Ovarian tissue freezing offers hope for extended fertility

Most women agree that menopause has its advantages and disadvantages. Some relish the end of menstruation and concerns about unplanned pregnancies, while others dread the possibililty of hot flashes, moodiness, and other unpleasant symptoms. What some women consider a brief and barely noticeable phase in their lives can evolve into lasting changes and discomfort for others.

Now, a new paradigm around the biological processes of menopause is capturing the attention of a small group of scientists around the country. The primary question: can menopause be delayed in healthy women, allowing them to extend their child-bearing years-;and perhaps even forestall some of the health risks and uncomfortable symptoms linked to plummeting estrogen levels? These questions can be controversial: Some people believe that such research could lead to life-changing benefits for women, while others consider menopause to be a biologically driven life stage that should not be pathologized by medical science.

At Yale School of Medicine (YSM), Kutluk Oktay, MD, PhD, an ovarian biologist who is director of the Laboratory of Molecular Reproduction and Fertility Preservation, recently added a new chapter to this conversation by publishing research on various possible outcomes when menopause is delayed in healthy women via ovarian tissue freezing.

Oktay, who developed and performed the world's first ovarian transplant procedure with cryopreserved tissue for a patient with a medical indication in 1999, sees a future in which healthy women could use this process of freezing tens of thousands of eggs within the ovarian tissue to stave off menopause for as long as several decades-;or even prevent its onset altogether.

"For the first time in medical history, we have the ability to potentially delay or eliminate menopause," said Oktay, who is also an adjunct professor of obstetrics, gynecology & reproductive sciences at YSM.

A mathematical model predicts outcomes for delayed menopause

Using data from hundreds of previous ovarian cryopreservation and transplantation procedures, and molecular studies of how ovarian follicles behave in ovarian tissue, Oktay and his colleagues built a new mathematical model, published in the American Journal of Obstetrics & Gynecology, to predict how long the surgery could potentially delay menopause under a range of circumstances in healthy women.

Since Oktay performed the first successful transplantation with cryopreserved tissue, ovarian tissue cryopreservation has been successfully used in cancer patients to preserve their fertility before their treatments, which can often permanently damage the egg reserve in the ovaries and trigger menopause. During this outpatient procedure, a surgeon laparoscopically removes the whole ovary or layers of the outer portion, which contains hundreds of thousands of dormant, immature eggs (known as primordial follicles).

These tissues are then stored in sealed containers after being frozen with a specialized process and kept as low as negative 320 degrees Fahrenheit. Freezing ovarian tissue with this specialized process preserves it for later use. At some point-;typically years-;in the future, the surgeon reimplants the thawed tissue into the patient either laparoscopically or with a simple procedure, using methods developed by Oktay, that places the tissue under the patient's skin while intravenous sedation is administered. Within three to 10 days after that, this transplanted tissue regains connections with the surrounding blood vessels and restores ovarian function in about three months.

The recently published mathematical model focusing on healthy women undergoing ovarian tissue cryopreservation considers multiple factors, including the age at which a patient gets the procedure, which plays a significant role in how long menopause can potentially be delayed.

The younger the person, the larger number of eggs she has, as well as the higher the quality of those eggs."

Kutluk Oktay, MD, PhD, ovarian biologist 

The model accounts for women between the ages of 21 and 40. Beyond age 40, data show that the procedure is unlikely to delay menopause for a woman with average egg reserve, but this can change with the development of more efficient freezing and transplantation methods in the future.

Furthermore, the model offers insight into the ideal amount of ovarian tissue to collect. The more tissue a surgeon removes, the longer the procedure can potentially delay menopause. However, the removal of too much tissue can lead to early menopause. "This model gives us the optimum amount of tissue to harvest for a person of a given age," said Oktay.

The model also takes into account the healing process after a surgeon returns the harvested ovarian tissue to the patient. During this healing process, some of the primordial follicles are lost. Studies on animal models show that as many as 60% of primordial follicles do not survive post-transplantation, leaving 40% that are viable. With newer technologies, Oktay said that he believes surgeons can attain a survival rate of up to 80%. As the procedure continues to improve, he hopes to eventually achieve a 100% survival rate. Thus, the model accounts for survival rates ranging from 40% to 100%.

Additionally, through transplanting portions of the harvested tissues over several procedures, the research indicates that menopause can be delayed even longer. For example, the team's model shows that returning a third of the outer portion of the ovary over each of three procedures delayed menopause longer than returning all of the tissue through one surgery.

Based on the model, Oktay predicts that for most women under 40, ovarian cryopreservation can significantly delay menopause. And for women under 30, the procedure may be able to prevent menopause altogether.

Because many women lose their ability to become pregnant sooner than they desire, ovarian cryopreservation could be an appealing option for them, said Hugh S. Taylor, MD, chair and Anita O'Keeffe Young Professor of Obstetrics, Gynecology & Reproductive Sciences at YSM. "Women are also frequently deferring pregnancy until later in life for professional or social reasons," he added. "The ability to freeze and later transplant ovarian tissue…offers a way to extend their fertile lifespan."

Does delaying menopause via cryopreservation offer health benefits?

Delaying menopause with ovarian cryopreservation also may confer certain health benefits associated with a later menopausal age. Based on new research by Oktay and his colleagues, around 11% of women experience late-onset natural menopause-;or menopause after age 55. Studies show that women who experience menopause later may live longer and have a lower risk for a range of conditions, including cardiovascular disease, dementia, retinal disease, depression, and bone loss. However, uncertainty remains over whether later menopause actually reduces those health risks. Oktay hypothesizes that those risks also may be mitigated in healthy women who delay menopause via ovarian tissue cryopreservation.

If risk for such chronic diseases is reduced in healthy women who undergo this procedure, it could be a significant benefit. However, Taylor said that "additional research is needed to determine long-term benefits as well as risks."

In ongoing research, Oktay and his team are studying the outcomes of healthy women who have opted to delay menopause through this procedure. Publication of these studies is far in the future, but in the meantime, the mathematical model offers a starting point for considering the feasibility and possible benefits of forestalling menopause in healthy women.

The study was co-authored by Joshua Johnson, PhD, of the University of Colorado School of Medicine; Sean D. Lawley, PhD, of the University of Utah; and John W. Emerson, PhD, of Yale University.