Hot flashes, insomnia and mood swings are among the difficult symptoms that affect some people experiencing menopause. While symptoms are typically temporary and treatable, menopause can also increase the risk of some chronic illnesses, such as osteoporosis and heart disease. Now a handful of researchers and companies are making a bold claim: collecting and freezing ovarian tissue when one is young and then transplanting it back into the body years later could restore hormone production—putting the onset of menopause on hold, potentially for many years.
The fact that there are few treatment options for menopause had led some clinicians to propose the unconventional intervention—a technique typically used to restore fertility in people who undergo chemotherapy or who have entered menopause prematurely. A recent modeling study in the American Journal of Obstetrics and Gynecology estimates that reimplanting bits of one’s own frozen ovaries every few years could maintain the cyclical hormonal fluctuations that cause menstruation. This could delay normal onset of menopause potentially for several decades if started in people younger than age 40.
Outside experts have raised concerns about using this technique to delay menopause in healthy individuals and question whether that goal is necessary in the first place. They say that the potential to reduce the risk of health conditions is oversold. Scientists have also said that existing treatments for menopause symptoms are simpler and safer than this elective procedure, which would require surgically extracting tissue from people in their 20s or 30s, freezing and storing the tissue for decades, and performing multiple surgeries to implant tissue with the goal of maintaining premenopausal hormonal function.
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Still, proponents of the technique say there is a need for new treatment options and that people are already interested. Kutluk Oktay, a reproductive biologist at Yale University and senior author of the nonclinical modeling study, says that about 20 “carefully screened” individuals have opted to store ovarian tissue at his clinic in anticipation of potentially delaying menopause. Those people qualified for select health reasons, including a family history of early menopause and a high risk for menopause-related illnesses. Others who initially banked the tissue for fertility reasons are leaving the option open to use the tissue for menopause delay. “As more proof comes in, it could be that we’re doing it for these general benefits for everybody," Oktay says. “But initially, I think we’re being more selective.”
In 2019 more than 100 women from multiple countries seeking menopause and fertility treatments were added to a waiting list to preserve their ovarian tissue for future transplantation, offered by then newly launched company ProFaM Health, based in Ireland. Regulatory delays as well as the pandemic have since stalled the company from enrolling people. “This is very new; I understand that,” says Christiani Amorim, ProFaM Health’s chief scientific officer and a fertility researcher at the Catholic University of Louvain in Belgium. Amorim, who has worked both animal and human ovarian cryopreservation, started to consider the procedure’s benefits for humans after witnessing her mother experience severe menopausal symptoms.
Maintaining premenopausal hormonal production—the basis of the ovarian tissue transplant technique—could potentially avert some health issues. The procedure relies on primordial follicles for producing those hormones. Female babies are born with a fixed number of immature eggs in the primordial follicles in their ovaries. The ovaries usually eject one egg for potential fertilization each month—using, in a lifetime, only about 500 eggs out of a million or so available. “If you do the math, 99.9 percent are wasted,” Oktay says. “They’re reserve.” The body produces estrogen when a primordial follicle begins to mature an egg, and then it produces progesterone after ovulation occurs. Whether or not follicles release an egg, their number declines over time as they are used or naturally degenerate with age. People reach menopause when the body goes a full year without a period—typically around age 50. By the time of menopause, very few follicles remain, and hormone production has plummeted.
When someone is younger than age 40, those follicles can be extracted and later transplanted back into the body where they can release mature eggs that could be fertilized—and hormones that could prevent menopausal symptoms. Oktay’s research suggests that beyond age 40, the procedure is unlikely to prevent the onset of menopause.
The process involves a keyhole surgery through the belly button to strip off part of an ovary’s glistening, pearl-like “skin”—a millimeter-thick cortex containing the primordial follicles. This is “like peeling an orange,” Oktay explains. The tissue is then sliced into thin slivers, bathed in antifreeze substances in test tubes and preserved in liquid nitrogen, where it awaits transplantation back into the body years later. Oktay says there is no practical limit for how long the tissue can be preserved and still remain effective. The process is ultimately the same for those seeking to restore fertility as it would be for those seeking to delay menopause. To prevent the risk of pregnancy in the latter group, however, the tissue could be grafted to the forearm or abdominal wall instead of in the pelvis, where it could still release hormones into the bloodstream but avoid releasing an egg that could encounter sperm and become fertilized. The procedure would also prolong menstruation, which few people anticipating menopause would welcome.
Since Oktay performed the first successful ovarian tissue transplant in 1999, the procedure has become an established fertility option for young people about to undergo chemotherapy, which can damage eggs and reduce blood flow to the ovaries. More than 200 babies have been born using the technique—about a 28 percent success rate for live births, according to a recent review. Data on the procedure’s effects on menopause and hormone restoration are limited to people who have had the transplant after undergoing treatment for serious illnesses. The efficacy of the transplant in healthy people remains unclear.
Even though menopause itself is not a disease, “it brings a lot of complications with it,” Oktay says. For instance, perimenopause (the years leading up to menopause) “can be quite nasty for some women to go through,” says Kirsten Louise Tryde Macklon, an oncofertility specialist at Copenhagen University Hospital. Perimenopause can cause life-disrupting sleep problems and hot flashes—sudden, sometimes debilitating surges of a heat sensation in the upper body. One UK-based survey found that one in 10 people left a job because of menopause symptoms.
People in menopause may face a higher risk of developing cardiovascular disease as levels of estrogen—which helps protect the heart—start to drop off. Estrogen also promotes bone health, which means that lower levels in menopause can raise the risk of osteoporosis. Some studies have found a link between early menopause (typically defined as occurring before age 45) and a higher risk of dementia.
Many experts, including Macklon and her colleague Stine Gry Kristensen, a reproductive biologist at Copenhagen University Hospital, question the need for ovarian tissue transplantation, given that hormone replacement therapy, or HRT, is already an effective and readily accessible intervention to manage menopause symptoms. HRT replenishes hormones with estrogen patches or pills, often combined with progesterone. This relieves symptoms such as hot flashes and sleep disturbances, and strong evidence suggests it helps prevent osteoporosis. Research on its effects on other chronic conditions is mixed. Some research suggest HRT can help reduce the risk of heart disease, stroke and cognitive decline, while other studies suggest it increases risk or has no effect.
Only a small proportion of women undergo hormone replacement therapy because of its controversial history, however, says Clarisa Gracia, chair of the practice committee of the American Society for Reproductive Medicine and a reproductive endocrinologist at Penn Medicine. Findings from the Women’s Health Initiative study in the early 2000s suggested HRT has potential links to breast cancer, heart disease and stroke. The study had significant limitations, but still “the pendulum swung,” Gracia says, “and we stopped prescribing it to women.”
Ovarian tissue transplants also produce hormones and may come with similar risks as HRT, but there are not enough data to know for sure. Oktay says naturally producing hormones in this way could be more beneficial than the synthetic hormones used in the current therapies; he says his patients tell him they feel better and more “like themselves” when their own hormones kick in after the transplant, compared with when they were on synthetic hormones. But Kristensen says there isn’t substantive evidence to back that comparison. “It sounds nice; it sounds better; but we have no data, really,” she says.
The success of the procedure, both for fertility and menopause, depends largely on the tissue’s survival rate. This process is not like a typical transplant, which connects an organ to existing blood vessels, explains Michael von Wolff, a reproductive endocrinologist at the University Hospital of Bern in Switzerland, who previously published a critique on the method. The ovarian tissue has to form new blood vessels and re-establish blood supply, which can take approximately 10 days. Additionally, restoring hormone production takes up to several months, von Wolff says. About 60 percent of the follicles die during the time the tissue is thawed, transplanted and reconnected to surrounding blood vessels. Over the long run, the tissue tends to last for two and a half years on average in the body. Oktay’s model estimates that a person who has a quarter of their ovarian reserve removed at age 30 could delay menopause for about 10 years. He is optimistic that better grafting can boost the tissue survival rate in the future, but other experts such as Macklon argue that “it’s simply too premature to say that.”
Age may also be a barrier. The transplant would be most effective if one has the tissue removed and frozen in their 20s. “I have a very hard time believing that a 25-, 30- or 35-year-old woman is even thinking about menopause,” Gracia says.
Despite the procedure’s limitations, momentum for the overall idea of restoring hormone production through ovarian tissue seems to be building. Oktay’s clinic and Amorim’s ProFaM Health are exploring this procedure, and other labs are investigating the use of drugs such as rapamycin to delay menopause by slowing down ovaries’ aging process. Kristensen says she’s engineering another version of ovarian tissue transplantation—a small, synthetic device that houses hormone-producing cells and could be implanted into the body. This field of research has “huge potential because so many women, [who make up] half of the human population, could benefit from this,” she says.