Yu Jun, Hu Longfei, Li Huixia, Li Xiaofeng, Ma Chaoye, Jiang Ting, Liu Yongxin, Wang Xue, Li Xia, Zuo Liandong, Lin Haocheng, Xu Wenming, Zhou Yiwen, Liu Yang, Chen Hao
Institute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong University, Nantong, Jiangsu, PR China.
Singleron Biotechnologies, Yaogu Avenue 11, Jiangsu, Nanjing, PR China.
Cell Biosci. 2025 Jul 20;15(1):106. doi: 10.1186/s13578-025-01445-3.
Transgender women (transfemales) often undergo gender-affirming hormone therapy (GAHT). However, the testicular impacts of feminising hormones present heterogeneity due to the complexity of testicular regulatory mechanisms.
In this study, we analyzed approximately 49,385 single-cell transcriptomes from transfemale human testicular tissue, comparing cellular composition with that of cisgender male individuals across a range of ages. Our approach included clustering of cell types, identification of marker genes, pseudotime analysis of germ cells, and comprehensive cell-cell interaction analyses. We employed immunohistochemistry, quantitative real-time PCR, and immunostaining to validate the key molecular signatures identified in the pathways of interest.
GAHT led to a significant reduction in spermatogenic cells, accompanied by an unexpected increase in Sertoli cell numbers per seminiferous tubule, suggesting disrupted germ cell-Sertoli cell interactions. Molecular analyses revealed upregulation of genes such as Decorin (DCN), Myoglobin (MB), and Beta-2-Microglobulin (B2M) in Sertoli cells, with enrichment in pathways related to cell adhesion, cytokine response, and wnt signaling. Notably, β-catenin was significantly elevated and translocated into the nucleus of Sertoli cells determined by immunostaining analysis. Additionally, collagen fiber infiltration disrupted the testicular microenvironment, further impairing germline-Sertoli cell communication.
This study provides novel insights into the testicular alterations associated with GAHT in transfemales, particularly highlighting the role of germline-Sertoli cell interactions in testicular injury. Our findings contribute to a deeper understanding of the testicular response to feminizing hormones, offering a foundation for future therapeutic strategies.
跨性别女性（变性女性）通常会接受性别确认激素疗法（GAHT）。然而，由于睾丸调节机制的复杂性，女性化激素对睾丸的影响存在异质性。
在本研究中，我们分析了来自变性女性人类睾丸组织的约49385个单细胞转录组，将细胞组成与不同年龄段的顺性别男性个体进行比较。我们的方法包括细胞类型聚类、标记基因鉴定、生殖细胞的伪时间分析以及全面的细胞间相互作用分析。我们采用免疫组织化学、定量实时PCR和免疫染色来验证在感兴趣的通路中鉴定出的关键分子特征。
GAHT导致生精细胞显著减少，同时每个生精小管中的支持细胞数量意外增加，这表明生殖细胞与支持细胞之间的相互作用受到破坏。分子分析显示，支持细胞中诸如核心蛋白聚糖（DCN）、肌红蛋白（MB）和β2微球蛋白（B2M）等基因上调，在与细胞粘附、细胞因子反应和Wnt信号相关的通路中富集。值得注意的是，通过免疫染色分析确定，β连环蛋白显著升高并转移到支持细胞的细胞核中。此外，胶原纤维浸润破坏了睾丸微环境，进一步损害了生殖系与支持细胞之间的通讯。
本研究为变性女性中与GAHT相关的睾丸改变提供了新的见解，特别强调了生殖系与支持细胞之间的相互作用在睾丸损伤中的作用。我们的发现有助于更深入地理解睾丸对女性化激素的反应，为未来的治疗策略提供基础。
