and Impact of Carbohydrate Variation on Human Follicle-Stimulating Hormone Function

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2018 Jun 6

PMID 29867757

Citations 29

Authors

George R Bousfield

Jeffrey V May

John S Davis

James A Dias

T Rajendra Kumar

Affiliations

Soon will be listed here.

Abstract

Human follicle-stimulating hormone (FSH) exhibits both macro- and microheterogeneity in its carbohydrate moieties. Macroheterogeneity results in three physiologically relevant FSHβ subunit variants, two that possess a single N-linked glycan at either one of the two βL1 loop glycosylation sites or one with both glycans. Microheterogeneity is characterized by 80 to over 100 unique oligosaccharide structures attached to each of the 3 to 4 occupied N-glycosylation sites. With respect to its receptor, partially glycosylated (hypo-glycosylated) FSH variants exhibit higher association rates, greater apparent affinity, and greater occupancy than fully glycosylated FSH. Higher receptor binding-activity is reflected by greater bioactivity and, in some cases, greater bioactivity. Partially glycosylated pituitary FSH shows an age-related decline in abundance that may be associated with decreased fertility. In this review, we describe an integrated approach involving genetic models, signaling studies, FSH biochemistry, relevance of physiological changes in FSH glycoform abundance, and characterize the impact of FSH macroheterogeneity on fertility and reproductive aging. We will also address the controversy with regard to claims of a direct action of FSH in mediating bone loss especially at the peri- and postmenopausal stages.

Citing Articles

Effects of Switching FSH Preparations on Sperm Parameters and Pregnancy: A Prospective Controlled Study.

Cannarella R, Leanza C, Crafa A, Aversa A, Condorelli R, Calogero A J Clin Med. 2024; 13(19).

PMID: 39407726 PMC: 11477313. DOI: 10.3390/jcm13195666.

Differential effects of follicle-stimulating hormone glycoforms on the transcriptome profile of cultured rat granulosa cells as disclosed by RNA-seq.

Zarinan T, Espinal-Enriquez J, Anda-Jauregui G, Lira-Albarran S, Hernandez-Montes G, Gutierrez-Sagal R PLoS One. 2024; 19(6):e0293688.

PMID: 38843139 PMC: 11156319. DOI: 10.1371/journal.pone.0293688.

Redefining human reproductive physiology as revealed by inefficiencies of contemporary ARTs.

Albertini D J Assist Reprod Genet. 2024; 41(4):815-816.

PMID: 38564151 PMC: 11052941. DOI: 10.1007/s10815-024-03109-6.

, glycans and drivers of health in the vaginal microbiome.

Sanozky-Dawes R, Barrangou R Microbiome Res Rep. 2023; 1(3):18.

PMID: 38046360 PMC: 10688826. DOI: 10.20517/mrr.2022.03.

Differential effects of follicle-stimulating hormone glycoforms on the transcriptome profile of cultured rat granulosa cells as disclosed by RNA-seq.

Zarinan T, Espinal-Enriquez J, Anda-Jauregui G, Lira-Albarran S, Hernandez-Montes G, Gutierrez-Sagal R bioRxiv. 2023; .

PMID: 37905087 PMC: 10614937. DOI: 10.1101/2023.10.18.562995.

References

Bhaskaran R, Ascoli M . The post-endocytotic fate of the gonadotropin receptors is an important determinant of the desensitization of gonadotropin responses. J Mol Endocrinol. 2005; 34(2):447-57. DOI: 10.1677/jme.1.01745. View

Hiyama J, Weisshaar G, Renwick A . The asparagine-linked oligosaccharides at individual glycosylation sites in human thyrotrophin. Glycobiology. 1992; 2(5):401-9. DOI: 10.1093/glycob/2.5.401. View

Jonas K, Fanelli F, Huhtaniemi I, Hanyaloglu A . Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies. J Biol Chem. 2014; 290(7):3875-92. PMC: 4326798. DOI: 10.1074/jbc.M114.622498. View

Geng W, Yan X, Du H, Cui J, Li L, Chen F . Immunization with FSHβ fusion protein antigen prevents bone loss in a rat ovariectomy-induced osteoporosis model. Biochem Biophys Res Commun. 2013; 434(2):280-6. DOI: 10.1016/j.bbrc.2013.02.116. View

Nguyen V, Singh V, Butnev V, Gray C, Westfall S, Davis J . Inositol phosphate stimulation by LH requires the entire alpha Asn56 oligosaccharide. Mol Cell Endocrinol. 2003; 199(1-2):73-86. DOI: 10.1016/s0303-7207(02)00297-6. View

Sun L, Peng Y, Sharrow A, Iqbal J, Zhang Z, Papachristou D . FSH directly regulates bone mass. Cell. 2006; 125(2):247-60. DOI: 10.1016/j.cell.2006.01.051. View

Bousfield G, Butnev V, Bidart J, Dalpathado D, Irungu J, Desaire H . Chromatofocusing fails to separate hFSH isoforms on the basis of glycan structure. Biochemistry. 2008; 47(6):1708-20. DOI: 10.1021/bi701764w. View

Ulloa-Aguirre A, Timossi C, Damian-Matsumura P, Dias J . Role of glycosylation in function of follicle-stimulating hormone. Endocrine. 2000; 11(3):205-15. DOI: 10.1385/ENDO:11:3:205. View

Manjunath P, Sairam M, Sairam J . Studies on pituitary follitropin. X. Biochemical, receptor binding and immunological properties of deglycosylated ovine hormone. Mol Cell Endocrinol. 1982; 28(2):125-38. DOI: 10.1016/0303-7207(82)90026-0. View

10.

Davis J, Weakland L, West L, Farese R . Luteinizing hormone stimulates the formation of inositol trisphosphate and cyclic AMP in rat granulosa cells. Evidence for phospholipase C generated second messengers in the action of luteinizing hormone. Biochem J. 1986; 238(2):597-604. PMC: 1147174. DOI: 10.1042/bj2380597. View

11.

Kumar T . Extragonadal Actions of FSH: A Critical Need for Novel Genetic Models. Endocrinology. 2017; 159(1):2-8. PMC: 5761596. DOI: 10.1210/en.2017-03118. View

12.

Green E, Baenziger J . Asparagine-linked oligosaccharides on lutropin, follitropin, and thyrotropin. II. Distributions of sulfated and sialylated oligosaccharides on bovine, ovine, and human pituitary glycoprotein hormones. J Biol Chem. 1988; 263(1):36-44. View

13.

Maghuin-Rogister G, Closset J, Hennen G . Differences in the carbohydrate portion of the alpha subunit of porcine lutropin (LH), follitropin (FSH) and thyrotropin (TSH). FEBS Lett. 1975; 60(2):263-6. DOI: 10.1016/0014-5793(75)80727-7. View

14.

Davis J, Weakland L, Farese R, West L . Luteinizing hormone increases inositol trisphosphate and cytosolic free Ca2+ in isolated bovine luteal cells. J Biol Chem. 1987; 262(18):8515-21. View

15.

Jiang X, Dias J, He X . Structural biology of glycoprotein hormones and their receptors: insights to signaling. Mol Cell Endocrinol. 2013; 382(1):424-451. DOI: 10.1016/j.mce.2013.08.021. View

16.

Ritter V, Thuering B, Saint Mezard P, Luong-Nguyen N, Seltenmeyer Y, Junker U . Follicle-stimulating hormone does not impact male bone mass in vivo or human male osteoclasts in vitro. Calcif Tissue Int. 2008; 82(5):383-91. DOI: 10.1007/s00223-008-9134-5. View

17.

Jiang X, Fischer D, Chen X, McKenna S, Liu H, Sriraman V . Evidence for Follicle-stimulating Hormone Receptor as a Functional Trimer. J Biol Chem. 2014; 289(20):14273-82. PMC: 4022893. DOI: 10.1074/jbc.M114.549592. View

18.

Sowers M, Jannausch M, McConnell D, Little R, Greendale G, Finkelstein J . Hormone predictors of bone mineral density changes during the menopausal transition. J Clin Endocrinol Metab. 2006; 91(4):1261-7. DOI: 10.1210/jc.2005-1836. View

19.

Kumar T, Low M, Matzuk M . Genetic rescue of follicle-stimulating hormone beta-deficient mice. Endocrinology. 1998; 139(7):3289-95. DOI: 10.1210/endo.139.7.6111. View

20.

Wang H, Butnev V, Bousfield G, Kumar T . A human FSHB transgene encoding the double N-glycosylation mutant (Asn(7Δ) Asn(24Δ)) FSHβ subunit fails to rescue Fshb null mice. Mol Cell Endocrinol. 2016; 426:113-24. PMC: 5130991. DOI: 10.1016/j.mce.2016.02.015. View