Parental Testosterone Treatment Induces Multi-Generational Reproductive and MetabolicEffects in a Mouse Model of Gender-Affirming Hormone Therapy

Document Type

Conference Proceeding

Publication Date

10-22-2025

Publication Title

J Endocr Soc

Keywords

estradiol, testosterone, adult, aged, androgen therapy, animal experiment, animal model, animal tissue, bone density, cardiovascular disease, CD-1 mouse, cholesterol level, conference abstract, controlled study, drug combination, female, femur, gender, gender affirming hormone therapy, gender affirming surgery, gender dysphoria, glucose tolerance, gonad, hormone substitution, human, hyperglycemia, hypertriglyceridemia, lipid storage, liver weight, male, microcapsule, mouse, mouse model, nonhuman, obesity, oophorectomy, osteolysis, sham procedure, trabecular bone, transgender

Abstract

An estimated 1.6 million Americans identify as transgender, non-binary, and gender diverse (TNG). Although gender-affirming hormone therapy (GAHT) is established as a safe and effective standard-of-care therapy for gender dysphoria experienced by many TNG patients, surprisingly little is known about the long-term effects of GAHT on diverse body systems such as metabolism and bone health. Removal of ovaries and decreased estradiol without hormone replacement therapy in individuals assigned female at birth is associated with increased cardiovascular disease, obesity, and decreased bone density and higher risk of fracture. However, there is very limited data on the health outcomes of removing versus retaining gonads if TNG patients using GAHT choose to undergo genderaffirming surgery. To address this paucity of data, we tested the hypothesis that ovary retention during testosterone (T)-GAHT is protective against adverse metabolic and osteologic health outcomes. Since controlled studies of GAHT cannot be ethically performed with human patients, we utilized a mouse model of T-GAHT developed by our lab to model a transmasculine GAHT regimen. We implanted 8-week-old adult female CD-1 mice with capsules containing either 10 mg T (T) or vehicle (Blank). At the same time, the mice underwent either bilateral ovariectomy (OVX) or sham (Sham) surgery. This resulted in four experimental groups: Blank+Sham (n=7, negative control), Blank+OVX (n=7, positive control), T+Sham (n=7), and T +OVX (n=8). After 6 weeks treatment, T+Sham mice displayed decreased fat deposition as compared to T+OVX mice and untreated groups (Two-way ANOVA with Tukey's post-hoc, p<0.05). Blank+OVX mice showed decreased glucose tolerance, hyperglycemia, and higher circulating cholesterol levels compared to intact mice, yet T-treatment rescued these to levels in negative controls. T-treatment led to higher levels of circulating triglycerides, increased heart and liver weight, and increased femoral trabecular bone density and radius strength regardless of ovary presence. These findings indicate that T-treatment is largely sufficient to prevent adverse metabolic and osteologic effects related to ovariectomy. This study also suggests that, with the exception of fat redistribution, there is likely no metabolic or skeletal health risk associated with ovary removal as opposed to retention in individuals receiving T-treatment. These findings support the safety of elective gender-affirming oophorectomy in transmasculine patients (provided T-GAHT remains a part of the therapeutic regimen) and may be used to help clinicians provide evidence-based advice to TNG patients considering ovary removal.

Volume

9

First Page

A1096

Last Page

A1097

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