YSM Issue 97.1

FOCUS
Reproductive Health
HITTING
THE PAUSE
BUTTON
How Freezing Ovarian
Tissue Delays Menopause
BY SARAH LI
PHOTOGRAPH COURTESY OF THERAPY FOR WOMEN
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 that 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 (twentyone
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. ■
8 Yale Scientific Magazine March 2024 www.yalescientific.org