TSH receptor gene mutations and familial gestational hyperthyroidism

‘Gestational hyperthyroidism’ is a clinical condition characterized by thyrotoxicosis and hyperemesis gravidarum and generally occurs in 1‐2% of all normal pregnancies. It represents an extreme degree of morning nausea and vomiting in early pregnancy, accompanied by weight loss, ketonemia, acetonuria, and profound volume depletion. Within the last decade, the association of abnormal thyroid function tests (suppressed thyrotropin (TSH) levels and high free thyroxine (FT4) concentrations) with hyperemesis gravidarum has been increasingly recognized and the severity of the hyperemesis has been linked to the biochemical severity of the hyperthyroidism (1‐3), even though a precise correlation between these two conditions is still unclear. Gestational hyperthyroidism has been attributed to the thyrotropic action of choriogonadotropin (CG) (3‐6). During early pregnancy, the high circulating levels of CG could be responsible for the transient thyroid stimulation leading to hyperemesis. The mechanism known as ‘specificity spillover’ could explain the ability of CG to stimulate the TSH receptor. The specificity spillover is related to the structural homology between CG and TSH molecules, and also between their mutual receptors. Using FRTL-5 cells, it was shown that highly purified CG increased iodide uptake and cAMP production (7), and induced thymidine incorporation and c-myc mRNA expression as indirect indices of cell growth (8). In addition, in cultured human thyroid follicles CG displaces TSH from its receptor and is able to stimulate adenylyl cyclase, iodide uptake, organification, and tri-iodothyronine (T3) secretion (9). These data clearly indicate that CG possesses TSH-like activity. This characteristic of the CG molecule and the high degree of homology among glycoprotein hormone (TSH, follicle-stimulating hormone (FSH) and luteinizing hormone (LH)/CG) receptors, which belong to the family of closely related G-protein coupled receptors, is responsible for the hyperthyroidism found in trophoblastic diseases, as well as in CG-producing tumors, such as choriocarcinomas.