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Erik Reiche, MD

Pronouns:

He/Him/His

Rank:

Fellow

Institution:

BWH/Johns Hopkins (Coon Lab)

Department:

Plastic Surgery Division, Department of Surgery

Authors:

Erik Reiche MD*, Patrick R Keller MD*, Yu Tan PhD*, Matthew R Louis MD*, Vance Soares MS*, Calvin R Schuster BA*, Tingying Lu BS*, Vanessa Mroueh BS*, Devin Coon MD MSE*

Principal Investigator:

Devin Coon

Exogenous Testosterone Inhibits Cutaneous Repair An A Murine Gender-Affirming Surgery Model

The most common reason for revision after chest masculinization is hypertrophic scarring and hormones may play a role. Prior studies have demonstrated that the sex hormones can interact with wound healing, but none have examined these effects in a transgender model.

We present a proof-of-concept animal model that recreates the hormone environment of gender affirming surgery. We found that exogenous testosterone administered to XX/OVX mice impairs wound healing, both on macroscopic planimetry and on histologic evaluation.

This report represents a pilot study, and our team is currently striving to elucidate many questions regarding mechanistic investigation of underlying pathways and validation in human clinical studies. Preliminary results suggest differences in wound healing between castrated XX and XY mice treated with testosterone, suggesting not just a difference in hormone milieu but potentially an epigenetic difference in wound healing response despite identical hormone profiles.

Overview

Wound healing problems are a major cause of morbidity for gender-affirming surgery (GAS) patients. Prior studies have shown sex differences in wound healing may exist. We hypothesized exogenous testosterone supplementation may impair post-GAS wound healing and developed a model to investigate this phenomenon.

 

Methods

Mice were randomized based on hormone regimen and gonadectomy (OVX). Gonadectomy or sham occurred on day 0 and mice were assigned to no testosterone (-T), mono- or bi-weekly (T/2T) testosterone groups. Dorsal splinted wounding occurred on day 14 and wound harvest on day 21. Serum testosterone levels were quantified with mass spectrometry. Wound tissue underwent analysis with planimetry, qPCR, ELISA and immunofluorescence.

 

Results

Mean testosterone trough levels for bi-weekly regimen were higher compared to mono-weekly (397ng/dL vs. 272ng/dL; p=.027). At POD5, 2T injections led to 24.9% and 24.7% increases in mean wound size relative to SHAM and OVX/-T, respectively (p=.004; .001). Wounds in OVX/+2T mice demonstrated increased gene expression for inflammatory cytokines (i.e., TNFa, VEGFa, TGFb1, MIF, Col-1, Col-3, aSMA) and macrophage marker F4/80 (p<.05). ELISA confirmed elevated wound TNFα levels (p<.05). Quantitative multiplex immunofluorescence with F4/80/NOS2/ARG1 showed significant increases in macrophage prevalence in OVX/+2T (p<.05).

 

Conclusions

We developed a novel model of the GAS hormonal milieu to study effects of exogenous testosterone on wound healing. Optimized twice-weekly dosing yielded serum levels comparable to clinical therapy. We show that exogenous testosterone administered to XX/OVX mice significantly impairs wound healing. A hyperinflammatory wound environment results with increased macrophage proliferation and elevated cytokines such as TNFα. Current efforts are directed towards mechanistic investigation and clinical validation. Preliminary results suggest differences in wound healing between castrated XX and XY mice treated with testosterone, suggesting not just a difference in hormone milieu but potentially a sex-based difference in wound healing response despite identical hormone profiles.