Objective:

To evaluate the association between hematopoietic loss of the X chromosome (LOX) and natural conception in women, specifically focusing on its implications for reproductive aging.

Key Findings:

• Higher LOX levels were found in infertile women compared to controls, significant after adjusting for age, BMI, and prior pregnancy.
• A LOX threshold of 0.87% indicated more than twofold odds of not achieving natural conception, highlighting its potential as a predictive marker.
• The association was strongest in women aged 35 to 39 years.
• LOX was not associated with outcomes of assisted reproductive technology, indicating its specificity to natural conception.
• LOX did not correlate with serum AMH or FSH levels, suggesting it reflects a distinct biological dimension.

Interpretation:

LOX may reflect a biological dimension of reproductive aging distinct from traditional ovarian reserve markers, potentially indicating systemic genomic instability or immune dysregulation, warranting further exploration.

Limitations:

• Case-control design limits causality inference.
• Study relied on peripheral blood rather than reproductive tissue.
• Participants were exclusively Asian, limiting generalizability.
• Most controls were sampled during pregnancy, which may affect leukocyte dynamics.
• The infertility cohort included heterogeneous causes of reduced fertility.

Conclusion:

Hematopoietic LOX may provide complementary information to conventional ovarian reserve markers, warranting further prospective studies to evaluate its role in fertility risk stratification among younger women.