Decreased Receptor Binding of Biologically Inactive Thyrotropin in Central Hypothyroidism

Abstract

Previous studies have suggested that certain cases of idiopathic central hypothyroidism of hypothalamic origin may result from the secretion of biologically inactive thyrotropin. To investigate this possibility and to define the mechanism of defective hormone action, we measured the adenylate cyclase-stimulating bioactivity (B) and receptor-binding (R) activity of purified immunoreactive serum thyrotropin (I) from seven patients with hypothalamic hypothyroidism. We found a strikingly decreased R/I ratio (less than 0.15) in patients as compared with controls (0.6 to 2.7) and a similarly decreased B/I ratio (less than 0.2 vs 2.8 to 5.6). After acute injection of thyrotropin-releasing hormone (TRH, 200 micrograms intravenously), the R/I ratio increased in two of three patients, but the B/I ratio became normal in only one. After administration of TRH for 20 to 30 days, an increase in immunoreactive serum thyrotropin was observed in all patients. Moreover, both ratios returned to normal in all but one patient, who had apparent desensitization. The increase in the amount and bioactivity of secreted thyrotropin after long-term TRH therapy resulted in enhanced secretion of serum thyroid hormones in all patients studied. We conclude that in certain cases of hypothalamic hypothyroidism, secreted thyrotropin lacks biologic activity because of impaired binding to its receptor; TRH treatment can correct both defects. These data suggest that TRH regulates not only the secretion of thyrotropin but also its specific molecular and conformational features required for hormone action.

Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene

“…There have been no patients with isolated TRH deficiency defined, but similar elevation has also been reported in some patients with central hypothyroidism (21). These patient's TSH activities were observed to be significantly reduced (22,23). Because the TRH Ϫ͞Ϫ mice showed the diminished thyroid hormone response to endogenous TSH after TRH stimulation, but normal response to exogenous TSH, it is concluded that the biological activity of circulating TSH in the TRH Ϫ͞Ϫ mice was attenuated.…”

Alteration of Hypothalamic–Pituitary–Thyroid Axis Function in Non-Small-Cell Lung Cancer Patients

“…Hormone resistance syndromes can be broadly defined as reduced or absent end-organ responsiveness to a hormone. Several general mechanisms have been identified, [37][38][39] and a quantitative reduction in receptor or defects in postreceptor signaling pathways seem to be the more probable explanations; but a different explanation may be plausible. A subset of depressed patients demonstrated a diminished TSH response to TRH stimulation.…”

A Case of Sheehan's Syndrome Associated with Severe Anemia and Empty Sella Proved 48 Years After Postpartum Hemorrhage.

“…It was reported that plasma TSH was increased in hypopituitarism due to biologically hypoactive TSH secretion [23], low capacity for binding to TSH receptor [24] and abnormality of the carbohydrate chain in the TSH molecule [25]. As glucocorticoid had a suppressive effect on TSH secretion [13], it may be considered that hyposecretion of glucocorticoid induced the increase in plasma TSH.…”