The loss of the X chromosome in blood cells may be associated with a lower likelihood of natural conception.
The findings suggest that age-related somatic mosaicism may capture reproductive-aging biology not reflected by conventional ovarian reserve markers.
In a multicenter, case-control study, rresearchers in Japan evaluated the hematopoietic loss of the X chromosome (LOX) in 381 female patients who failed to achieve natural conception after the exclusion of male-factor infertility and 123 female patients who conceived naturally. The LOX burden in peripheral blood was quantified using a multiplex single-cell droplet digital polymerase chain reaction assay capable of detecting low-level mosaicism.
The proportion of blood cells with LOX increased with age. The researchers found that the participants with infertility had higher LOX levels compared with controls, and the association remained significant following adjustment for age, body mass index, and prior pregnancy history.
Receiver operating characteristic curve analysis identified a LOX threshold of 0.87% for a reduced likelihood of natural conception. For instance, those above the threshold had more than twofold the odds of not achieving natural conception compared with participants below the threshold. The association was strongest among female patients aged 35 to 39 years.
In contrast, hematopoietic LOX wasn't associated with assisted reproductive technology outcomes in a prospective subgroup analysis of 172 women undergoing in vitro fertilization or intracytoplasmic sperm injection. After adjustment for age and anti-Müllerian hormone levels, LOX didn't differ significantly between female patients who achieved pregnancy within three embryo-transfer cycles and those who didno't.
LOX also didn't correlate with serum AMH or follicle-stimulating hormone concentrations, suggesting it may reflect a biologic dimension distinct from traditional ovarian reserve markers. AMH remained strongly associated with the number of retrieved oocytes, whereas hematopoietic LOX didn't.
The researchers proposed several potential mechanisms underlying the findings. They suggested LOX may function as a surrogate marker of systemic genomic instability or biologic aging, may share genetic predisposition pathways with reproductive decline, or could influence fertility through immune dysregulation. Prior studies have shown that leukocytes with sex chromosome loss can demonstrate altered immune-related gene expression.
The researchers noted that the discriminative performance of LOX alone was modest, with an area under the curve of 0.60, comparable to reported performance for some established ovarian reserve biomarkers in predicting natural conception. They emphasized that LOX may provide complementary rather than replacement information.
The study had several limitations, including its case-control design, reliance on peripheral blood rather than reproductive tissue, and enrollment of exclusively Asian participants. Most controls were sampled during pregnancy, raising the possibility that gestational immune or hormonal changes could have influenced circulating leukocyte clonal dynamics. The infertility cohort also included heterogeneous causes of reduced fertility.
Lead study author Taiki Kikuchi, of the Laboratory of Cardiovascular Mosaicism at the National Cerebral and Cardiovascular Center in Osaka, Japan, and colleagues concluded that hematopoietic LOX “may capture information that is complementary to conventional ovarian reserve markers” and called for prospective longitudinal studies evaluating whether LOX could help stratify fertility risk among younger women with otherwise normal ovarian reserve testing.
Taiki Kikuchi reported being the founder of TL Genomics, and senior study author Soichi Sano reported serving as a scientific adviser to the company. The study was funded by multiple Japanese research grants and foundations.
Source: Reproductive BioMedicine Online
