In 2001, Annie Dauer—a 28-year-old woman with no children—was diagnosed with stage 4 Non-Hodgkin's lymphoma. Her doctor told her she needed aggressive chemotherapy within the week. Annie knew that the radiation could damage her eggs, and jeopardize her future fertility—but egg or embryo freezing required weeks of preparatory hormone shots. That was time she didn’t have.
Recognizing her desperation, Dauer’s doctor referred her to Kutluk Oktay, a professor of obstetrics and gynecology at the Yale School of Medicine and one of the preeminent experts of a new process called ovary freezing.
Oktay walked her through the steps: He would remove one of her ovaries, slice pieces from the top tissue layers, and freeze the slices in liquid nitrogen. If the chemotherapy worked, and she remained cancer-free for two years, he would re-implant the tissue and hope that the eggs would begin maturing normally.
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No one had ever gotten pregnant post-transplant before, and the procedure had only been attempted a few times in humans—but Dauer was desperate. She barely looked at the consent forms. “I did not pay any attention,” she told RadioLab’s Molly Webster, as part of Friday’s episode "Fronads" of “Gonads,” the limited series exploring human reproduction. “I just wanted a chance.”
For years, egg and embryo freezing have been heralded as the gold standard in fertility preservation technology, allowing women to delay childbirth until they’re ready—instead of the moment sperm meets egg.
But ovary freezing is poised to challenge their dominance, used most often to preserve the fertility of cancer patients who don’t have time to freeze their eggs before undergoing chemotherapy. It could even save the ovaries of young cancer patients who can’t yet produce mature eggs.
"Fronads" follows Dauer, one of the first patients to undergo the groundbreaking procedure. And miraculously, it worked. Dauer, who had been once been told that she had a one in five million chance of ever becoming pregnant, had three children within six years of reimplantation. The procedure was so successful that her husband, Greg, had a vasectomy.
Now, almost 20 years after Oktay’s pioneering experiment, the science behind ovary freezing has progressed dramatically. According to a meta-analysis Oktay published in Reproductive Sciences, the procedure has nearly a 40 percent global success rate. The study, which covered cases between 1999 and 2016, reported 84 births and eight ongoing pregnancies from 309 cases—but two years later, Oktay estimates that the number of births is actually closer to 120.
And even if it doesn’t restore fertility, ovary freezing provides patients with a way to restore their hormone balance; Oktay’s meta-analysis found that natural hormonal function resumed in almost two-thirds of cases, which can delay the ugly, painful side effects of menopause like arthritis and osteoporosis.
One of the biggest differences between egg freezing and ovary freezing, preparation time, was the crux of Annie’s case. She couldn’t have frozen her eggs, RadioLab’s Webster notes, because the procedure requires weeks-long hormone treatments to induce what RadioLab likened to “20 periods at the same time.” Ovary freezing, on the other hand, is a simple 45-minute outpatient procedure that requires no hormonal preparation.
But there are other important differences. With egg freezing, once a patient has finished their hormone treatments, a doctor will retrieve the eggs with a needle inserted into their vagina and gather about 10-20 mature eggs. Once the eggs are thawed any number of years later, they are ready to be fertilized in-vitro and placed back into the uterus as embryos. Embryo freezing requires similar hormonal treatments—the key difference is that the eggs are fertilized in-vitro before they’re frozen, not after.
At the Center for Human Reproduction in Manhattan, one cycle of egg removal, freezing, fertilization, and reimplantation costs approximately $17,000, plus a $1,000 per year storage fee, a representative told The Daily Beast. Embryo freezing costs about $4,000 more.
With ovary freezing, on the other hand, “you have the source,” Oktay told The Daily Beast, which means that a doctor can gather hundreds or even thousands of eggs in various stages of maturity with one surgical removal. At the Center for Human Reproduction—which has banked ovarian tissue, but never re-implanted it—the process would cost approximately $18,000, in addition to the yearly storage fee.
Although most of the eggs will not be ready for fertilization immediately after re-implantation, immature eggs on the once-frozen tissue will continue to mature as if nothing had happened.
As a result, ovary freezing provides an opportunity for pre-pubescent cancer patients—who cannot yet produce the mature eggs required for egg or embryo freezing—to preserve and regain their fertility after chemotherapy.
“In many ways, it’s a superior approach [to egg and embryo freezing],” Oktay said. “It provides years of egg supply and hormonal function and natural fertility, which egg or embryo freezing cannot do.”
“Sometimes, women have had two or even three children from one graft, which is amazing,” Richard Anderson, a professor of Clinical Reproductive Science at the University of Edinburgh who conducted another meta-analysis of ovary freezing cases in Human Reproduction Open, told The Daily Beast.
The procedure is simple. Through laparoscopy, or surgical incisions in the abdominal wall, a doctor removes all or part of an ovary. They then slice off tiny pieces—often measuring a quarter inch by a quarter inch inch by ¼-inch, Oktay said—mixing them with antifreeze to prevent tissue damage, slowly cooling the pieces to -112 degrees Fahrenheit.
When the slices have been cooled to that temperature, they can be placed in liquid nitrogen.
Once the tissue is in the liquid nitrogen, “there’s no sell-by date,” Anderson said. The cells can last indefinitely, until the patient is cancer-free and ready for reimplantation.
To try to ensure that none of the cells marked for reimplementation are cancerous, Anderson adds, a doctor will biopsy an adjacent piece of frozen tissue to search for signs of cancer. Although it’s impossible to biopsy the exact pieces of tissue that will be reimplanted, Anderson notes that the risk of cancerous cells re-entering the body “seems very small” for most types of cancer.
When Annie had her tissue reimplanted, Oktay put the tissue near her stomach.
The idea was to allow the eggs to mature there, and then to remove them and fertilize in-vitro. But then, the nearly unimaginable happened: before any eggs had been removed from her stomach, Dauer got pregnant. Oktay still doesn’t know how that happened—but he hypothesizes that her brain might have recognized the hormones in the new tissue, and sent a signal to the other, untouched ovary to mature any remaining eggs it had.
Now, unless a patient has scarring or other medical complications, Oktay says that best practice is to re-transplant the tissue “as close to the natural position as possible.” Once the tissue is reattached, it must connect to the existing tissue and form new blood vessels in a process called revascularization. This, both Oktay and Anderson note, is one of the least efficient parts of the procedure—Anderson estimates that “more than half” of the re-implanted eggs die for lack of blood as connectivity is reestablished. Oktay hopes that surgical improvements, especially those in robot-assisted surgery, will reduce this loss in the years to come.
But even as is, Oktay says, ovary freezing is moving forward scientifically. The procedure is no longer considered “experimental” in Israel, Australia, and Germany, and Oktay believes that the American Society of Reproductive Medicine, which controls the procedure’s designation, will move to follow suit within the next six months. If this happens, Oktay predicts, ovary freezing could potentially be covered by insurance, and could spread to smaller practices. He hopes that the procedure will soon reach the popularity of egg and embryo freezing, so that more female cancer patients can have a chance at fertility.
He also notes that the treatment isn’t just for cancer patients; it can help anyone who wants to ensure fertility, like trans men hoping to retain the chance to have children, or even just benefit from an increased influx of hormones that will delay the effects of menopause.
Oktay is amazed with the progress he’s seen in the last two decades. “About 15 years ago, the procedure was completely theoretical,” he said. “And now we’re talking about a procedure that has a consistent success rate, and gives hope to a lot of cancer survivors.”
Audio courtesy of Radiolab. Other episodes of "Gonads" are available here.
