Mitochondrial DNA in sperm linked to fertility and pregnancy probability

Published 19 October 2020

A cohort study in non-IVF couples trying to get pregnant has found that sperm mitochondrial DNA copy number may be useful as a biomarker of male reproductive health and the likelihood of pregnancy, even in the general population.

The viability of female gametes has been tested considerably more than male. Yet estimates suggest that between one-third and one half of couple infertility can be attributed to a male cause. Despite the emergence of tests for DNA fragmentation in sperm cells, such attribution continues to rest largely on the thresholds of the WHO’s basic semen analysis, without any more accurate test in sight for the reliable prediction of fertilisation and pregnancy.

Now, however, a new report raises the potential of mitochondrial DNA measurement in sperm as a reliable biomarker of male reproductive health and the likelihood of pregnancy.(1) This study found, as had been earlier suggested in embryos, that a higher sperm mtDNA copy number was associated with a lower probability of pregnancy and a longer time to pregnancy – and vice versa.

As background to the study the authors explain that mitochondria are active during spermatogenesis and contribute to sperm motility, with levels declining during normal spermatogenesis ‘by approximately 8 to 10-fold’. This, they add, ensures that sperm mtDNA copy number is low at the point of fertilisation, when mtDNA is inherited from the mother. The authors had already tested the significance of mtDNA copy number during spermatogenesis in a study showing that higher levels of mtDNA were indeed associated with decreases in sperm concentration, sperm count and sperm motility.(2)

Now, this latest study takes the hypothesis a step further by extending the significance of mtDNA from semen quality to fecundity and its prediction of pregnancy. The study was a population-based prospective cohort study of non-IVF couples trying to become pregnant recruited from 16 US counties between 2005 and 2009 and followed for up to 16 months. The semen samples were taken in the subjects’ own homes, with sperm mtDNA copy number measured from 384 samples and assessed by quantitative PCR. The probability of pregnancy within one year was compared according to four quartiles of mtDNA measurement.

The results showed a significant decline in the probability of pregnancy with increasing mtDNA copy number: those in the fourth quartile (highest levels) had a pregnancy probability of 63.5% and in the first quartile (lowest level) of 82.3%. This was calculated as an 18.8% lower chance of pregnancy, a difference which persisted after adjustments for potential confounders.

The investigators, whose subjects in this NIH-funded study were enrolled from the Longitudinal Investigation of Fertility and the Environment (LIFE) study, thus now propose with some confidence that sperm mtDNA copy number ‘may represent a sensitive molecular marker of abnormal spermatogenesis and serve as an integrated measure of conventional individual semen parameters’. In emphasising the latter point, they note the weak association between the WHO’s semen references and a couple’s fertility status. Indeed, in an earlier report from this same LIFE study an evaluation of 36 semen parameters found that only one was reliably associated with time to pregnancy in multivariate models.

They further note that a biological explanation for the finding – and for mtDNA as a measure of semen quality - remains ‘unclear’. One possibility, they suggest, may be the susceptibility of mtDNA to oxidative damage, but they emphasise that the mechanism explaining any association of sperm mtDNA and male fecundity needs yet to be explored.

The findings, however, bring to mind the somewhat controversial argument of Fragouli et al in 2015 in proposing mtDNA measurement as a biomarker of embryo viability.(3) The group’s first study also reported an inverse relationship between mtDNA levels and viability, that embryos which went on to become viable pregnancies contained significantly lower levels of mtDNA than those which did not implant. Further analysis even proposed a threshold level of mtDNA above which no embryos would ever implant. The findings, as Fragouli said at the time, further bring to mind the ‘quiet embryo’ hypothesis of embryologist Henry Leese, by which viability appears to increase with declining levels of metabolic activity in a similarly inverse relationship. Could mtDNA as an agent of energy also now be a marker of ‘quiet’ sperm cells?

1. Rosati AJ, Whitcomb BW, Brandon N, et al. Sperm mitochondrial DNA biomarkers and couple fecundity. Hum Reprod 2020; doi:10.1093/humrep/deaa191
2. Wu H, Huffman AM, Whitcomb BW, et al. Sperm mitochondrial DNA measures and semen parameters among men undergoing fertility treatment. Reprod Biomed Online 2019; 38: 66–75.
3. See https://www.focusonreproduction.eu/article/News-in-Reproduction-mDNA

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