A monkey born from frozen testicular tissue offers fertility hope to pediatric cancer survivors

Cancer treatments like chemotherapy can wipe out sperm production, so men who want to one day have children sometimes freeze some before they undergo treatment.

Boys who haven’t gone through puberty don’t have that option. An estimated 30 percent of childhood cancer survivors will be infertile.

But a study published Thursday suggests it might be possible to save a piece of a boy’s testicular tissue and later coax it to produce mature sperm, opening up the possibility of biological children.

In the study, which appeared in the journal Science, researchers reported they did just that with a sample of immature testicular tissue from monkeys, and that in one case, the sperm was used to start a pregnancy and led to a birth.

Experts said the birth of the rhesus macaque, named Grady (short for “graft-derived baby”), indicated the approach could work in people.

“It’s going to give hope I think to a lot of young boys who have cancer and are hoping to have genetic families as they grow into adulthood,” said Susan Taymans, a program director at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, who was not involved in the research. The institute, which is part of the National Institutes of Health, provided funding for the study.

Now, the senior author of the paper says he hopes to start a clinical trial of the technique — which requires grafting the testicular tissue back into the patient. The researcher, Kyle Orwig of the University of Pittsburgh School of Medicine, directs a fertility preservation program that has already collected testicular and ovarian tissue from hundreds of patients whose fertility is at risk following toxic therapies.

“The only reason for doing this study is because there is a patient that it directly relates to,” Orwig said.

Testicular tissue contains spermatogonial stem cells that mature into sperm starting in puberty; these cells are also destroyed by chemotherapy and radiation and cannot be replaced. Researchers have explored different ways of using the tissue to preserve boys’ fertility. One approach — so far attempted only in animals — involves saving the tissue and then grafting it back into the patient during puberty, essentially restoring the cells to the environment in which they would normally develop and start producing sperm.

Scientists have tried that strategy in the past in monkeys, but failed to generate much sperm. But in the new study, for reasons the researchers do not fully understand, the grafts successfully developed into sperm factories. It was also the first monkey study that resulted in the birth of a baby.

For the study, the researchers first removed testicular tissue from five rhesus macaques who had not yet begun puberty. Then, as the monkeys started puberty, the team transplanted the tissue back into the animals, right under the skin either in the back or in the scrotum. The researchers also grafted both fresh tissue and tissue that had been frozen.

Starting in puberty, the brain sends out hormonal signals that drive testosterone production and generate sperm. And as the months passed, the researchers tracked a rise in the monkeys’ testosterone levels — a sign that the tissue was maturing. For research purposes, the monkeys had been castrated, so the scientists knew the testosterone production was coming from the grafts.

Then, after eight to 12 months, the researchers removed the grafts and found that all of them — from both fresh and frozen tissue, and from both the back and the scrotum — had produced live sperm.

The next step was to make embryos. The researchers chose to use sperm made from tissue that had once been frozen, given that’s how the process would almost certainly work with people. A boy who had to go through chemotherapy at age 5, for example, might have his tissue frozen for years before endeavoring to get sperm from it.

The researchers fertilized 138 macaque eggs with the sperm, but they only produced 16 embryos. Eleven of them were transferred into the wombs of six female macaques, one of whom became pregnant.

Grady was born on April 16, 2018, via caesarean section.

Researchers are concerned that transplanted testicular tissue, removed from a cancer patient before treatment, might harbor malignant cells that could reintroduce cancer into his body. For that reason, the procedure might not be recommended for patients who survived childhood leukemia, lymphoma, or testicular cancer. Instead, it would be more appropriate for people who had solid tumors that didn’t spread to the testicles, or people who had beta thalassemia or sickle cell anemia and who had to go through “gonadotoxic” treatments in preparation for a bone marrow transplant.

In an editorial also published Thursday in Science, Nina Neuhaus and Stefan Schlatt of the Center of Reproductive Medicine and Andrology in Germany wrote that “the procedures reported in the study … bring this experimental approach close to clinical application” and called for clinical trials.

Taymans, of the NIH, said she first wanted to see the results of a monkey study in which the animals were not castrated. After all, people participating in a clinical trial will still have some testicular tissue, even if they can no longer produce sperm following treatments.

“They need to show that the animals don’t have to be castrated first, that if there’s any remaining testicular tissue that it’s not going to interfere with the graft,” Taymans said.

Orwig agreed that replicating the study in monkeys that are not castrated “will be critical.” But he said he feels like he owes it to the children whose tissue he and his colleagues have already collected to try to push the research into clinical trials at the same time.