# Project 4: Age-Related Changes in Gonadotropin Glycosylation and Function

> **NIH NIH P01** · WICHITA STATE UNIVERSITY · 2024 · $298,377

## Abstract

Project Summary/Abstract – Project 4(Bousfield)
Our long-term goal is to understand how carbohydrate modulates the biological activity of follicle-stimulating
hormone (FSH). The human ovary becomes resistant to FSH stimulation with age and circulating FSH
concentrations rise, keeping serum estrogen concentrations normal until 2 years before the final menstrual cycle.
Around the same time pituitary FSH changes from predominantly hypo-glycosylated hFSH21 and hFSH18 (due
to loss of FSHβ subunit N-glycan at Asn24 or Asn7, respectively) to a predominantly fully-glycosylated hFSH24,
which possesses all 4 N-glycans. Hypo-glycosylated hFSH18 and hFSH21 exhibit greater apparent affinity for
the FSHR, can occupy more FSHR sites, and associate with FSHR more quickly than fully-glycosylated hFSH24.
Our collaborators have demonstrated hFSH18 and hFSH21 exhibit greater biological activity in vitro, rescue
fertility in transgenic Fshb-null mice, and exhibit distinct patterns of gene expression in granulosa cells. The
overall hypothesis of this proposal is that in the face of a senescing ovary the additional switch from hypo-
glycosylated FSH18 and FSH21 to fully-glycosylated FSH24 further compromises fertility and contributes to bone
loss. The objective of this proposal is to study the mechanisms for these differences in FSHR binding via the
following specific aims: 1: Develop FSH glycoform immunoassays with multi-species antibodies. Our
working hypothesis is that fully- and partially glycosylated FSH glycoforms secretion patterns diverge in women.
The fact that hFSH18 and hFSH21 induce unique gene expression profiles makes it imperative to develop
specific immunoassays for all three physiologically relevant glycoforms, hFSH18, hFSH21, and hFSH24. 2:
Determine FSHR/FSH-glycoform structures. Our working hypothesis is that FSH18, FSH21, and FSH24
induce different FSHR conformations that result in biased signals. The Project will purify FSHR and FSH/FSHR
complexes. Cryogenic electron microscopy (cryo-EM) will be conducted in collaboration with Dr. Zhao Wang at
Baylor College of Medicine. Highly purified FSH glycoforms, hFSH18, hFSH21, and hFSH24 are available for
both aims. Glycoform-specific assays are expected to provide novel information regarding FSH glycoform
changes during the normal human menstrual cycle and as women age. FSH glycoform/FSHR structures are
expected to reveal the role of FSH N-glycans in fully activating the FSHR.
The potential translational outcomes of this project are unique immunoassays for measuring FSH glycoforms
and knowledge of FSHR function to facilitate development of drugs to enhance or inhibit FSHR function.

## Key facts

- **NIH application ID:** 10848248
- **Project number:** 5P01AG029531-12
- **Recipient organization:** WICHITA STATE UNIVERSITY
- **Principal Investigator:** GEORGE R BOUSFIELD
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $298,377
- **Award type:** 5
- **Project period:** 2009-04-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848248

## Citation

> US National Institutes of Health, RePORTER application 10848248, Project 4: Age-Related Changes in Gonadotropin Glycosylation and Function (5P01AG029531-12). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10848248. Licensed CC0.

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