Follicle-Stimulating Hormone Glycobiology
FSH glycosylation varies in two functionally important aspects: microheterogeneity, resulting from oligosaccharide structure variation, and macroheterogeneity, arising from partial FSHb subunit glycosylation. Although advances in mass spectrometry permit extensive characterization of FSH glycan populations, microheterogeneity remains difficult to illustrate, and comparisons between different studies are challenging because no standard format exists for rendering oligosaccharide structures. FSH microheterogeneity is illustrated using a consistent glycan diagram format to illustrate the large array of structures associated with one hormone. This is extended to commercially available recombinant FSH preparations, which exhibit greatly reduced microheterogeneity at three of four glycosylation sites. Macroheterogeneity is demonstrated by electrophoretic mobility shifts due to the absence of FSHb glycans that can be assessed by Western blotting of immunopurified FSH. Initially, macroheterogeneity was hoped to matter more than microheterogeneity. However, it now appears that both forms of carbohydrate heterogeneity have to be taken into consideration. FSH glycosylation can reduce its apparent affinity for its cognate receptor by delaying initial interaction with the receptor and limiting access to all of the available binding sites. This is followed by impaired cellular signaling responses that may be related to reduced receptor occupancy or biased signaling. To resolve these alternatives, well-characterized FSH glycoform preparations are necessary. (Endocrinology 160: 1515-1535, 2019) F SH is a pituitary gonadotropin that plays a central role in reproduction. In females, FSH stimulates antrum formation in secondary follicles, growth and maturation in antral follicles, and it prepares the latter for ovulation in response to the LH surge (1). In males, FSH stimulates Sertoli cell proliferation during testicular development and maintains Sertoli cell function in the mature testis (2). Whereas FSH is essential for female fertility, in some species, such as mice, FSH is clearly not essential in the male, as Fshb-null males retain complete fertility (3). In other species, such as humans, FSH may be required for male fertility, as some men deficient in FSH or in FSH receptor (FSHR) function are azoospermatic (4). However, others produce sperm, making the necessity for FSH action in the human testis uncertain (5). In recent years FSH has been suggested to contribute to bone loss in rodent models (6) and perhaps in humans. Recently, it has been proposed to play a role in promoting obesity (7). FSH involvement in these nontraditional targets is controversial (