Puberty Blocker and Aging Impact on Testicular Cell States and Function

Area of Science:

• Reproductive Biology
• Developmental Biology
• Genomics

Background:

• Spermatogonial stem cells (SSCs) are crucial for producing genetically diverse gametes during puberty.
• Puberty blockers (PB) inhibit this process, but their impact on juvenile SSCs is poorly understood due to limited data.
• A shift in pediatric demographics on PB treatment necessitates research into their effects on reproductive health.

Approach:

• Established the largest clinically annotated juvenile testicular biorepository from children with gender dysphoria on chronic PB treatment.
• Generated an extensive integrated single-cell RNA dataset (>100K cells; 25 patients) combining public and novel data.
• Developed a computational approach to analyze germ cell development and the impact of PB and aging on SSCs.

Key Points:

• Identified mild-to-severe sex gland atrophy in PB-treated children.
• Defined constitutional ranges for testicular cell types and revealed distinct effects of PB and aging on SSCs.
• Observed post-meiotic cells in spermatogenic epithelium regardless of age, puberty status, or PB treatment.
• Developed predictive models for sexual maturity based on cell type proportions and gene expression.

Conclusions:

• PB treatment and aging have distinct effects on testicular cell lineage composition and SSC function.
• Data suggest potential concerns regarding the complete reversibility and reproductive fitness of SSCs post-PB treatment.
• The biorepository and data offer a unique resource for studying PB's impact on testicular reproductive health.