Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications

Abstract

The gonadotropins, luteinizing hormone, human chorionic gonadotropin and follicle-stimulating hormone, are key regulators of reproduction. As a result of this function, they have been the focus of research for many years. Isolated or recombinant proteins have been successfully used therapeutically for the treatment of infertility; and, in the case of compounds that block gonadotropin activity, for their potential utility in contraception. Until recently, selective small molecules modulating gonadotropin receptor activity have proven difficult to identify. The gonadotropins are glycoproteins that are released into the plasma as differently glycosylated isoforms and bind to specific G protein-coupled receptors. The degree of glycosylation on the gonadotropins has been shown to be important for the biological activities of these hormones and is differentially regulated depending on the steroidal status. Recent data from the study of glycosylated variants of LH, hCG and FSH have revealed that these isoforms have distinct signaling properties that allow for gonadotropin pleiotropic signals to be transduced effectively at the level of the receptor. Thus, glycosylated variants of the gonadotropins behave as biased agonists. Recently, newly developed, small molecule, synthetic allosteric compounds have been identified that are capable of mimicking this biased signaling. This opens the door to development of orally available, drug-like therapies for reproductive disorders that offer similar pleiotropic richness as that offered by the complex, endogenous hormones.

Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles

“…Both LH and hCG exist as compilations of isohormones that differ with respect to post-translational modification (predominantly glycosylation) and state of degradation, which influences their biological activity and half-life in circulation [27,28]. Early in the follicular phase, estradiol exerts a negative feedback effect on LH; however, some LH activity occurs to stimulate thecal cell production of androgens that serve as substrates for estradiol production by granulosa cells.…”

The Role of Glycosylation in Receptor Signaling

“…Of particular interest to the development of new therapies is the role that glycosylation plays in affecting protein-protein interactions. Intermolecular association that occur between protein ligands and their cognate receptors or between activated receptors and their intracellular signaling machinery have been shown to be modulated by the presence of glycosylation (4). Many examples exist that suggest that glycosylation of either a receptor or its ligand aids in determining the resulting biological responses.…”

“…For many years, this hypothesis was poorly understood and was thought to be an artifact of recombinant cell systems. With the recent development of allosteric agonists, antagonists and modulators to GPCRs, more light has been shed on this concept; e.g., direct targeting of specific signaling pathways has been demonstrated for various ligands (4,44). This phenomenon has most recently been termed, biased signaling.…”

“…This phenomenon has most recently been termed, biased signaling. Simply put, the concept of biased signaling describes the ability of ligands to direct specific and distinct biological responses via activation of select signaling pathways in a ligandspecific manner (4). There are many receptors that are known to associate with multiple naturally occurring ligands.…”

“…The gonadotropins, LH and FSH are excellent examples of this phenomenon. Since varying glycosylation of gonadotropin isoforms is known to alter their physicochemical properties, one can consider gonadotropin isoforms as different ligands with potentially subtle, but unique association with their cognate receptors (4,24). In addition, interaction of these diverse ligands with the receptor would result in multiple ligand-receptor conformations, which in turn lead to the observed activation of differing biological signaling pathways for LH, hCG and FSH (13,45,46).…”