When Candice learned that her nine-year-old son Jayden had a bladder sarcoma, the last thing on her mind was whether Jayden would want to have kids himself someday.

“We had so much information going into our minds at that moment, so I was surprised when our doctor said, ‘That’s something that you guys maybe want to think about,’” she recalls.

For families and clinicians supporting children with cancer diagnoses, the primary focus is understandably on the immediate: dealing with the rogue cells at hand, and getting treatment started as soon as possible. Only later are the long-term survivorship issues discussed.

“A somewhat unanticipated consequence of us getting better at treating childhood cancers is that these patients sometimes, unfortunately, have long-term chronic side effects of the treatments that enabled them to survive to adulthood,” says Michael Hsieh, a urologist at Children’s National Health System in Washington, D.C. “Infertility is one of the major ones.”

It’s a problem that exists for both boys and girls, although the solutions for each population are progressing on separate tracks. Researchers say that the biological systems are too different for a one-size-fits-all fertility treatment.

First in Mice, Now in Men

Hsieh is part of a team running clinical trials of experimental procedures to preserve fertility in boys and young men undergoing chemotherapy. Infertility caused by chemotherapy primarily affects those with cancer, but the patient population he works with, ranging from infants to 17-year-olds, also includes boys receiving treatment for sickle cell and other metabolic diseases.

In spite of recent innovations and increasing survivorship rates, chemotherapy is still a blunt instrument. It’s a type of poison that targets and kills rapidly dividing cells, but that’s a characteristic that cancer cells unfortunately share with many other good cells in the body, and mainstream cancer treatments aren’t sophisticated enough to tell the difference. Hair cells also rapidly divide—it’s the reason why so many cancer patients lose their hair—and so do the stem cells that make sperm.

Unlike hair, which often grows back, the stem cells that become sperm usually don’t regenerate after they’re hit by chemotherapy. The common drug cyclophosphamide is particularly notorious for this.

“A somewhat unanticipated consequence of us getting better at treating childhood cancers is that these patients sometimes, unfortunately, have long-term chronic side effects of the treatments that enabled them to survive to adulthood... Infertility is one of the major ones.” Michael Hsieh, Urologist at Children’s National Health System in Washington, D.C.

A patient who has gone through puberty has the option of banking sperm before undergoing treatment. Healthy, mature sperm can be cryogenically frozen for later in life, if and when the patient wants to have biologically-related children. Frozen sperm can then be used for intrauterine insemination (IUI), where sperm is placed directly into the uterus, or in vitro fertilization (IVF), where the sperm fertilizes an egg in a lab and the resulting embryo is then implanted.

IUI and IVF have both been available for decades, and by now are highly successful fertility treatments, but for younger boys — whose bodies haven’t started producing mature sperm — or for patients who are unable or unwilling to bank sperm, there are no other clinically mainstream options.

The study that Hsieh is working on looks at ways to restore or preserve fertility using testicular tissue samples—the tissue contain cells that will become sperm. Earlier work successfully demonstrated that this was possible with mice and nonhuman primates. After having testicular tissue biopsied, frozen, and reintroduced, the animals’ bodies were able to produce healthy sperm — and they were able to procreate.

Now, the research has moved on to human clinical trials, which Jayden is taking part in.

Before he started chemotherapy at Children’s National, Jayden’s oncologist mentioned Hsieh’s study, Candice says, and provided the family with some reading material. They familiarized themselves with the procedure of testicular tissue removal, but also grappled with the idea that this is all still a bet for the future. No human males have successfully preserved their fertility this way after undergoing chemotherapy.

“We’re just hoping that maybe (Jayden) can help the people do the research,” Candice says. “We don’t know if it will be successful or not, we’re just hoping one day it will be. It’s not hard to try.”

That’s exactly what Hsieh and his team are banking on. Cryogenic preservation works well enough that theoretically someone’s testicular tissue can live for an indefinite period of time, he says. That creates a time buffer for other reproductive technologies to catch up and still benefit today’s survivors when they do.

Candice says that the annual fee her family pays to keep Jayden’s tissue frozen is manageable, and it’s something they can afford to keep doing until the future comes.

Girls Take the Lead

For girls, the future is almost now. At Northwestern University, Monica Laronda runs a lab involved in research running parallel to what Hsieh and others are doing for boys. She is studying several approaches to preserving or restoring fertility in girls and young women who’ve undergone chemotherapy, such as freezing ovarian tissue to be reimplanted in the patient later in life.

The problems are broadly similar in boys and girls. Chemotherapy kills male and female reproductive cells for the same reason, and the standard of care for women is also to simply bank eggs. But in girls who are too young, this is not yet an option, as with boys and banking sperm.

The similarities end there. Each area of research is progressing on a separate track because the biological systems underpinning male and female reproduction are so distinct. And, for once, research on the women’s health side of things is ahead.

Laronda attributes this progress to work that began decades ago in adult women undergoing cancer treatments. For women, reproductive health is deeply tied to general health, and loss of fertility does not just mean loss of ability to get pregnant — it also means a patient goes through early menopause, which carries with it increased risk of heart disease, osteoporosis, diabetes, and other severe health concerns. That’s why preserving fertility for young girls is so important: not only does it impact their ability to have a biological family, it impacts their future health, too.

“Everyone else on their care team may rightfully focus on (the patient) just plain surviving, (but) then to think beyond that, to survivorship issues, tells the family that they should remain hopeful.” Michael Hsieh, Urologist at Children’s National Health System in Washington, D.C.

Laronda’s research looks at three possibilities for preserving fertility in cancer patients: freezing mature unfertilized eggs, preserving ovarian tissue — which contains immature eggs — for later re-implantation, and 3-D printing ovaries using a patient’s own cells. Today, only the first is considered a mainstream practice, and would be possible for patients who’ve gone through puberty. For young girls, however, preserving ovarian tissue is the best bet, although it is still an experimental procedure — and 3-D printed ovaries are still very much confined to the lab and not yet in clinical trials. For her pediatric patients, Laronda says that she draws inspiration from all of these branches of research, which began in adult women; however, pediatric care requires its own line of thinking.

“Pediatric patients are not just small adults, so some of their tissue is actually quite different,” she says. “We're preserving cells in a state that would not normally contribute to fertility because the body hasn’t matured yet.”

She cites a recent study that showed the quality of the eggs that come from girls who haven’t yet reached puberty is lower than those from women of reproductive age.

Another consideration, which she has in common with researchers who work with patients of any age or sex, is being careful to make sure a cancer hasn’t metastasized. Any fertility treatment that involves preserving and reintroducing a cancer patient’s own tissue or cells runs the risk of unintentionally preserving and reintroducing cancer cells in the process.

Despite the obstacles, there have been steps toward success. There are a few reports of using preserved ovarian tissue to help girls at least go through puberty after receiving chemotherapy. In the popular press, there have also been stories about childhood cancer survivors going as far as successfully giving birth to healthy babies after having frozen ovarian tissue re-implanted — but there are no peer-reviewed studies yet.

To recruit people for her crucial research, Laronda works with families, patients, and clinicians at Lurie Children’s Hospital in Chicago to assess a girl’s risk of post-chemotherapy infertility based on chemotherapy dose and age. Because girls are born with all the eggs their body will ever make, and egg counts decline with age, the older a girl is, the higher her risk of developing infertility from chemotherapy.

Laronda also works with a patient’s clinical team to pair a surgery for ovarian tissue retrieval with another procedure that’s already scheduled, to minimize physical and emotional pain as much as possible. Laronda says that many of the families and patients she speaks to are surprised, like Jayden’s mom was, to be thinking about infertility in the midst of a cancer diagnosis.

“I think (a child’s) parents or guardians don't really think about fertility. They're not a reproductive being yet, you know?” Laronda says. “Some of it is education and getting people to understand that the cells they're affecting now will have results in the future."

Thinking Ahead

Although being involved in experimental procedures can leave a lot to chance, it can also be a source of optimism for families and patients.

“This study conveys a very important message to families, of hope,” says Hsieh. “Everyone else on their care team may rightfully focus on (the patient) just plain surviving, (but) then to think beyond that, to survivorship issues, tells the family that they should remain hopeful.”

Lingering over fertility treatments for children is the question of how best to ethically involve young kids in such a grownup decision. Hsieh says that while his study legally requires parental consent for a child’s involvement, he also seeks out what he calls patient assent. In children seven years or older, Hsieh wants them to be aware of any procedures and also to have the opportunity to express their thoughts about future parenthood.

“We of course talked to him,” Candice says about Jayden, who has one brother, but has persistently been asking for a sister. She remembers him saying, “Of course!” when asked if he wanted to be a father someday, but he also had some questions about how this would all actually work in reality.

Candice recalls, “We told him ‘We don’t know yet, but we can do this so that in the future you might have a family too.’”