Endocrine Abstracts

The glycoprotein hormones are proteins comprising a common alpha subunit and specific beta subunits having substantial sequence similarity. The glycoprotein hormone receptors (GPHr) (FSH, LH/CG and TSH receptors) present a bipartite structure, with a large extracellular domain (ECD) responsible for high affinity hormone binding and a carboxylterminal serpentine region, shared by G-protein-coupled-receptors (GPCRs), implicated in transmission of the activation signal. Mutagenesis experiments and the phenotypes of natural GPHr mutants lead to a model for activation, in which the actual agonist of the serpentine domain would be an “active conformation” of the ECD, triggered by binding of the hormone without need for a direct interaction of the ligand with the serpentine region. In agreement with this view, full activation of the TSHr can be achieved by a single amino acid substitution within the ECD, as well as by binding of antibodies with stimulating activity. Despite these similarities, co-evolution of the hormone-receptor couples resulted in the establishment of tight specificity barriers, preventing promiscuous activation under normal physiological conditions. The emergence of chorionic gonadotropin (CG) in primates, constituted an evolutionary challenge to the specificity barrier in GPHr couples. In humans, during the first trimester of pregnancy, hCG reaches concentrations at which it displays some thyrotropic activity, bringing most pregnant women on the fringe of hyperthyroidism. In agreement with these notions, one would expect mutations affecting the hormone binding surface of the TSHr or FSHr to be responsible for rare cases of gestational hyperthyroidism or spontaneous ovarian hyperstimulation syndrome (sOHSS). Whereas this prediction has been verified in one case of gestational hyperthyroidism caused by a mutation in the ECD of the TSHr, up to now, all cases of sOHSS have been associated with mutations in the serpentine domain of the FSHr. From these observations, we hypothesized that establishment of the specificity barrier against CG followed different evolutionary paths in the TSH and FSH receptor lineages.