Hematopoietic loss of the X chromosome Is associated with lower likelihood of natural conception and is independent of conventional ovarian reserve markers

Somatic loss of the X chromosome (LOX) increases with age in women, but its reproductive relevance is unclear. We asked whether hematopoietic LOX is associated with the likelihood of natural conception. Multicenter case–control study at three hospitals in Osaka, Japan. Cases were women who did not achieve natural conception after exclusion of male-factor infertility (n=381). Controls were women who conceived naturally (n=123). LOX burden in peripheral blood (%LOX) was quantified by multiplex single-cell droplet digital PCR developed for this study. Serum anti-Müllerian hormone (AMH) was measured by standardized chemiluminescent assays. The primary outcome was the difference in %LOX between cases and controls. Secondary analyses assessed assisted reproductive technology (ART) outcomes (pregnancy within three embryo-transfer cycles) among a prospectively followed subset. Exploratory analyses examined correlations of %LOX with age and AMH. %LOX increased with age and was higher in cases than controls (p<0.001). This difference remained significant after adjustment for age, BMI, and prior pregnancy (β=0.82; 95% CI, 0.70-0.96; p=0.013). ROC analysis identified an optimal %LOX threshold of 0.87% (AUC 0.60; 95% CI, 0.54-0.66). Women with %LOX ≥0.87% had over twofold higher odds of not achieving natural conception (OR=2.16; 95% CI, 1.40-3.30; p<0.001; age-stratified, BMI-adjusted). In contrast, %LOX was not associated with ART pregnancy (adjusted p=0.23) and did not correlate with AMH (ρ=-0.06; p=0.25) or FSH (ρ=-0.01; p=0.84). In this study, hematopoietic LOX was associated with a lower likelihood of natural conception, while no clear association with ART outcomes was observed.