Work

2. Wound Healing Impairment by Testosterone Involves Disruption of Epithelial-Granulation Equilibrium in Murine and Porcine Models

Year: 2023

Type: article

Abstract: PURPOSE: Wound healing problems are a major cause of morbidity for gender-affirming surgery (GAS) patients. Exogenous hormone therapy in the transgender male patient may play a role in these complications that include hypertrophic scarring and urethral stenosis post-phalloplasty. Prior male mouse studies suggest testosterone (T) may affect wound healing, but this has not been shown clinically. We developed novel mouse and swine models that mimic a GAS patient’s hormonal milieu to study how testosterone influenced wound healing. METHODS: Animals underwent surgical castration and assigned to no-T (-T) or biweekly T (+T) experimental groups. Mice had bilateral excisional splinted wounds harvested at POD7, while pigs had excisional wounds harvested at POD14. Pig wounds were topically treated with either vehicle or flutamide, an anti-androgen. Wound healing rate was measured via planimetry. Tissue was analyzed via qPCR, histology, immunofluorescence, spatial transcriptomics, flow cytometry, and whole-genome sequencing. RESULTS: Porcine +T wounds demonstrated a characteristic pattern of increased granulation and delayed re-epithelialization when compared to -T wounds. Histology analysis showed topical treatment with flutamide was associated with a decrease in epithelial gap, dermal gap, and granulation tissue area and thickness compared to the placebo group (p=0.002, p=0.039, p=0.012, respectively). Gene set analysis showed POD14 wounds exposed to T had upregulation of genes related to extracellular matrix degradation. Gene ontology analysis showed T was associated with an upregulation of genetic pathways associated with lymph vessel development and angiogenesis throughout the wound bed. In the mouse, comparison of POD5 wounds showed T injections led to 24.9% and 24.7% increase in mean wound size relative to sham and ovariectomy controls (p=0.004; p=0.001). Spatial transcriptomics demonstrated opposing T effects spatially: pathways such as epithelial-mesenchymal transition and angiogenesis were highly upregulated in granulation tissue but downregulated in neo-epidermis. CONCLUSIONS: Testosterone impairs wound healing in a preclinical model, potentially via altering the homeostatic balance of re-epithelialization and granulation. This was largely reversed by androgen receptor blockade. Future studies will characterize the molecular mechanisms driving these effects.

Source: Plastic & Reconstructive Surgery Global Open

DOI: 10.1097/01.gox.0000937604.83962.e9