Molecular and Functional Insights into Thyrostimulin and Its Subunits-GPA2/GPB5

Thyrostimulin is a heterodimeric glycoprotein hormone composed of two subunits, GPA2 and GPB5, first identified in 2002. It is considered an ancestral member of the glycoprotein hormone family and is highly conserved across species, including vertebrates and invertebrates. Unlike classical pituitary glycoprotein hormones such as TSH, LH, and FSH, thyrostimulin appears to function predominantly through paracrine and autocrine mechanisms, with its expression reported in diverse tissues such as the pituitary, ovary, skin, and brain. In humans, thyrostimulin has been implicated in ovarian cancer cell proliferation, stem cell quiescence in the pituitary, and metabolic regulation. However, its role in metabolism remains unclear, with studies showing both beneficial and adverse effects such as weight loss in some models and elevated levels in polycystic ovary syndrome and metabolic syndrome patients. In Caenorhabditis elegans, orthologs of GPA2 and GPB5 have been shown to influence growth and intestinal function via a neuroendocrine pathway involving thyrotropin hormone-like peptides. These findings suggest that thyrostimulin has conserved multifunctional roles in development, metabolism, and endocrine signaling. The aim of this review is to summarize the structure-function relationships and the currently known roles of thyrostimulin and its subunits, GPA2/GPB5, particularly in the reproductive system, metabolic syndrome, skeletal development, and obesity.