DNA-Damaged Sperm Identified as New Biological Marker for Repeated Miscarriages

Sperm animation, with one breaking apart from damage

A study published in Clinical Chemistry earlier this month has linked sperm with more DNA damage to repeated miscarriages. Recurring miscarriages, defined as three or more consecutive miscarriages before 20 weeks of pregnancy, occur in 1-2 percent of couples. Typically, the woman is screened for any underlying causes, but about half of the cases can’t identify anything linked to the miscarriages, making helpful medical interventions difficult.

“Traditionally, doctors have focused attention on women when looking for the causes of recurrent miscarriage,” Channa Jayasena, a clinical senior lecturer in endocrinology at the Imperial College London and first author of this study, said in a statement. “The men’s health – and the health of their sperm – wasn’t analysed.”

In recent years, the focus has shifted from mother to father, linking lower sperm quality to otherwise unexplained miscarriages. However, the cause of reduced sperm quality has been difficult to pinpoint, preventing screening and treatment options from being successfully utilized.

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Identifying new miscarriage markers

This study identified new biological markers in the sperm of men whose partners have had repeated miscarriages. Hormone levels, semen reactive oxygen species (ROS), and sperm DNA damage were measured in 50 men whose partners had recurring miscarriages and 63 men whose partners did not experience miscarriages. Reduced hormone levels in the blood and increased ROS levels in the semen were found in the men with partners who have recurrent miscarriages.

Compared with healthy men, men in the recurrent miscarriages group had 15 and 16 percent lower levels of testosterone and estradiol (a form of estrogen), respectively. Their sperm also had reduced motility and were abnormal-looking, suggesting the decreased hormone production affected sperm quality. This makes sense as both testosterone and estrogen are important for sperm development.

Interestingly, men in the recurring miscarriage group had four times the amount of ROS in their semen. Reactive oxygen species, as the name suggests, are very reactive molecules called oxidants. They are normally produced by cells in small amounts to fight off bacteria but can damage DNA at high enough concentrations. While none of the men had any ongoing infections known to impact sperm health, such as chlamydia, the authors hypothesized that lingering bacteria from previous infections in the prostate (where semen is made) may cause permanently higher ROS levels in the semen.

Notably, the men in the recurrent miscarriages group were also slightly more overweight and older (an average age of 37 compared with 30 in the non-miscarriages group), both of which could contribute to elevated ROS levels in the semen. Obesity has been linked to fertility problems and is known to cause increased ROS levels.

But here’s the kicker - the men with elevated ROS levels in their semen showed twice as much DNA damage, specifically DNA fragmentation, in their sperm compared to the healthy men. Sperm health is being increasingly recognized as important for a healthy pregnancy, as sperm play a key role in forming the placenta, the crucial lifeline between the mother and baby.

“It has taken medicine a long time to realise sperm health has a role to play in miscarriage – and that the cause doesn’t lie solely with women,” Jayasena added.

Ultimately, both partners should be tested to better determine causes of the recurrent miscarriages.

“Endocrine and molecular sperm profiling may offer a potential novel approach to stratifying future miscarriage risk,” said Waljit Dhillo, professor of endocrinology and metabolism at Imperial College London and lead researcher of this study.

As this is a small study, more investigative work needs to be done before solutions are available.

“The study picked up small differences in hormone levels; it is not clear if these findings are of clinical relevance, because the average hormone levels of all groups were well within normal range,” Kevin McEleny, chair of education and training for the British Fertility Society, who was not involved in the study, told The Guardian. “Minor differences in sperm quality were observed but the significance of that isn’t clear.”

Further studies will evaluate whether dietary, lifestyle, or hormonal interventions affect the men’s hormone and ROS levels – and ultimately fertility.

Current assessments and treatments

Currently, common male infertility testing involves basic semen analysis and hormone measurements. If their hormone levels are low, hormone therapy may be a treatment option. However, there can be unwanted side effects of taking hormone supplements and it may take a year or more of therapy before a difference in sperm production and fertility can be seen.

While basic sperm analysis (count, appearance, motility) is routine for assessing male infertility, advanced testing (such as measuring ROS levels) has been proposed for otherwise unclear infertility cases, especially for couples suffering from recurring miscarriages. Current sperm oxidative stress tests are time-consuming and tedious, making them an inconvenience to implement regularly. A lack of universally accepted sperm oxidative stress analysis has also contributed to the limitations of measuring ROS levels during male infertility assessment.

Given that oxidative stress is one of the infertility culprits, decreasing ROS levels could be a possible treatment. Multiple studies have suggested that increasing dietary antioxidant consumption, such as vitamin C and E, correlates with lower sperm DNA damage. Exactly how dietary antioxidants act on ROS and prevent sperm DNA damage is still largely not well understood.

Numerous clinical trials have tested the effect of antioxidant supplements, such as vitamin C and E, on sperm DNA damage. Overall, adding antioxidant supplements have provided benefit, showing decreased sperm DNA damage. However, caution should be demonstrated as these trials have been small and have given some inconsistent results. This in combination with the risk of vitamin overconsumption provides inconclusive evidence of the efficacy of antioxidant supplement treatment.

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