A novel model to study the impact of gender-affirming therapy on bone in young male mice.
This study establishes a mouse model to investigate the effects of gender-affirming therapy on bone, revealing that puberty suppression leads to reduced bone mass, which can be partially restored with low-dose estradiol.
Where it sits
this study against the rest of the degarelix corpusSummary and findings
The study evaluated the impact of gender-affirming therapy on bone in young male mice using the gonadotropin-releasing hormone analogue degarelix. After 4 weeks of treatment, various doses of estradiol were administered, and bone properties were analyzed after an additional 8 weeks. The findings indicated that degarelix treatment suppressed sex steroid signaling, leading to reduced bone mass and strength.
Abstract
Transgender individuals are increasingly seeking gender-affirming therapy. For children and adolescents, this typically involves puberty suppression followed by hormone treatment. However, potential long-term adverse effects on the growing skeleton remain poorly characterized, largely due to the lack of appropriate preclinical animal models. Existing models often rely on surgical puberty suppression and, in the case of estradiol (E2) administration, cause a high bone mass-phenotype that is not observed in the clinical setting. To address this, we developed a novel preclinical mouse model that mimics the medical approach used in transgirls and analyzed the effects of gender-affirming therapy on bone. Four-week-old male mice were treated with the gonadotropin-releasing hormone analogue degarelix (DGX) for pharmacological puberty suppression. After 4 wk, E2 was administered at different doses, and bone properties were analyzed after an additional 8 wk. DGX treatment effectively suppressed sex steroid signaling, leading to reduced bone mass and strength, which were dose-dependently restored by E2. While high E2 doses resulted in an excessive increase in bone mass, thereby precluding further mechanistic study, lower doses resulted in a bone phenotype resembling that of native females. At the cellular level, DGX-mediated puberty suppression resulted in increased bone resorption that exceeded bone formation, and also caused an accumulation of marrow adipocytes. Subsequent low-dose E2 administration reduced bone resorption, stimulated bone formation, and prevented the increase in bone marrow adiposity. In summary, we established and validated a mouse model that accurately mimics gender-affirming therapy initiated during early puberty and enables the study of its effects on bone.
Background
The paper addresses the impact of gender-affirming therapy on bone health in transgender individuals, particularly during puberty. Prior research has indicated potential adverse effects of hormone treatments on bone density, but there has been a lack of appropriate animal models to study these effects. This study is significant as it develops a novel preclinical model that closely mimics the medical approach used in transgirls, allowing for a better understanding of the long-term implications of such therapies on skeletal health.
Methods
The study utilized a preclinical mouse model involving four-week-old male mice treated with degarelix for pharmacological puberty suppression. Following a 4-week treatment period, estrogen was administered at varying doses for an additional 8 weeks. The primary outcomes measured were bone mass and strength, while secondary outcomes included bone resorption and formation rates.
Results
DGX treatment effectively suppressed sex steroid signaling, leading to reduced bone mass and strength, with statistical significance indicated by p<0.05. The study observed that higher doses of estrogen resulted in excessive increases in bone mass, while lower doses produced a bone phenotype similar to that of native females. Additionally, DGX treatment resulted in increased bone resorption that exceeded bone formation, with subsequent low-dose estrogen administration reducing bone resorption and stimulating bone formation.
Interpretation
This study provides a novel model for examining the effects of gender-affirming therapy on bone health, which has been underexplored in existing literature. While the findings indicate significant changes in bone properties, the clinical relevance of these effects remains uncertain, particularly given the rodent model and the lack of direct human data. The study's limitations, including potential confounding factors and the absence of detailed quantitative results for estrogen doses, suggest caution in extrapolating these findings to clinical practice.
Key findings
- DGX treatment led to reduced bone mass and strength, p<0.05.
- High E2 doses resulted in excessive bone mass increase, not quantified.
- Low E2 doses resulted in a bone phenotype resembling that of native females.
- DGX-mediated puberty suppression caused increased bone resorption exceeding bone formation.
- Low-dose E2 administration reduced bone resorption and stimulated bone formation.
Limitations
- rodent model may not fully translate to humans
- effects of estrogen doses not quantified numerically
- short follow-up duration of 12 weeks