# Defining the neurophysiologic mechanisms engaged by estradiol feedback in regulating reproductive neuroendocrine function

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $30,592

## Abstract

Project Summary
15-20% of American couples struggle with infertility problems. The most common cause of infertility in women
is anovulation, thus understanding how ovulation is controlled is critical for assisting the formation and growth
of families, improving the reproductive health of our country, and increasing our fundamental knowledge of
reproduction. Ovulation is stimulated by a switch in the pattern of luteinizing hormone (LH) secretion from
episodic to continuous release (LH surge). At low physiological concentrations, estradiol regulates episodic
secretion (negative feedback). Sustained elevation of estradiol at the end of the follicular phase (proestrus in
rodents) stimulates the onset of the LH surge (positive feedback). In most mammals, the LH surge is triggered
by an estradiol-induced surge in gonadotropin-releasing hormone (GnRH) secretion and an accompanying
increase in pituitary response to this hormone. Although a shift in the pattern of GnRH input is not needed to
induce an LH surge in humans, both pre-ovulatory and estradiol-induced surges have been observed in rhesus
macaques, suggesting a GnRH surge likely plays a role in typical reproductive function in primates as well. The
goals of this proposal are to increase our knowledge of the central neuronal mechanisms driving the transition
from negative to positive feedback during the cycle, and to determine if these mechanisms are estradiol-
sensitive. GnRH neurons themselves do not express detectable levels of estrogen receptor α (ERα), thus
estradiol-sensitive afferents are needed in this process The anteroventral-periventricular nucleus (AVPV) is
postulated to be a critical site for estradiol positive feedback as it contains neurons that co-express both
kisspeptin, a potent activator of GnRH secretion, and ERα, AVPV kisspeptin neurons express more kisspeptin
and are more active in an estradiol-dependent manner during positive feedback, suggesting increased
signaling from these cells helps drive positive feedback. There are still gaps in our understanding of how
estradiol activates AVPV kisspeptin neurons and modulates their transmission of kisspeptin and fast synaptic
signals to GnRH neurons. We hypothesize estradiol modulates potassium currents and synaptic properties of
AVPV neurons during positive feedback to increase their activity and subsequent transmission of excitatory
signals to GnRH neurons. In two Aims, we will measure potassium currents, functional synaptic connectivity
and plasticity, and kisspeptin release by AVPV kisspeptin neurons to determine if these parameters are
modified by the transition from negative to positive feedback during the cycle by comparing diestrous and
proestrous mice. To examine which mechanisms are specifically regulated by estradiol, we will utilize a murine
estradiol-induced LH surge model. These studies will help provide mechanistic insights that will help build on
our understanding of the neurophysiological mechanisms by which estradio...

## Key facts

- **NIH application ID:** 10242735
- **Project number:** 5F31HD097830-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Joseph Rudolph Starrett
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,592
- **Award type:** 5
- **Project period:** 2018-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242735

## Citation

> US National Institutes of Health, RePORTER application 10242735, Defining the neurophysiologic mechanisms engaged by estradiol feedback in regulating reproductive neuroendocrine function (5F31HD097830-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242735. Licensed CC0.

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