Abstract
It is well accepted that pituitary follitropin is secreted into the circulation as a mixture of variants, which differ not in primary structure but rather at the level of glycosylation. These glycosidic forms vary in the number of glycosylation sites filled, complexity of glycosidic chains, and sialylation and sulfation. It is generally agreed that high sialylation, 2,3 sialic acid capping of terminal N-acetyl galactosamine or galactose leads to longer circulating half-life, by blocking binding of asialoglycoprotein receptor (ASGPR) in the liver. In contrast, 2,6 sialic acid found in humans does not prevent recognition of galactose and N-acetyl galactosamine by ASGPR. Few studies on clinical outcomes comparing differences in sialylation of follitropin found in commercially available preparations are available. Thus, there is a clear need for a consortium of open data to address this unmet need. Recently, FSH glycosylation, primarily on the β-subunit, which varies as women age, has emerged as a key modifier of follitropin action, with profound biological effects in vivo in animal models. To date, limited information of recombinant follitropin hormone preparations is available. Thus, most of the studies with FSH that is well characterized biochemically have been done in vitro, with engineered non gonadal host cells bearing recombinant receptors or in animal models. Since limited studies in human granulosa cells are available, a question is whether structural differences in glycosylation in commercially available follitropin affects biological function and clinical effect in humans. The presence of fucose, for example, has not been studied greatly even though, in the case of antibody therapy it has been shown to have a large effect on antibody targeting. This review on glycosidic variability of follitropin from the biochemical/structural point of view reflects on this question and presents an assessment in the context of available published data. If clinical differences are to be expected or not, the readers will have a better understanding of the evidence for and limitations of such expectations.
Highlights
In this review, the gonadotropin follitropin is discussed exclusively in the context of how the carbohydrate structures modulate biochemical activity and pharmacodynamics
The gonadotropin follitropin is discussed exclusively in the context of how the carbohydrate structures modulate biochemical activity and pharmacodynamics. It is an objective of this review that consideration should be given to how the nature of FSH carbohydrate complexity may impact the quaternary and tertiary structure of the heterodimeric gonadotropin molecule and how it may affect its biological activity from a pharmacodynamic perspective as well as from well accepted information on pharmacokinetics impacts
Despite administration of identical bioactive doses to women, of Gonal-F® and Rekovelle® the data revealed slower clearance for Rekovelle® and significantly higher pharmacodynamics responses of this preparation in terms of serum E2 and inhibin, as well as number and size of follicles [56]. This seemed remarkable because the patent discloses that a a2,6 sialic acid preparation of follitropin had a drastically reduced half-life compared to the a2,3 sialic acid follitropin prepared in the same cells [60]
Summary
The gonadotropin follitropin is discussed exclusively in the context of how the carbohydrate structures modulate biochemical activity and pharmacodynamics. That prior to the advent of recombinant DNA technology, the therapeutic form of follitropin was purified from the urine of postmenopausal women using standard biochemical methods amenable to crude starting materials [3]. These preparations of human menopausal gonadotropin (hMG) generically referred to as urofollitropin, proved useful in the clinic (Table 1). Follitropin in urine differed from naturally occurring pituitary follitropin in degree and complexity of their glycans and contamination with a related glycoprotein hormone (luteinizing hormone) and other proteins (Table 1). The antennae are extended by GlcNAc and galactose, the latter of which can be capped by TABLE 1 | Naturally occurring and commercially available recombinant follitropin preparations and nomenclature
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