Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

Objective: Determine the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs).

Design: This is a cross-sectional study.

Setting: TMIs (n=444) underwent chest-contouring surgeries to treat their gender dysphoria between 2013 and 2019 at an urban medical center.

Participants: Of the 444 TMIs, 425 had pathology images analyzed by our deep-learning algorithm to extract breast tissue composition. A subset of 42/444 TMIs had mammography prior to surgery; mammography files were available for 25/42 TMIs and analyzed using a breast density software, LIBRA.

Main Outcomes And Measures: The first outcome was the association of duration of TT and breast tissue composition assessed by pathologists (categories of lobular atrophy and stromal composition) or by our algorithm (% epithelium, % fibrous stroma, and % fat). The second outcome is the association of TT and breast density as assessed by a radiologist (categorical variable) or by LIBRA (percent density, absolute dense area, and absolute non-dense area).

Results: Length of TT was associated with increasing degrees of lobular atrophy ( <0.001) but not fibrous content ( =0.821) when assessed by the pathologists. Every six months of TT was associated with decreased amounts of both epithelium (exp(β)=0.97, 95% CI 0.95-0.98, adj =0.005) and stroma (exp(β)=0.99, 95% CI 0.98-1.00, adj =0.051), but not fat (exp(β)=1.01, 95%CI 0.98-1.05, =0.394) in fully adjusted models. There was no association between TT and radiologist's breast density assessment ( =0.575) or LIBRA measurements ( >0.05).

Conclusions: TT decreases breast epithelium and fibrous stroma, thus potentially reducing the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk.

Summary Box: Very little is known about the effect of gender-affirming testosterone therapy on cancer risks, such as breast cancer.Epidemiological studies had different conclusions about the association between testosterone and breast cancer in cisgender women (positive association) and trans masculine individuals (inverse association).More laboratory-based research are needed to understand the effect of testosterone on breast cancer risk in the understudied trans masculine population.Our study provides quantitative histological evidence to support prior epidemiological reports that testosterone may reduce breast cancer risk in trans masculine individuals.