# Sex-specific role of androgen signaling in neuroendocrine-behavior interface

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $412,349

## Abstract

Abstract/Project Summary
Disorders of androgens imbalance are highly prevalent in both sexes. Hyperandrogenic females experience
reproductive dysfunction, whereas low androgens disrupt sexual behavior, decrease libido and fertility, and
induce fatigue, depression, and bone loss in both sexes. Studies using mouse genetics (e.g., androgen
receptor knockout) replicate male reproductive dysfunctions caused by low androgens or AR insensitivity. In
females, AR insensitivity results in subfertility, with disrupted uterine morphology, fewer corpora lutea,
abnormal estrous cycles and accelerated reproductive senescence. AR is highly expressed in multiple brain
sites, but the role of specific neuronal circuitry or individual subpopulations has not been demonstrated, and
the causes and mechanisms underlying disorders of androgen imbalance mediated by brain AR remain
unknown. This is particularly important in androgens abuse and for gender dysphoric/gender incongruent
individuals which seek gender-affirming hormone treatment. The consequences and potential effects of
supraphysiologic androgens on brain function are largely unknown. Our main goal in this application is to
determine the role of direct androgen actions in highly interconnected brain sites that express low or virtually
no aromatase, i.e., neuronal circuitry not susceptible to estrogen actions following site-specific conversion of
testosterone to estradiol. The circuit is comprised of the posterior nucleus of the amygdala (PA) and the ventral
premammillary nucleus (PMv). The PA relays conspecific olfactory signals and is highly relevant for human’s
physical and sexual health. Functional neuroimaging studies, neurological insults or brain lesions have shown
that the PA has a critical role in sexual drive, hyper- or hyposexuality, and sexual disorders (e.g., paraphilias)
in a sex specific mode. The PA densely projects to the PMv which has a fundamental role in the modulation of
the neuroendocrine reproductive axis. Our goal is to determine the role of AR in specific brain nuclei of male
and female mice focused on the integration of environmental signals, sexual behavior, and neuroendocrine
control. We hypothesize that AR in PA neurons is necessary for sex recognition, and sexual arousal, and that
PA inputs to PMv AR neurons connect sexual arousal to neuroendocrine (gonadotropins) and behavioral
responses. We will employ Cre-loxP and FlpO-Frt approaches to conditionally delete Ar in these neuronal
populations, viral vectors, TeTox and DREADDs technology to remotely silence or activate AR expressing
neurons, different steroids milieu, and molecular mapping of chemically defined AR neurons in two
independent aims. Our findings will open new opportunities for a better understanding of the mechanisms
associated with the pathophysiology of altered levels of androgens mediated by neuronal AR. Unraveling the
role of AR in defined neuronal circuitry is an essential step toward the prevention of adverse heal...

## Key facts

- **NIH application ID:** 10895594
- **Project number:** 5R01HD106962-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Carol Fuzeti Elias
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $412,349
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895594

## Citation

> US National Institutes of Health, RePORTER application 10895594, Sex-specific role of androgen signaling in neuroendocrine-behavior interface (5R01HD106962-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10895594. Licensed CC0.

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