Scientists in Japan have identified a female-specific chromosomal change in blood cells that may help explain why some women struggle to conceive naturally even when conventional fertility markers appear normal.
Study: Haematopoietic loss of the X chromosome is associated with a lower likelihood of natural conception. Image credit: Prostock-studio/Shutterstock.com
Mosaic loss of the X chromosome (LOX) is a condition in which some female blood cells lose one of their two X chromosomes, while other cells retain the normal pair. A recent study from Japan, published in the journal RBMO, suggests that LOX in blood cells may be associated with a lower likelihood of natural conception and could represent a female-specific indicator of reproductive aging.
Female blood cells lose X chromosomes with age
Hematopoietic LOX is a natural phenomenon whereby one of the two X chromosomes is lost in a subset of female somatic cells. This commonly occurs in hematopoietic cells and is therefore called hematopoietic LOX by the authors. Similarly, loss of the Y chromosome (LOY) occurs in a subset of blood cells in men, increasing with age, though LOX is less common than LOY.
The result of LOX is mosaic aneuploidy; not all somatic cells have the same chromosome number. Some have monosomy X, while most have two X chromosomes. This is therefore a female-specific chromosomal marker of age-related changes in fertility.
Later childbirth raises concerns over declining fertility
The relevance of this finding stems from the increasing age at first childbirth in many countries, driven by greater access to education, increased workforce participation among women, and evolving societal perspectives on marriage and parenthood.
As more women choose to have children later in life, there is growing interest in understanding how reproductive biology changes with age. This is because natural fertility generally declines over time, while the risks of miscarriage and chromosomal abnormalities in offspring increase with maternal age.
Traditional fertility biomarkers show limited predictive accuracy
Earlier researchers relied on markers such as anti-Mullerian hormone (AMH), FSH, and inhibin B to assess ovarian reserve. However, more recent studies have raised doubts about their accuracy as predictors of the success of natural conception, especially towards the end of the natural reproductive period.
X inactivation and LOX
Compared to autosomes, the X chromosome is much more likely to be lost during cell division in some female somatic cells. Of the two X chromosomes in all female somatic cells, one is always inactivated, so that both male and female somatic cells have only one active X chromosome at any time.
However, X inactivation is incomplete, and about 15 % of genes on the inactive X remain active: the escape genes. The inactivated X is disproportionately lost in LOX, resulting in cells with different dosages of the escape genes, which might affect cell function.
LOX and health risks
Epidemiological studies have shown that hematopoietic LOX is linked to an excessive risk of hematological malignancies like the leukemias, and of pneumonias and other infectious complications. Genomic studies have also identified inherited variants linked to a higher risk of hematopoietic LOX, which affect various physiological processes. The current study sought to understand whether LOX implicates female-specific processes related to fertility.
Earlier cytogenetic studies suggested such associations, but with limited validity due to their low sensitivity and susceptibility to artifacts. The current study uses a multicenter case-control design to resolve this question using a highly sensitive multiplex single-cell droplet digital PCR assay. The aim was to quantitatively measure LOX and assess its association with natural conception.
Case versus control profile
The cases comprised 381 infertile women who did not achieve natural conception after exclusion of male-factor infertility, while 123 women who conceived naturally were included in the control group. The median age in the control and case groups was 32 and 34 years, respectively. The mean body mass index (BMI) was lower in the case group compared to controls.
Cases had a higher prevalence of multiple reproductive disorders, most commonly polycystic ovarian syndrome and endometriosis.
LOX linked to age
Across both groups, the %LOX increased modestly with age, but not with history of pregnancy, BMI category, or history of medical conditions, including gynecological issues.
There were no significant correlations between serum AMH or FSH and %LOX.
LOX linked to conception
Women with hematopoietic LOX were less likely to conceive naturally. The threshold that discriminated most accurately between success and failure of natural conception was determined to be 0.87 %. Though the performance of this threshold was modest and was considered by the authors to be comparable to existing single-marker tests of ovarian reserve, like AMH.
After adjusting for age and BMI, the odds of failing to conceive naturally were 2.2-fold higher above this threshold compared with those who had %LOX below this value.
LOX and fertility treatment outcomes
After excluding cases that did not undergo fertility treatment, and those who did but failed to conceive and stopped treatment within three cycles, 172 women were left who were treated for at least three embryo-transfer cycles. Among these, 126 conceived within three treatment cycles, while 46 failed to conceive.
The group who conceived with treatment were younger, the median age being 34 years, versus 39 years in the group who failed to conceive. However, the adjusted %LOX was not different between these groups.
Serum AMH levels were higher in the group that conceived with treatment. The levels were strongly associated with the number of oocytes retrieved, but %LOX showed no correlation. This suggests that “haematopoietic LOX reflects a biological dimension distinct from classical ovarian reserve.”
Putative mechanisms
The authors suggest several possible mechanisms underlying this association. Firstly, hematopoietic LOX is a blood-based proxy for systemic genomic instability or biological aging that also involves the reproductive tissues. In agreement with this, earlier studies showed that chromosomal abnormalities were increased in embryos of mothers with hematopoietic LOX.
Secondly, both the reduced fertility and hematopoietic LOX might be due to a shared underlying genetic predisposition, termed the “common soil” hypothesis. A third potential explanation is LOX-associated immunological changes that reduce fertility.
Study limitations
The case-control study design precludes causal inference. Second, hematopoietic LOX was assessed only in peripheral blood, leaving its profile in reproductive tissues unknown. Ongoing research aims to clarify this point by both developing sensitive tissue-level genomic profiling methods and using existing human tissue banks. Mechanistic research into the link between mosaicism and fertility is also essential.
Most control participants were sampled during pregnancy, raising the possibility that hormonal and immune changes influenced leukocyte clonal dynamics.
The cases and controls differed in that the former were seeking fertility treatment, suggesting that other unmeasured confounding factors may have affected the observed associations.
All participants were Asian, limiting the generalizability of the findings beyond the Japanese study population. Only conception was evaluated as a fertility outcome, indicating the need for future long-term studies using long-term reproductive outcomes.
LOX may complement conventional fertility biomarkers
The authors conclude that hematopoietic LOX is a potential marker of successful natural conception and may be used to enhance the predictive power of conventional ovarian reserve biomarkers such as AMH.
However, the authors emphasize that its clinical utility remains to be established and that these findings require validation in prospective longitudinal studies. These are preliminary findings and require validation in future studies.
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