Biased signaling by human follicle-stimulating hormone variants

Follicle-stimulating hormone (FSH) or follitropin plays a fundamental role in several mammalian species, including humans. This gonadotropin is produced by the anterior pituitary gland and has as its main targets the granulosa cells of the ovary and the Sertoli cells of the testis. Structurally, FSH is composed of two non-convalently linked subunits, the α- and β-subunit, as well as highly heterogenous oligosaccharide structures, which play a key role in determining a number of physiological and biological features of the hormone. Glycosylation in FSH and the other members belonging to the glycoprotein hormone family, is essential for many functions of the gonadotropin, including subunit assembly and stability, secretion, circulatory half-life and biological activity. Carbohydrate heterogeneity in FSH comes in two forms, microheterogeneity, which results from variations in the carbohydrate structural complexity in those oligosaccharides attached to the α- or β-subunit of the hormone and macroheterogeneity, which results from the absence of carbohydrate chain at FSHβ Asn-glycosylation sites. A number of in vitro and in vivo studies have conclusively demonstrated differential, unique and even opposing effects provoked by variations in the carbohydrate structures of FSH, including circulatory survival, binding to and activation of its cognate receptor in the gonads, intracellular signaling, and activation/inhibition of a number of FSH-regulated genes essential for follicle development. Herein, we review the effects of the FSH oligosaccharides on several functions of FSH, and how variations in these structures have been shown to lead to functional selectivity of the hormone.