The thyroid axis just got more complicated.

As a first-year medical student, you could count on the simplicity and elegance of the thyroid axis, because all its details had apparently been elucidated. Hypothalamic thyrotropin-releasing hormone (TRH) promoted the synthesis, release, and glycosylation of pituitary thyrotropin, thyroid-stimulating hormone (TSH), which in turn acted on the thyroid follicle, leading to the synthesis and release of thyroid hormones (T4 and T3). Furthermore, precise control of the axis was maintained by thyroid hormone negative feedback at both the hypothalamic and pituitary levels (Figure 1). Now, a new pituitary hormone, termed thyrostimulin, may change our established view of this axis. TSH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are a family of heterodimeric pituitary and placental glycoprotein hormones that share a common α subunit (1). Their biological specificity at either the thyroid or the gonad is conferred by a unique β subunit that is noncovalently linked to the common glycoprotein α subunit. All of these hormones have been purified by classical means, and their biological activities established by in vivo assays. Nakabayashi et al. in this issue of the JCI (2) describe a novel heterodimeric glycoprotein hormone containing two unique subunits, which they term A2 and B5. These investigators identified A2 and B5 in a homology search of the human genome (GenBank). In a nearly simultaneous paper in another journal, the same group describes orthologs of these subunits found in diverse species (3). A2 and B5 share only modest amino acid similarity with the related glycoprotein hormone subunit family members, but they contain all of the cysteine residues required to form the characteristic cysteine knot structure found in these and other growth factors, including PDGF and TGF-β. The authors show here that A2 interacts strongly with FSH-β, CG-β, and B5 in a yeast two-hybrid assay (2). After determining that the A2/B5 pair can stimulate cAMP production via the TSH receptor, Nakabayashi and colleagues pursued the thyrotropic activity of A2/B5 in greater detail.