# Central Actions of Estrogens: Effects on GnRH Neurons

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $464,815

## Abstract

Project Summary
Between 15 and 20% of couples have difficulty conceiving; failures of the reproductive system thus affect many
individuals. In females, understanding the control of ovulation is critical for helping infertility patients conceive
single, as opposed to multiple, births while minimizing side effects. The goal of this proposal is to increase our
understanding of how the brain responds to ovarian estradiol to generate the central neural signal that
ultimately leads to ovulation. This signal is provided by a shift in output of gonadotropin-releasing hormone
(GnRH) neurons from one that is strictly episodic, producing on/off GnRH pulses that drive pituitary hormone
release, to one in which GnRH release is continuously elevated for several hours. Estradiol initiates this GnRH
surge, which induces the luteinizing hormone (LH) surge that triggers ovulation. To induce the GnRH surge,
estradiol action switches from negative to positive feedback. Ovariectomized (OVX) mice treated with constant
physiological levels of estradiol (OVX+E) undergo daily shifts from negative and positive feedback that are
timed to the light-dark cycle, allowing mechanistic studies in a reduced variable model. In ovary-intact mice
undergoing reproductive cycles, this switch in estradiol feedback mode occurs on proestrus; our previous work
indicates cyclical changes in estradiol induce cycle-dependent changes in the properties of the hypothalamic
neurons involved in generating the GnRH surge. This previous work established several mechanisms engaged
by estradiol that would lead to suppression of GnRH neurons during negative feedback and activation of these
cells during positive feedback. In the proposed work, we will expand upon this base in experiments that range
from continued investigation of neurobiological mechanisms to whole animal studies, all aimed at elucidating
estradiol feedback and GnRH surge generation. In Aim 1, we will study GnRH neurons as well as kisspeptin
neurons in the anteroventral periventricular (AVPV) and arcuate regions, which are postulated to convey
estradiol positive and negative feedback to GnRH neurons, respectively. These experiments will move us
towards understanding a more complete reproductive neuroendocrine network by studying how synaptic and
intrinsic properties interact with one another within these different cell types, and how these cell types interact
with each other. We will also study how deleting estrogen receptor (ER)  in kisspeptin-expressing cells alters
the properties of these cells when done prepubertally via cre-lox methods vs in adulthood using CRISPR/Cas9
gene editing. Psychosocial stress interferes with homeostasis and disrupts many physiologic systems including
reproduction. In Aim 2, we will study the mechanisms by which acute stress exposure perturbs the shift from
estradiol negative to positive feedback, disrupting the LH surge. We will examine how another hypothalamic
system, that producing corticotropin-relea...

## Key facts

- **NIH application ID:** 10003346
- **Project number:** 5R01HD041469-19
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Suzanne M MOENTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $464,815
- **Award type:** 5
- **Project period:** 2002-02-11 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003346

## Citation

> US National Institutes of Health, RePORTER application 10003346, Central Actions of Estrogens: Effects on GnRH Neurons (5R01HD041469-19). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10003346. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*