Five years of support are requested to study the aging pituitary ovarian axis. We seek to understand pituitary-ovarian communication via follicle-stimulating hormone (FSH). It is well known that in women over the age of 35 fertility declines compared with younger women. Infertility clinics report decreased responsiveness of older women to exogenous FSH preparations. This project will focus on the response of the aging ovary to a change in relative abundance of two major human (h) FSH glycoforms. The classic hFSH possessing both alpha subunit and beta subunit oligosaccharides is designated tetra-glycosylated hFSH and a novel hFSH glycoform possessing only alpha subunit oligosaccharides is designated di-glycosylated hFSH. Women aged 21-24 express more di-glycosylated hFSH than tetra-glycosylated hFSH, perimenopausal women express slightly less di-glycosylated hFSH, while post-menopausal women express primarily tetra-glycosylated hFSH. Project 1 will investigate the changes in relative abundance of hFSH glycoforms during the menstrual cycle that are associated with increasing age and study mechanisms for glycan modulation of FSH receptor binding and activation. Project 2 will compare the activities of hFSH glycoforms in a variety of signal transduction assays in the ovary in order to identify possible mechanisms that enhance the biological activity of di-glycosylated hFSH. The differential effects of both glycoforms on bone resorption will also be studied. Project 3 will create mouse models to test the hypothesis that both hFSH glycoforms are necessary for reproductive function. A double hFSH? glycosylation mutant will replace the normal mFSH? gene. This line will be crossed with FSH? null mice to see if it can rescue female infertility. Purified hFSH glycoforms will also be tested in vivo using FSH null mice. The WSU FSH process core laboratory (Core B) will provide well characterized purified hFSH glycoforms, to all projects. The initial products will be di-glycosylated hFSH and tetra-glycosylated hFSH, which are of interest to all the scientific projects, but are not available from other sources. Recombinant di-glycosylated hFSH will be expressed first, due to low abundance in natural sources. Core B will characterize glycan populatlons at each occupied N-glycosylation site, thereby providing fully characterized glycoforms with known, rather than assumed glycosylation differences. Core B will also provide cell culture and assay services to project investigators. The WSU bioinformatics core (Core C) will provide a data-sharing platform readily accessible to all investigators via the internet. The outcome of this research will be a better understanding of the mechanisms for reduced ovarian responsiveness with aging that may lead to the development of more effective FSH preparations for treating infertility. While currently available preparations work well in young women, they become increasingly ineffective in older women, requiring higher doses and prolonged administration yet producing fewer oocytes.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-5 (J5))
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Fuldner, Rebecca A
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Wichita State University
Schools of Arts and Sciences
United States
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Roy, Sambit; Gandra, Divya; Seger, Christina et al. (2018) Oocyte-Derived Factors (GDF9 and BMP15) and FSH Regulate AMH Expression Via Modulation of H3K27AC in Granulosa Cells. Endocrinology 159:3433-3445
Kumar, T Rajendra (2018) Fshb Knockout Mouse Model, Two Decades Later and Into the Future. Endocrinology 159:1941-1949
Das, Nandana; Kumar, T Rajendra (2018) Molecular regulation of follicle-stimulating hormone synthesis, secretion and action. J Mol Endocrinol 60:R131-R155
Gilbert, Sara Babcock; Roof, Allyson K; Rajendra Kumar, T (2018) Mouse models for the analysis of gonadotropin secretion and action. Best Pract Res Clin Endocrinol Metab 32:219-239
Kumar, T Rajendra (2018) Extragonadal Actions of FSH: A Critical Need for Novel Genetic Models. Endocrinology 159:2-8
Kumar, T Rajendra (2017) The SO(H)L(H) ""O"" drivers of oocyte growth and survival but not meiosis I. J Clin Invest 127:2044-2047
Romereim, Sarah M; Summers, Adam F; Pohlmeier, William E et al. (2017) Gene expression profiling of bovine ovarian follicular and luteal cells provides insight into cellular identities and functions. Mol Cell Endocrinol 439:379-394
Liu, Peng; Ji, Yaoting; Yuen, Tony et al. (2017) Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546:107-112
Wang, Huizhen; Hastings, Richard; Miller, William L et al. (2016) Fshb-iCre mice are efficient and specific Cre deleters for the gonadotrope lineage. Mol Cell Endocrinol 419:124-38
Wang, Huizhen; May, Jacob; Butnev, Viktor et al. (2016) Evaluation of in vivo bioactivities of recombinant hypo- (FSH21/18) and fully- (FSH24) glycosylated human FSH glycoforms in Fshb null mice. Mol Cell Endocrinol 437:224-236

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