a picture of the physiological actions of thyroid hormones by considering the phenotypes of these genetically modified mice.

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Hypothalamic Hypothyroidism Caused by Lesions in Rat Paraventricular Nuclei Alters the Carbohydrate Structure of Secreted Thyrotropin

Cited by 40 publications

References 39 publications

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

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

Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin

Insight into the physiological actions of thyroid hormone receptors from genetically modified mice

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