The Male Factor: Infertility and Recurrent Miscarriage

By Jenna Haines
Monday, January 6, 2020

Emerging studies are exploring the relationship between DNA and male infertility.

While the majority of past infertility research has focused on diagnosing and treating infertility in women, fertility issues affect both men and women at approximately the same rate. In fact, according to the National Institutes of Health, roughly one-third of infertility cases are due to male factors, one-third of cases are due to female factors, and one-third of cases are due to problems with both the man and the woman or have no identifiable cause.

Recently, researchers are looking to better understand the varying male-related causes of infertility and recurrent miscarriage in the hopes that these findings will lead to better diagnoses and more effective treatments. Two of these studies center around the potential role of genetics.

“Male infertility is still an understudied field and requires more awareness, attention and funding.”
— Manon Oud, MSc, PhD candidate at the Radboud University Medical Centre in Nijmegen, the Netherlands

Genetic Mutations and Infertility

A study presented at the annual conference of the European Society of Human Genetics in June 2019 was able to identify a possible relationship between de novo mutations (DNMs) — genetic mutations not found in either parent — and male infertility.

Led by Manon Oud, MSc, a PhD candidate at the Radboud University Medical Centre in Nijmegen, the Netherlands, the research team compared DNA samples from 108 infertile men with DNA samples from their fertile parents. After eliminating nine patients whose cause of infertility lay elsewhere, they were able to identify 83 total protein-altering DNMs — 22 of which are involved in the production of sperm.

Moving forward, Oud and her researchers are working to screen the DNA of more patients and their parents in search of patterns in the locations of these novel mutations and to further examine the role these 22 DNMs play.

“We are interested in learning more about the function of the genes that are affected by a mutation since their link with infertility has never been established before,” Oud says. “We are studying the role of these genes in residual material from testicular biopsies of our patients. Additionally, we are performing experiments in fruit flies to study whether disruption of the newly associated genes causes infertility in flies.”

“When couples are investigated for fertility issues and recurrent miscarriage, almost all of the investigation is centered around the important role women play. However, having spoken to and treated couples for these issues, I understand how important it is for them to get any extra information they can that could potentially prevent a miscarriage from happening again — regardless of whether the problem is the result of the man or the woman.”
— Channa Jayasena, MD, PhD, Clinical Senior Lecturer and Consultant in Reproductive Endocrinology and Andrology at Imperial College and Hammersmith Hospital in London, England

DNA Damage and Recurrent Miscarriage

Another study, published in the journal Clinical Chemistry in January 2019, found that men whose partners experienced three or more successive miscarriages were more likely to have higher levels of both DNA damage and reactive oxygen species in their sperm cells. Channa Jayasena, MD, PhD, the study’s lead researcher and a Clinical Senior Lecturer and Consultant in Reproductive Endocrinology and Andrology at Imperial College and Hammersmith Hospital in London, England, suspects these findings are interrelated.

“Reactive oxygen species play a critical role in cellular metabolism and are necessary for the normal functioning of mitochondria,” Dr. Jayasena says. “However, reactive oxygen species can also cause cellular damage and cell death if they are produced in excessive amounts.”

Dr. Jayasena says he and his research team are now looking into what is triggering these high levels of reactive oxygen species. He hopes the results of this research will help lead to new potential treatments, such as antioxidant supplements, for men struggling with infertility and/or recurrent miscarriage.

“There is a widening awareness around the role of the male partner when it comes to reproductive disorders,” Dr. Jayasena says. “There have been tremendous advancements in the treatment of women for reproductive disorders over the past few decades, and I think we are just now playing catch-up for the men.”

Chlamydia and Male Infertility

While chlamydia has long been highlighted as a potential cause for infertility in women, much less attention has been placed on the potential effect this sexually transmitted infection has on male fertility. However, a recent study published in the journal Human Reproduction found that chlamydia was present in 40% to 54% of the fixed diagnostic testicular biopsies collected from a group of 95 moderately to severely infertile men with no known cause of infertility.

Chlamydia was also present in three (16.7%) of the fresh therapeutic testicular biopsies collected from a separate group of 18 moderately to severely infertile men — 13 of whom, including the three that tested positive for chlamydia, had no known cause of infertility. Two of these three men tested negative for chlamydia based on a urine test (a urine test result was not able to be provided for the third participant).

Additionally, chlamydia-specific antibodies were present in 12 (66.7%) of these 18 fresh biopsies — an indication that the men were previously exposed to chlamydia trachomatis, the bacteria responsible for chlamydia infections.

While these findings do not demonstrate causality, this the first study to come forward with evidence that previously undetected cases of chlamydia can reside in testicular tissue and to suggest that these hidden infections may be a large contributor to male infertility.