Stem cells reverse chemo-induced infertility in monkeys: Next step humans?

TORONTO – Scientists have long been searching for a way to preserve fertility in young boys who undergo cancer treatments and may be unable to father a child later in life. That’s because chemotherapy and radiation can destroy the stem cells in the testes that give rise to sperm with the onset of puberty.

Now researchers, using macaque monkeys, have shown that small samples of testicular tissue that have been frozen can be thawed and re-implanted following chemotherapy to begin producing sperm.

The success in monkeys raises hope that the technique might one day be safely used in human males left infertile by life-saving treatment for cancer, say researchers, whose work is described in the November issue of the journal Cell Stem Cell, published Thursday.

“This demonstrates in an animal model that in fact it’s feasible,” said principal researcher Kyle Orwig, director of the fertility preservation program at the University of Pittsburgh.

Not only were most of the animals able to produce sperm cells, but sperm from one macaque was able to fertilize the eggs from female macaques, he added.

The monkey eggs were fertilized in the lab and allowed to grow through cell division only to the point in which they would have been able to implant in the female animal’s uterine wall. There were no live macaque offspring produced.

Not all cancer therapy leads to permanent infertility – that depends on the type and dose of chemo drugs used, as well as the areas of the body targeted by radiation.

Still, uncertainty about one’s ability to have a family in the future is no trivial matter for childhood cancer patients, most of whom must contend with a range of adverse health effects arising from treatment, often for the rest of their lives.

“Cancer patients report that their fertility status has a major impact on their quality of life, both in terms of their psychological well-being, but also their ability to develop relationships,” Orwig said.

In fact, there are several clinics around the world that have preserved testicular tissue from pre-pubescent boys subsequently treated for cancer, “in anticipation that (their) stem cells can be used in the future to achieve a pregnancy,” he said.

“We’re all gambling that things that are in the research pipeline will be translatable to the clinic … I think we’ve demonstrated that it’s feasible and I think this is an important step towards translating it to the clinic.”

However, more research is needed before the experimental technique can be tried in humans, Orwig stressed.

For one thing, there is disagreement in the field as to when the stem cell-bearing tissue should be transplanted back into a testis.

“Some people think that you should put the cells in as soon as possible before the testis deteriorates to the point where it can’t support sperm production,” he said, referring to completion of treatment and a cancer-free status.

“Some people think you should wait all the way until these boys grow up and are ready to have children, which could be 20 years in the future.”

Orwig believes that patients whose testicular tissue has been biopsied for cryopreservation will ultimately make that decision themselves.

But before researchers even attempt the procedure in humans, there is a risk they must deal with: the potential they could re-seed cancer cells into a testicle along with the stem cell transplant.

Leukemia, for instance, is a cancer of the blood, and that blood circulates through the tissues of the body, including the testes. Testicular tissue removed before treatment could potentially contain cancer cells, Orwig explained.

“And so if you take that tissue out before treatment and then you plan to transplant it back in later, there’s a chance you could re-introduce a cancer,” he said.

“That is certainly a risk. This is why there is more work to do in pre-clinical studies before it’s time to translate to the clinic, because that would be the worst outcome, to re-introduce a cancer into a survivor. That would be terrible.”

In an accompanying commentary, French researchers say the ability of transplanted stem cells to produce functional sperm in a non-human primate is a significant breakthrough.

“The work … constitutes a milestone in the field of reproduction and generates hope for restoring fertility in survivors of childhood cancer,” write Virginie Firlej, Pierre Fouchet and Virginie Barraud-Lange of the National Institute of Health and Medical Research in Paris.

However, they cautioned that much work still needs to be done to make sure the technique is safe before it is even tested in human males, given the potential for re-introducing cancer in certain cases.

Orwig pointed out that the procedure would not be an option for post-pubescent teens or men who have been treated for cancer but did not store a semen sample prior to chemotherapy and radiation.

“Our study won’t help those men, because they probably don’t have stem cells,” he said.

“We know that chemotherapy and radiation for their cancer or other conditions can cause permanent infertility. And for that reason, a man who desires to have a family after their treatment, they should freeze a sperm sample.

“And there are a variety of ways those sperm can be used in the future to achieve a pregnancy,” including in-vitro fertilization.