Michelle Foley, Illustrations Editor
As a women’s health specialist at the School of Medicine, Kutluk Oktay regularly treats patients experiencing menopause symptoms. Now, he’s hoping that he might be able to halt the biological process in its tracks.
The reproductive endocrinologist and ovarian biologist recently developed a mathematical model that can predict outcomes for delayed menopause using a technique called ovarian tissue cryopreservation, in which tissue from the ovaries is extracted, frozen and transplanted years later into the body.
Published in the American Journal of Obstetrics & Gynecology, Oktay’s model predicts that harvesting tissue from the ovaries at earlier adult ages and using better transplant techniques can delay menopause and extend the timeframe in which women might be able to have children. He said he sees a future where people could use the process, which freezes tens of thousands of eggs from ovarian tissue, to delay menopause for several decades.
Done effectively, Oktay believes, it might even avert menopause altogether.
“He’s extending it from just trying to preserve somebody’s ability to have a child to potentially preserve somebody’s reproductive lifespan in a way that is not just about preserving childbearing, but preserving all of the hormones … that prevent a lot of medical problems,” said Hugh Taylor, the chief of obstetrics and gynecology at Yale New Haven Hospital, of Oktay. “It is very exciting work he’s doing, and we’re lucky to have the world’s leader here.”
Oktay is known for spearheading transformative advancements in the field of women’s reproductive health. He performed the world’s first ovarian transplantation with frozen — or cryopreserved — tissue in 1999, which was later published in the New England Journal of Medicine in 2000.
The procedure was considered experimental until 2019 when the American Society of Reproductive Medicine announced in a committee opinion that ovarian tissue cryopreservation could be considered an established medical procedure.
Menopause is a natural biological process that usually occurs around the age of 50. It signals the end of monthly menstruation due to loss of ovarian follicular function: the ovaries stop releasing eggs for fertilization.
According to Mary Jane Minkin, a practicing gynecologist at the School of Medicine with a focus on menopause, the disruption of normal fertilization cycles can make it challenging for people to have children.
“Once you go from 40, say 42, 43, you get a pretty significant decline [in reproduction],” Minkin said. “And once we get beyond 43 or so, it’s reasonably tough to have a kid. It doesn’t mean it doesn’t happen, but your chances aren’t fabulous.”
According to the National Institutes of Health, menopause symptoms including heat flashes, mood changes, weight changes, trouble sleeping or depression. Some people experiencing menopause consult their doctors about lifestyle changes, while others are prescribed medications to alleviate symptoms.
By surgically removing and freezing the parts of the ovary that contain immature egg cells, Oktay’s cryopreservation process might be able to postpone that process. Years after freezing the ovarian tissue, doctors could thaw out those tissue samples and transplant them back into the body, returning a pool of healthy, unused egg cells.
For women receiving treatment for cancer or other diseases that affect the ovaries, cryopreservation can be a game-changer. Many common cancer therapies can disrupt a patient’s fertility and hormone production, preventing them from having children in years to come.
Through cryopreservation, doctors can remove and freeze a healthy portion of a patient’s ovaries before treatment starts. Years later, after chemotherapy, surgery, or radiation therapy, that tissue can be transplanted back into the body — theoretically making pregnancy possible once again.
Re-inserting the ovarian tissue also allows the body to restart the natural production of hormones like estrogen, effectively delaying the onset of menopause and the physical symptoms associated with it. According to Oktay, women who experience late menopause face lower rates of depression, osteoporosis, cardiovascular disease and Alzheimer’s disease.
For patients who undergo Oktay’s cryopreservation procedure, the process typically takes an hour. Cuts are made through the bikini line and the belly button, and doctors remove the outer layer of one ovary. The patient goes home the same day, Oktay said.
Then, the tissue is put through a freezing process that takes three to five hours before being stored in liquid nitrogen at a long-term tissue storage facility. The tissue can last for decades if needed, Oktay added.
Compared to other methods of fertility preservation, like egg freezing, ovarian cryopreservation has the advantage of scale.
During traditional fertility treatments, a combination of medications and procedures designed to stimulate the ovaries might yield approximately 10 or 15 eggs that are subsequently frozen, Oktay said. When those frozen eggs are retrieved, Oktay estimated, about 80-90 percent might survive; doctors might be able to fertilize three or four embryos, which may grow into one or two babies.
For Oktay, though, ovarian freezing could be a better solution. With ovarian tissue freezing, doctors can freeze and harvest portions of the outer ovary itself, which Oktay calculates could contain tens of thousands of eggs. By freezing and re-transplanting pieces of the ovary in the future, the process could scale up the number of potential, unfertilized eggs that women might have in reserve.
Like egg freezing, ovarian freezing can improve fertility, allowing people to become pregnant and have children at older ages. As of 2019, scientists have documented more than 130 live births after transplanting of cryopreserved ovarian tissue, and almost all patients recovered their ovarian function after the implantation procedure.
By delaying menopause, freezing the outer ovary could also help maintain natural hormonal function for longer and alleviate the symptoms associated with hormone changes during menopause.
Sometimes, more ovary transplants, Oktay said, could mean delaying menopause even longer.
“If that [ovary tissue] starts running out, you can come back and put more tissues and extend [fertility for] 20 years,” Oktay said. “So egg freezing is kind of a one-shot deal just for fertility. Ovarian freezing is to restore natural hormone production and, if desired, fertility for a protracted period of time.”
A model to end menopause
Using data from previous research that counted a woman’s egg reserves at different ages, Oktay designed his new mathematical model to predict how long — and how effectively — the surgery could delay menopause.
Based on the model, the researchers also developed an interactive online tool to calculate menopause delay, based on patient age, the amount of the outer ovary removed, and the number of ovarian follicles — the fluid-filled pockets in the ovary that release monthly egg cells during ovulation — that survive the freezing process.
Their research found that the amount of tissue removed during the procedure is tied to the amount of time menopause can be delayed. The more tissue a surgeon removes, the longer the procedure can delay menopause. However, if doctors remove too much tissue from the ovaries, it may result in early menopause.
Age was also a key factor, Oktay said. If patients undergo the ovarian freezing procedure before they turn forty, they typically get at least five years of menopause delay.
By transplanting back portions of the harvested, frozen ovary tissue over several procedures instead of all at once, menopause can be delayed even longer, the model indicated. Returning a third of the outer portion of the ovary at a time over three procedures delayed menopause longer than returning all the tissue through one surgery.
If younger patients undergo the procedure in combination with a split-up retransplantation process, menopause might not even be a consideration, Oktay said.
“If done before 30, or closer to mid-20s, and if you end up transplanting [the ovarian tissue back] in fractions, you may get 50 to 60 years in delay, which means the elimination of menopause,” he told the News.
However, for Lubna Pal, the director of the menopause program at the Yale School of Medicine, that idea seems unrealistic in practice.
“In my mind, having your ovaries removed in your 20s so that you’re planning to achieve a pregnancy in your 60s doesn’t make sense to me,” Pal said.
‘Not just a mere academic exercise’
For Oktay, developing the model is about more than just mathematics. As a practicing reproductive endocrinologist, he sees patients every day facing health challenges related to menopause.
“It’s also clinical for me. I’ve seen how severely my patients suffer from menopause complications,” he said.
“This is not just a mere academic exercise,” Oktay said. “There are 26 years on average a woman spends in menopause, which for many women is associated with significant health complications … So far, nobody’s addressed menopause directly. I foresee that in the next four to five years, this is going to become more mainstream. You could have it even sooner.”
However, Minkin is more skeptical about the imminence of widespread cryopreservation. Without widespread insurance coverage, the procedure is expensive. Insurance companies usually don’t pay for elective procedures involving cryopreservation, Oktay said, but situations are sometimes decided on a case-by-case basis.
Oktay, however, insisted that insurance companies would recognize cryopreservation as a preventive treatment to minimize the rising cost of menopause symptoms and treatments. A 2023 study by the Mayo Clinic found that missed workdays because of menopause symptoms cost the U.S. economy $1.8 billion in the previous year.
For now, though, the often uninsured cost of the procedure remains a sticking point. As is the procedure’s invasiveness in women’s bodies.
“I just don’t see it happening,” Minkin said. “Right now,for a fairly small amount of money, I can give people estrogen and progesterone, which are the hormones that the ovaries make primarily, for a heck of a lot less money than it’s going to take to do these procedures.”
The biological problem with ovarian cryopreservation, though, is an increased risk of cancer. According to Pal, extending exposure to natural reproductive hormones for longer time periods is linked with an increased risk of cancers, including breast and endometrial cancer. It’s a process that happens during chronological aging, she said.
Since transplanting the frozen ovary tissue back into the body can restart natural hormone production for women, Pal is wary that the technique may have unintended consequences.
“What would it mean for that female?” Pal said. “It may be good for her bones, questionably better for cardiovascular health, but what about breast cancer risk? What about endometrial cancer risk?”
But that increased risk of cancer, Oktay pointed out, is also true for women undergoing more conventional menopause treatments like hormone replacement, in which patients take medication to replace declining estrogen levels in the body. Eleven percent of women also naturally experience late menopause after the age of 55, placing them at a higher risk for cancer, regardless of therapy.
In his experience, the breast cancers linked to hormone replacement tend to be more “aggressive” than those associated with naturally late menopause, Oktay said. In the case of cryopreservation, which prompts the body to restart its own hormone production, Oktay believes the risks may be worthwhile.
“If you’re going to take hormone replacement versus having late menopause, you’d rather have late menopause,” Oktay told the News. “Women who take birth control pills also have increased breast cancer risk. But we still take them because the benefits outweigh the risks.”
‘Thoughtfulness, pause and responsibility’
Laura Bothwell, an ethicist and historian of public health at the School of Public Health, also pointed out “myriad” ethical dilemmas that the procedure poses. By delaying menopause symptoms, ovarian tissue cryopreservation could reduce premature morbidity and prolong periods of healthy living — outcomes that Bothwell considers to be “ethically valuable.”
But she highlighted concerns that the procedure could shift the idea of menopause: altering it from a natural biological process to a medical problem that needs a fix.
“Interventions that fall outside the realm of healing maladies and instead pathologize what it means to be human and the normal human life cycle become ethically suspect,” Bothwell said.
As a result, some experts said they believe that Oktay’s work, while promising, needs a more careful look.
“It’s tremendously interesting, intriguing, and exciting that people are looking into this,” Pal said. “But the translation from science to clinical application requires tremendous thoughtfulness, pause and responsibility.”
“This whole extending menopause is a brave new world,” Taylor added. “I think it has tremendous possibilities, but again, has to be carefully studied.”
Approximately 1.3 million women enter menopause per year in the United States, according to the NIH.