# Microbiome mediated effects of gender affirming hormone therapy in mice

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $377,894

## Abstract

PROJECT SUMMARY
Gender affirming hormone therapy (GAHT) is used by transgender (TG) people to alleviate gender dysphoria.
GAHT for male to female TG subjects (transwomen) consists of a gonadotropin-releasing hormone agonist
(GnRHa) to block testosterone production and cross-sex hormone treatment (CSHT) with estrogen. GAHT for
female to male TG subjects (transmen) is based on testosterone CSHT without a GnRHa. CSHT is often started
at 12-16 years of age, before the pubertal surge in bone mass and the completion of skeletal maturation. In
addition, male and female adolescents with gender dysphoria are sometime treated temporarily with a GnRHa
without CSHT to suppress puberty. The effects of puberty blockade followed by CSHT and those of CSHT
without prior puberty blockade on skeletal maturation are mostly unknown. The gut microbiome is pivotal
regulator of skeleton postnatal maturation, bone health, and bone responsiveness to GnRHa and sex steroids.
Moreover, the composition of the microbiome is regulated by sex steroids. Thus, modifications to the gut
microbiome composition may mediate the effects of GnRHa and CSHT on the skeleton. Supporting this
hypothesis, our preliminary metagenomic analysis revealed that CSHT induced differences in the composition
of the gut microbiome. Preliminary studies also showed that CSHT impacts gut permeability, which can lead to
further changes in the gut microbiome composition. We further show that CSHT-induced modifications to the
composition of the gut microbiome alters indices of bone volume and structure, and the frequency of intestinal
and bone marrow (BM) T regulatory cells (Tregs), which is a T cell lineage expanded by estrogen and
testosterone. Tregs are essential in the regulation of bone formation and bone resorption. Based on our
preliminary data and on published reports, we hypothesize that GnRHa treatment and CSHT affect skeletal
maturation, and that these effects are mediated, in part, by modifications in gut microbiome composition and
changes in gut permeability. Aim 1a will investigate the extent to which microbiome depletion by antibiotic
treatment alters the skeletal effects of the GnRHa Leuprolide with and without subsequent CSHT in young male
and female mice. Aim 1b will utilize fecal material transfers (FMTs) to directly determine the extent to which stool
microbiome contributes to the skeletal effects of GnRHa treatment with and without subsequent CSHT in young
male and female mice. Aim 2a will determine the contribution of microbiome dependent expansion and migration
of gut Tregs to the skeletal effects of GnRHa treatment with and without subsequent CSHT. Aim 2b will
determine the contribution of increased gut permeability to the skeletal effects of GnRHa treatment with and
without subsequent CSHT, and Aim 2c will investigate if colonization of GF mice with bacteria mediating the
skeletal effects of Leuprolide with and without subsequent CSHT restores effects that are absent in GF mice.
This p...

## Key facts

- **NIH application ID:** 10944419
- **Project number:** 1R01HD115881-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** RHEINALLT MELFYN JONES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $377,894
- **Award type:** 1
- **Project period:** 2024-08-06 → 2025-03-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944419

## Citation

> US National Institutes of Health, RePORTER application 10944419, Microbiome mediated effects of gender affirming hormone therapy in mice (1R01HD115881-01). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10944419. Licensed CC0.

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