An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Thyroid-Stimulating Hormone

Inappropriate secretion of thyroid-stimulating hormone (IST), also known as central hyperthyroidism, is a clinical condition characterized by elevated free thyroxine and triiodothyronine concentrations concurrent with detectable thyroid-stimulating hormone (TSH) concentrations. Similarly, the term syndrome of IST (SITSH) is widely used in Japan to refer to a closely related condition; however, unlike that for IST, an elevated serum free triiodothyronine concentration is not a requisite criterion for SITSH diagnosis. IST or SITSH is an important indicator of resistance to thyroid hormone β (RTHβ) caused by germline mutations in genes encoding thyroid hormone receptor β (TRβ) and TSH-secreting pituitary adenoma. Recent evidence has accumulated for several conditions associated with IST, including RTH without mutations in the TRβ gene (non-TR-RTH), the phenomenon of hysteresis involving the hypothalamus-pituitary-thyroid axis (HPT-axis), methodological interference, and Cushing’s syndrome after surgical resection. However, little information is available on the systematic pathophysiological aspects of IST in previous review articles. This report presents an overview of the recent advances in our understanding of the etiological aspects of IST that are relevant for diagnosis and treatment. Moreover, the report focuses on the potential mechanism of IST caused by hysteresis in the HPT-axis (lagging TSH recovery) in terms of epigenetic regulation.