Tip of the Iceberg? Advances in Fertility Preservation and Restoration

At ENDO 2021, the first time the Endocrine Society’s annual conference will be presented virtually, attendees can tune into the live session “Ice Ice Baby: Fertility Preservation and Restoration” to learn about the scientific advances that are enabling young cancer survivors to have genetic children. Endocrine News talks to Mary B. Zelinski, PhD, and Ina Dobrinski, DrMedVet, MVSc, PhD, about the cutting-edge research they will be discussing.

Conditions like cancer that strike at an early age can leave survivors with a diminished reproductive capacity. The research strides being made — in cryopreservation, tissue transplantation, “organoids,” and more — will be described at ENDO 2021 in a virtual session entitled “Ice Ice Baby: Fertility Preservation and Restoration.” The session will be held on March 20 from 12:30 to 2:00 p.m. EST.

Mary B. Zelinski, PhD, a professor in the Division of Reproductive and Developmental Sciences at the Oregon National Primate Research Center and in the Department of Obstetrics and Gynecology at Oregon Health and Science University in Beaverton, will speak on “Preserving Ovarian Function.”

“There are certain treatments that patients go through or conditions they are born with that cause damage to their reproductive systems,” Zelinski says. “For example, cancer treatments like chemotherapy and radiotherapy can be very toxic to the eggs in the ovary.”

The need to respond to these effects is growing because the survival rate of children with cancer is above 80%, and perhaps 30% of childhood cancer survivors will be infertile as adults, according to Ina Dobrinski, DrMedVet, MVSc, PhD, professor of reproductive biology at the University of Calgary in Alberta, Canada. Dobrinski will speak at the symposium on “Approaches to Preservation of Male Fertility.”

Cryopreservation

The freezing of eggs, sperm, and embryos is a long-established technology. But that kind of cryopreservation can only help people who have reached an age of maturity to supply something to freeze. Both speakers will talk about techniques that move beyond those currently in use, such as taking tissue from a patient, perhaps culturing and cryo-preserving it, and transplanting it back into the patient much later.

“There are over 130 births in the world from cryopreserved ovarian tissue that has been transplanted back to the patient, with oocytes then retrieved from that tissue. They can in some cases be fertilized in vivo, depending on where you transplant the tissue back. Or they can be extracted from a follicle that grew from that cryopreserved transplanted tissue, and then in vitro fertilization can be used to get an embryo. Then the embryo is put back into the patient’s uterus for a pregnancy.”  – Mary B. Zelinski, PhD, a professor, Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center; Department of Obstetrics and Gynecology, Oregon Health and Science University, Beaverton, Ore.

Zelinski tells Endocrine News that researchers have successfully used cryopreservation to store ovarian tissue “in order to have it function again. There are over 130 births in the world from cryopreserved ovarian tissue that has been transplanted back to the patient, with oocytes then retrieved from that tissue. They can in some cases be  fertilized in vivo, depending on where you transplant the tissue back. Or they can be extracted from a follicle that grew from that cryopreserved transplanted tissue, and then in vitro fertilization can be used to get an embryo. Then the embryo is put back into the patient’s uterus for a pregnancy.”

Slow Freezing vs. Vitrification

Almost all of these births have occurred in Europe, where researchers have made many advances using the process of slow freezing to preserve more complex tissues. However, slow freezing requires expensive equipment, so it has been generally replaced for cryopreserving eggs and embryos in fertility clinics in the U.S. by the easier and less expensive process of vitrification. In vitrification, the cooling is done extremely quickly, so fast as to avoid the formation of ice crystals, which are deadly to the frozen tissue or eggs.

Vitrification works on the few cells of eggs or embryos, but preserving tissue is more complicated. “It is difficult because you are trying to preserve the function of many cells within this piece of tissue,” Zelinski says. “Vitrification of ovarian tissue has been done by one group in in the U.S. where transplantation to an ovarian site has resulted in two births. A group in Japan has actually transplanted vitrified ovarian tissue to nonovarian sites and then extracted the oocyte to do IVF and get an embryo, and there are as many as three births reported.”

“My research group has been working for the past six or seven years to develop a protocol for being able to vitrify ovarian tissue in the non-human primate model,” Zelinski says. “Many times if a patient is getting both chemotherapy and radiotherapy, the damage to any remaining ovary that a physician might leave in is pretty extensive. There is not a good vascular bed there to re-transplant ovarian tissue to, so the ovarian site is not going to be available. So we are looking at nonovarian sites in our rhesus monkey model. For example, can you just put these tissues under the skin or can you put them in a retro-peritoneal site? Are there easy places to be able to access any oocyte that would be inside of a follicle growing after you transplant the tissue again?”

Their goal is to find non-ovarian sites where transplanted “tissue will function pretty much every time you transplant it back. These are auto-transplants. The patient is getting their own tissue, which won’t be rejected,” Zelinski says.

Auto-Transplants in Males

Dobrinski and colleagues recently published an article in Science reporting on a similar procedure in males. Just as treatments can result in infertility in girls and women, “chemotherapy and radiation treatments for cancer and other conditions can deplete spermatogonial stem cells in the testis, resulting in permanent infertility,” that study notes. “Testicular tissue cryopreservation is an experimental method to preserve the fertility of prepubertal patients before they initiate gonadotoxic therapies for cancer and other conditions.”

The researchers removed the testes from prepubertal rhesus macaques and cut them into small pieces. They examined the tissues to confirm that they were immature at the time of castration. Some were cryopreserved and others used fresh. The researchers surgically inserted the tissues under the back skin and under the scrotal skin of the same individuals from which they came.

“[O]rganoids … are these tiny pieces of tissue that you can generate in vitro that resemble the organ they came from. They can be generated from cells that you collect, such as primary cells or stem cells. It is a bit like an android, which is not really a person, but it looks like one. An organoid is not really an organ, but it looks and works like one.” – Ina Dobrinski, DrMedVet, MVSc, PhD, professor, reproductive biology, University of Calgary, Alberta, Canada

The researchers report: “During the 8- to 12-month observation period, grafts grew and produced testosterone. Complete spermatogenesis was confirmed in all grafts at the time of recovery. Graft-derived sperm were competent to fertilize rhesus oocytes, leading to preimplantation embryo development, pregnancy, and the birth of a healthy female baby.”

In addition to describing this work with testicular tissue, Dobrinski says she will describe work with “organoids, which are these tiny pieces of tissue that you can generate in vitro that resemble the organ they came from. They can be generated from cells that you collect, such as primary cells or stem cells. It is a bit like an android, which is not really a person but it looks like one. An organoid is not really an organ, but it looks and works like one.”

And in that futuristic realm, Zelinski will describe “what is being called in the popular press the artificial ovary but people in the field prefer to call a bio-engineered ovary” comprised of a 3D-printed scaffold with isolated ovarian follicles.

In just these two presentations among others, this symposium will be taking participants from descriptions of current applications to glimpses of the future.

  • Seaborg is a freelance writer based in Charlottesville, Va. In the January issue, he wrote about reevaluating combination therapy for hypothyroid patients.

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