# Reproductive physiology of gonadotropin synthesis

> **NIH NIH R37** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $565,628

## Abstract

Reproduction is a tightly regulated function of an organism that is crucial to the perpetuation of a species. The
pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), play an essential role
in the reproductive process to control fertility by directing steroidogenesis and gametogenesis. Befitting their
important roles in endocrine physiology, the synthesis and secretion of LH and FSH are under complex
regulation by hypothalamic neuropeptide inputs (most notably gonadotropin-releasing hormone, or GnRH) and
gonadal sex steroid and peptide hormones. The precisely coordinated integration of these signals leads to
appropriate LH and FSH subunit gene expression, protein synthesis, and secretion to promote sexual
maturation and control normal reproductive function.
With the support of this R01 award, we have identified molecular and cellular mechanisms and pathways by
which these factors control gonadotropin gene expression and secretion. We have identified signaling
pathways, transcription factors, and cis-regulatory elements by which varying patterns of pulsatile GnRH
differentially regulate LH and FSH subunit gene expression using cellular, animal and human models. The
overarching goal of this project is to delineate the mechanisms and pathways underlying the carefully
orchestrated control of LH and FSH release to allow for reproductive integrity and fertility. We hypothesize
that these cellular factors modulate the pathways by which varying GnRH pulse frequencies regulate
gonadotropin subunit gene expression to contribute to appropriate regulation of gonadal function, cyclicity and
fertility in vivo. Over the next five years, we propose to: (1) generate new mouse models to further translate
our cellular studies into the in vivo context; (2) extend our studies of the downstream mechanisms by which
the pulsatile GnRH signal is decoded to investigate the role of the Nr4a1 nuclear receptor family we have
identified to be highly differentially regulated by varying frequencies of pulsatile GnRH; and (3) test the
hypothesis that GnRHR couples differentially to G
α
s and G
α
q/11 depending on GnRHR numbers, serving as the
gonadotrope GnRH pulse frequency decoder to result in subsequent differential regulation of LH and FSH.
We are in a unique position to take advantage of our perifusion system combined with our molecular and
cellular biology expertise in parallel with our experience in mouse genetics and physiology to successfully
perform the proposed studies. The successful completion of these aims is expected to provide insight into the
mechanisms by which gonadotropes decode GnRH pulse frequency to differentially regulate LH and FSH,
critical for physiologic control of reproduction and fertility. The elucidation of these pathways will generate new
potential therapeutic targets for treatment of infertility, precocious or delayed puberty, hypothalamic
amenorrhea, and polycystic ovarian syndrome. The results obtained from...

## Key facts

- **NIH application ID:** 11057743
- **Project number:** 4R37HD019938-32
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Ursula B. Kaiser
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,628
- **Award type:** 4N
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11057743

## Citation

> US National Institutes of Health, RePORTER application 11057743, Reproductive physiology of gonadotropin synthesis (4R37HD019938-32). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11057743. Licensed CC0.

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