Testicular Graft Success Raises Hope for Boys With Cancer

Kristin Jenkins

March 25, 2019

A research breakthrough has raised hopes that prepubertal boys with cancer who undergo treatment that affects their fertility will be able father their own biological children.

Grady at her 2-week checkup.

The breakthrough is Grady, a rhesus macaque.

She is the first-ever healthy live birth in a nonhuman primate using sperm produced from autologous transplants of frozen prepubertal testicular tissue, say researchers.

The monkey is living proof that the technique meets the gold standard for reproductive technology, according to Kyle Orwig, PhD, professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh School of Medicine in Pennsylvania, and colleagues.

Grady will be 1 year old on April 16, and her name is an amalgamation of "graft-derived" and "baby."

In a statement, Orwig called Grady's birth "an important step toward offering young cancer patients around the world a chance at having a family in the future. Having produced a live-born and healthy baby, we feel that this is a technology that is ready to be tested in the clinic."

"Future studies are needed to confirm that graft development proceeds in a similar fashion in the scrotum or under the skin of individuals with intact testes," the authors write in a report published online March 22 in Science.

Orwig told Medscape Medical News that testicular tissue grafting could be ready for clinical testing in the next 2 to 5 years.

"Clinics around the world, including ours, have been storing testicular tissues for patients for about 10 years," he said. "We believe this study provides important safety and feasibility data that will help to support translation of this technology to the fertility clinic."

Other researchers have demonstrated that sperm can be produced from autologous transplants of frozen prepubertal testicular tissue, said first author Adetunji Fayomi, PhD, a postdoctoral scholar at the University of Pittsburgh, in a statement.

The fact that Orwig's team used a different cryopreservation protocol and grafted larger pieces of testicular tissue may have contributed to their success in achieving a healthy live birth, the researchers say.

"With Grady's birth, we were able to show proof-of-principle that we can cryopreserve prepubertal testicular tissue, and later use it to restore fertility as an adult," said Fayomi, who worked in Orwig's lab as a graduate student.

Not Suitable for All Cancers

The investigators caution that survivors of childhood leukemia and lymphoma, as well as survivors of testicular cancer, may not be candidates for autologous grafting. In these patients, testicular tissues collected before cancer treatment could harbor malignant cells, they point out.

Still, autologous testicular tissue grafting may be appropriate for patients receiving bone marrow transplants for nonmalignant conditions such as b-thalassemia and sickle cell anemia, the researchers say. It may also be an option in patients with solid tumors — including sarcomas and neuroblastomas — that do not metastasize to the testes.

More than 60% of young patients with cryopreserved testicular tissues at the Fertility Preservation Program at the University of Pittsburgh Medical Center/Magee-Womens Research Institute & Foundation fall into these two categories, they note.

Since receiving regulatory approval in 2010, the program has cryopreserved testicular tissue for 206 boys and ovarian tissue for 41 girls and women with cancer, Orwig told Medscape Medical News.

"Some of those patients have emerged as survivors of their initial disease and may be ready to have tissues implanted back into their bodies," he explained. "Based on our results, I would probably implant tissues back into the scrotum, which seems like a good place to produce sperm."

Ovarian tissue transplantation is already being used to offer reproductive options to prepubertal girls with cancer and has produced more than 150 children worldwide, he noted. "Usually the tissue is placed in the abdomen, on the ovary and frequently eggs are ovulated into the uterus in the normal way."

The program is also approved for cryopreservation of testicular tissues from transgender individuals who are either on puberty blockers or about to go on puberty blockers. The researchers are working on a similar protocol to freeze ovarian tissues for transgender individuals, Orwig said.

Study Details

For the study, the researchers removed one testis each from five prepubescent rhesus macaques and cryopreserved 9 to 20 mm3 pieces of immature testicular tissue. Five to 7 months later, the remaining testis was removed from each animal and cut into pieces with some reserved for fresh tissue grafting.

Three fresh and three cryopreserved grafts were placed under the back skin of each animal and one fresh and one cryopreserved graft was placed under the scrotal skin. Four fresh or frozen testicular tissue fragments were also sutured to a subcutaneous skin flap at each site.

After the animals entered puberty 8 to 12 months later, the circulating testosterone levels increased in all monkeys and remained elevated above baseline in four of five animals.

The researchers also observed normal — rather than castrate — levels of circulating follicle-stimulating hormone for pubertal and adult rhesus macaques. This indicated a functional negative-feedback loop from the grafted testicular tissue to the hypothalamus and pituitary, they say.

Removal of the grafts revealed large quantities of viable sperm.

Collaborators at the Oregon National Primate Research Center at the Oregon Health and Science University in Beaverton used the sperm to create 11 viable embryos (10 fresh and one frozen). These were then transferred to six recipient females.

A pregnancy from a fresh blastocyst transfer was confirmed by ultrasound in one recipient female on December 15, 2017. Grady was born by caesarian section on April 16, 2018. Thirty minutes after delivery, Grady had an Apgar score of 7.

Counseling About Fertility Preservation

Orwig emphasized that counseling patients about fertility preservation in the compressed timeframe between diagnosis and the beginning of treatment can be very challenging.

For this reason, the fertility preservation program is made up of a multidisciplinary team of oncologists, reproductive specialists, researchers, medical support staff and others, he pointed out.

"Our mission is to make sure all patients and their families are informed about the effects of their treatments on infertility and about options to preserve fertility," Orwig told Medscape Medical News.

"For patients who choose to pursue fertility preservation, we work with them and their doctors to ensure that fertility preservation occurs as quickly as possible to prevent delay in treatment for their disease."

This study was funded by the National Institutes of Health and the Magee-Womens Research Institute & Foundation. Orwitz and co-authors disclosed no relevant financial relationships.

Science. Published online on March 22, 2019. Abstract

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