Molecular and morphological alterations in breast tissue of transgender patients undergoing dihydrotestosterone therapy

Jinho Lee ¹, Maryam Foroughi ², Vanderlene Kung ²

⁰Department of Biology, Knight Cancer Center, Portland, Oregon, United States of America.

Plos One +

|

July 29, 2025

View abstract on PubMed

Summary

Dihydrotestosterone (DHT) treatment before gender-affirming surgery causes significant changes in breast tissue morphology and protein expression. These alterations, including altered estrogen and androgen receptor levels, may influence breast cancer development.

Area Of Science

Endocrinology
Oncology
Surgical Pathology

Background

Gender-affirming surgery (GAS) often involves breast reconstruction.
The effects of dihydrotestosterone (DHT) on breast tissue are not fully understood.
Hormonal therapies are increasingly used in gender affirmation.

Purpose Of The Study

To evaluate morphological and molecular changes in breast tissue following short-term (STT) and long-term (LTT) DHT treatment before GAS.
To assess the impact of DHT on estrogen receptor (ER) and androgen receptor (AR) expression.
To investigate potential links between DHT treatment and breast cancer (BC) development.

Main Methods

Analysis of 230 breast tissue samples from nontreatment, STT (<12 months), and LTT (≥12 months) groups.
Immunohistochemical staining for ER and AR on paired samples (n=33).
NanoString Digital Spatial Profiling (DSP) on a subset (n=17) for protein expression analysis.

Main Results

Significant morphological changes (atrophy, secretory changes) observed with DHT treatment.
Elevated ER-alpha in LTT lactiferous ducts; increased AR H-scores in STT and LTT groups.
Strong correlation between ER and AR expression (r=0.93-0.99) in treated groups.
DSP revealed increased ER in treated groups and higher peripheral lobule AR in LTT.
Decreased Ki-67, CDK6, CD45; increased INPP4B, BCL6 in LTT group.

Conclusions

DHT treatment induces significant morphological and molecular alterations in benign and cancerous breast tissue.
Altered expression of INPP4B and CD45 in LTT and BC samples suggests a potential role in breast cancer development.
Further research is warranted to explore the implications of these findings for breast cancer risk.

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