Impact of Carbohydrate Heterogeneity in Function of Follicle-Stimulating Hormone: Studies Derived from in Vitro and in Vivo Models1

Abstract

Carbohydrates attached to the protein core of glycoprotein hormones influence a number of intracellular and extracellular processes. As with other members of the glycoprotein hormone family, FSH is produced and released as an array of isoforms that differ from each other in the structure of their oligosaccharide attachments. In this review, we discuss how carbohydrate heterogeneity can impact on FSH action in different in vitro and in vivo systems. We present evidence for diverse effects of distinct charge isoforms at the target cell level, including differential and unique effects on various end responses, and discuss how the use of multiple cell-type assays has allowed identification of some specific effects of FSH isoforms on different cell populations and follicle compartments as well as oocyte maturation. Finally, we discuss recent information on the ability of naturally occurring and laboratory manufactured FSH isoforms to evoke particular effects on granulosa cell function and ovarian follicular maturation in vivo. Such studies have provided evidence that the type(s) of FSH signal delivered may in fact regulate distinct biological outcomes irrespective or in addition to outcomes dictated solely by clearance rate differences.

Sequential (hFSH + recFSH) vs homogenous (hFSH or recFSH alone) stimulation: clinical and biochemical (cumulus cell gene expression) aspects

“…FSH isoforms, i.e. protein variants with a different glycosylation profile [3][4][5], regulate distinct biological pathways and have specific effects on granulosa cell function and ovarian follicular maturation [6][7][8][9]. Dynamic changes in FSH isoforms occur during the follicular cycle with short-living forms predominating in the pre-ovulatory phase, whereas long-acting molecules characterize the luteal-follicular transition [10,11].…”

“…Several types of FSH isoforms with different glycosylation patterns [6] (recombinant and human-derived) are routinely used for ovarian stimulation [12][13][14], but very rarely with a dynamic modulation. A single product type with fixed isoform mix is used throughout the stimulation protocol.…”

Interaction between ascorbic acid and follicle-stimulating hormone maintains follicular viability after long-term in vitro culture of caprine preantral follicles

“…In this way, ascorbic acid acts intensively in follicular growth through its action in the biosynthesis of collagen, which influences the process of cellular membrane remodeling [15]. Regarding the role of FSH in growth, some studies report that FSH receptors are expressed in the granulosa cells from the primary stages onward [17] and [18]. Although FSH receptors are not present in primordial follicles, FSH seems to play an indirect role in early follicular development through the release of paracrine factors produced by the larger follicles or by ovarian stroma cells [20].…”

“…Follicle-stimulating hormone receptors are expressed in granulosa cells [17] and [18] from the primary follicle stage onward [19]. However, although these receptors are not present in primordial follicles, FSH seems to play an indirect role in early follicular development through the release of paracrine factors produced by large follicles or ovarian stroma cells [20].…”

Follicle-stimulating hormone isoforms and plasma concentrations of estradiol and inhibin A in dairy cows with ovulatory and non-ovulatory follicles during the first postpartum follicle wave

“…In human beings, a shift toward greater pituitary release of less acidic serum 45 FSH isoforms in response to GnRH is observed during the preovulatory period (13). It is currently thought that frequent transient stimulation with more bioactive, faster clearing isoforms represents a key mode of FSH action during the preovulatory period (14).…”