Fertile Parents Can Possibly Pass Infertility to Sons
While it seems counterintuitive to think parents who conceived a child can pass down infertility, new research indicates it's possible. A study published in January 2022 in Nature found de novo mutations—those not present in either parent—might be associated with male infertility.
An international team of researchers examined the DNA sequences of 185 infertile men and their unaffected parents.
"We investigated all these men and found 145 rare, protein-altering de novo mutations—new mutations that don't appear in their parents that are unique to them—that could be the cause of their infertility," said Miguel Xavier, Ph.D., a postdoctoral research associate at Newcastle University in England and one of the study's authors. "These would be genes that would be causing how you produce the sperm, how the sperm is matured and how it gets processed through the final stages. If it doesn't work, you don't get to produce sperm."
The science is complicated, but researchers are finding specific de novo gene mutations in infertile men that they are not finding in fertile men. Larger studies that include infertile men and their fertile parents are needed to find more causative relationships between specific mutations and their effects on sperm production and maturity.
A new area of infertility research
Infertility is understudied despite affecting 1 in 7 couples worldwide. Depending on the source of information, about one-third to one-half of the cases are due to "male factor" infertility. This particular de novo mutation study is the first of its kind, Xavier said.
"In terms of genetic research, we are in the infancy of this type of [infertility] research," he said, adding that it's too early to say what's causing this kind of infertility and how to solve it.
But he believes identifying these gene mutations will bring peace of mind to some patients.
"Sometimes they say, 'I'm infertile, I don't know why.' We're able to say, 'This is why you're infertile. There's nothing wrong with you. You were just unlucky in the lottery of genetics,'" Xavier said.
Even if a man is infertile, he may still produce some cells that can be used for in vitro fertilization (IVF) or other assisted reproductive technology (ART) in an attempt to conceive with their partner. While these men may be able to have a child this way, their child can be infertile, as well, Xavier said.
"We're happy to help these men conceive, but at least we put all the cards on the table and say, 'OK, we're just passing the ball down to the next generation,'" he said.
Researchers have two hot spots
Genetics and stem cells are the two hottest areas of infertility research, according to T. Mike Hsieh, M.D., a professor of urology and the director of the Men's Health Center at University of California San Diego Health.
The most significant previous advancement was IVF, which has helped millions of couples get pregnant. Today, while we have a better knowledge of gene sequencing, we don't fully understand what it means, Hsieh said.
"Now, you get a book in a completely different language. How do you decipher it?" he said. "That's why we try to identify what mutation is related to what disease, whether it's cancer, whether it's Alzheimer's, whether it's infertility. Unfortunately, we still don't know what to do with this information."
The testing arsenal for male-factor infertility is extremely limited, said Martin Kathrins, M.D., an assistant professor of surgery at Harvard Medical School and a urologist at Brigham and Women's Hospital in Boston. Identifying any clinically frequent mutations to test for would be welcome because that could lead to pre-implantation genetic diagnosis: a screening test used with IVF where the embryo is genetically profiled before implantation.
Idiopathic, or unexplained, infertility is all too common, Kathrins said. It affects 30 percent of infertile couples worldwide, according to research.
"It's frustrating for the patient and it's frustrating for the providers to not be able to give them a real answer. A lot of them have a lot of shame, and I think there can be a lot of guilt," Kathrins said. "If we were able to identify some of these men with more severe male-factor infertility, explain to them why they have it—and certainly de novo mutations are no fault of anybody—[and] contextualize the reason for it, I think that's sort of the global picture for this."
Focus on what you can change
You can't change your genetics. Hsieh said men should not focus on genetic abnormalities but rather on aspects of their life that they can change. Lifestyle modifications, including eating better, exercising, getting a good night's sleep and reducing stress, have been shown to improve fertility.
"We're understanding more about genetics, but a lot of infertility, like lower sperm count, is probably related to a lot of the lifestyle issues, whether it's obesity, poor diet patterns, drinking and smoking," Hsieh said.
Xavier said he hopes more genetic causes of infertility are identified and researchers begin developing the means to overcome infertility. For this to happen, a better understanding of the basics of sperm development and the genetic factors that disrupt it is necessary.
"We're about to publish a companion piece," he said. "Even with this [study], we didn't solve all the cases with these men. We started doing genome sequences where we sequence everything. With the same approach, we're going to say, 'What can we find that can be causative?'"