Hitting the Pause Button

Image Courtesy of Therapy for Women Center.

Every night, six thousand women experience an internally staged rebellion. Waves of heat engulf them, and their skin prickles with discomfort. Mood swings become their unwelcome companions—a rollercoaster ride of emotions they can’t control. Menopause’s arrival reshapes a woman’s world in unexpected ways. Researchers at Yale have pioneered a groundbreaking method to potentially delay or eliminate menopause and its unwanted symptoms. Kutluk Oktay, a reproductive endocrinology and infertility specialist at Yale, led a collaboration between physicians and data scientists aimed at modeling the delay of menopause. Their efforts could pioneer a path toward innovative interventions that may revolutionize women’s health and reproductive options.

Oktay was the first physician and reproductive surgeon to research and complete an ovarian transplant for cancer patients using cryo-banked ovarian tissue. He began wondering if his research on preserving fertility in cancer patients could be expanded to benefit a larger population. Cancer patients often lose their eggs due to chemotherapy, pushing them to develop premature menopause. During the procedure, Oktay removes a section of ovarian tissue and freezes it, preserving fertility and effectively delaying this premature response. No treatment is currently available to delay menopause and extend the natural fertility period in healthy women, but Oktay suspected ovarian tissue freezing could be a successful approach. Because this study would take decades to conduct experimentally, Oktay turned to mathematical modeling to begin his research. By altering the variable inputs of a previously developed model that determines the feasibility of follicle behavior in the human ovary, a new modeling system for his research was born.

“The human ovarian cortex’s primordial follicles (PFs) [are] the key to predicting the onset of menopause,” Oktay explained. In women, menopause has been biologically determined to occur after the depletion of PFs in the ovaries. This is a natural process that starts before puberty begins. Using this information and past research as guidance, the team put together a model predicting the delay of menopause. They considered four main parameters: age of ovarian tissue harvest (twenty-one to forty years old), amount of ovarian cortex harvested, whether or not the transplantation procedure was done in a single step or multiple fractions (one or three transplants), and percentage of post-freezing PF survival (forty percent is ‘average’, eighty percent is ‘improved’, and one hundred percent is hypothetical).

So, what did the model reveal? First, it confirmed Oktay’s suspicions that this procedure could be applied to healthy women. Next, it affirmed the impacts of the four parameters on the success of menopause delay. The model also suggested that for most women under forty, the procedure can postpone menopause, with procedures performed earlier in life delaying menopause for longer. The model further found that with an increase in the amount of tissue harvested in most women, the delay period also increased. Three separate cortex transplantation procedures resulted in greater menopause delay than one procedure, and the group reported that more procedures would further the delay of menopause. However, each additional procedure yields a smaller marginal increase in the delay. As expected, the larger the percentage of viable PF in the tissue after thawing, the longer menopause can be delayed. 

From these modeled results, the team believes the ovarian transplantation procedure is suitable for healthy women to extend their fertility period, delaying menopause. In cases where all favorable parameters are maximized, the extent to which menopause is delayed could surpass the natural lifespan. This means that some women with ideal conditions may never experience menopause. Though this may seem like a dream, some critics argue that the procedure is working against natural biological processes and stress that there could be serious consequences for trying to disrupt this natural cycle. The main concern is that with an extended estrogen-producing cycle, there is an increased risk of breast cancer—an association already observed among women who naturally have delayed menopause. “Delaying menopause to sixty is well within [the age of] naturally occurring menopause,” Oktay said. “You have to do the cost-benefit analysis.” Though there is a risk, it is likely outweighed by the improved quality of life afforded by extra menopause-free decades. 

Mathematical modeling offers us a glimpse into the future, but all models have their limitations. Looking to expand their work, the team hopes to apply their research to a clinical setting. With the world of medicine becoming more focused on improving quality of life and beating the biological clock, this cryopreservation procedure could bring icy relief to millions.