# Central Actions of Estrogens: Effects on GnRH Neurons

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $423,343

## Abstract

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 vs multiple births while minimizing side effects. Psychosocial stress interferes with homeostasis and
disrupts many physiologic systems including reproduction. Completing this research will help us understand
how the brain responds to ovarian estradiol to generate the central neural signal that ultimately leads to
ovulation and how stress disrupts this. The signal for ovulation is provided by a change in the output of
gonadotropin-releasing hormone (GnRH) neurons from strictly episodic, producing on/off GnRH pulses that
drive pituitary hormone release, to a surge mode in which GnRH release is continuously elevated for hours. To
induce the GnRH surge, estradiol action switches from negative to positive feedback. Ovariectomized (OVX)
mice treated with constant physiologic levels of estradiol (OVX+E) undergo daily shifts from negative to
positive feedback that are timed to the light-dark cycle, allowing mechanistic studies of estradiol action in a
reduced variable model. In cycling ovary-intact mice, 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 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, and the effects of stress on this
system. In Aim 1, we will study estradiol modulation of three important circuits: from kisspeptin neurons in the
anteroventral periventricular (AVPV) nucleus to GnRH neurons, from arcuate kisspeptin to AVPV kisspeptin
neurons, and among AVPV kisspeptin neurons. These experiments will move us towards understanding a
more complete reproductive neuroendocrine network by studying how synaptic properties are modulated by
estradiol. In Aim 2, we will study the mechanisms by which acute stress exposure in adulthood perturbs the
shift from estradiol negative to positive feedback, disrupting the LH surge. We will test involvement of the
adrenal glands and of neurons producing corticotropin-releasing hormone (CRH). We will examine how acute
stress mechanistically changes estradiol positive feedback effects on GnRH neurons. Finally, we will test how
the stress neuroendocrine axis interacts with the reproductive neuroendocrine axis by examining connectivity
between CRH and GnRH neurons and CRH and kisspeptin neurons and their modulation by estradiol. These...

## Key facts

- **NIH application ID:** 10894781
- **Project number:** 5R01HD041469-23
- **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:** 2024
- **Award amount:** $423,343
- **Award type:** 5
- **Project period:** 2002-02-11 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894781

## Citation

> US National Institutes of Health, RePORTER application 10894781, Central Actions of Estrogens: Effects on GnRH Neurons (5R01HD041469-23). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10894781. Licensed CC0.

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