Recent research by a team of biologists in the United States has explored the various possible outcomes of delaying menopause – or even preventing it altogether – via the freezing of ovarian tissue.
The question of whether menopause can be delayed in healthy women, allowing them to extend their child-bearing years, and perhaps even eliminate some of the health risks and symptoms tied to reduced oestrogen levels, is a controversial one.
Some experts believe such research could lead to life-changing benefits, while others consider menopause to be a biologically-driven life stage that should not be pathologised by medical science, reports Newswise.
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, has added a new chapter to this conversation.
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 where healthy women could use the process of freezing tens of thousands of eggs within the ovarian tissue to delay 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, gynaecology & reproductive sciences at YSM.
Mathematical model predicts outcomes
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 & Gynaecology, 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 specialised process and kept as low as negative 160 degrees C. Freezing ovarian tissue with this process preserves it for later use.
At some point, typically years, in the future, the surgeon re-implants 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 she is, the more eggs she has, as well as the higher the quality of those eggs,” Oktay said. The model accounts for women aged between 21 and 40. Beyond 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.
It 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 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 Taylor, MD, chair and Anita O’Keeffe Young Professor of Obstetrics, Gynaecology & Reproductive Sciences at YSM.
“Women are also frequently deferring pregnancy until later in life for professional or social reasons. The ability to freeze and later transplant ovarian tissue…offers a way to extend their fertile lifespan.”
Any 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 55.
Studies show that women who experience menopause later may live longer and have a lower risk for various conditions, including cardiovascular disease, dementia, retinal disease, depression, and bone loss. However, uncertainty remains over whether later menopause actually reduces those health risks.
Oktay hypothesises 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.
Study details
Modelling delay of age at natural menopause with planned tissue cryopreservation and autologous transplantation
Joshua Johnson, Sean Lawley, John Emerson, Kutluk Oktay.
Published in American Journal of Obstetrics & Gynaecology on 4 January 2024
Background
Ovarian tissue cryopreservation has been proven to preserve fertility against gonadotoxic treatments. It has not been clear how this procedure would perform if planned for slowing ovarian ageing.
Objective
This study aimed to determine the feasibility of cryopreserving ovarian tissue to extend reproductive life span and delay menopause by autotransplantation near menopause.
Study Design
Based on the existing biological data on follicle loss rates, a stochastic model of primordial follicle wastage was developed to determine the years of delay in menopause (denoted by D) by ovarian tissue cryopreservation and transplantation near menopause. Our model accounted for (1) age at ovarian tissue harvest (21–40 years), (2) the amount of ovarian cortex harvested, (3) transplantation of harvested tissues in single vs multiple procedures (fractionation), and (4) posttransplant follicle survival (40% [conservative] vs 80% [improved] vs 100% [ideal or hypothetical]).
Results
Our model predicted that, for most women aged <40 years, ovarian tissue cryopreservation and transplantation would result in a significant delay in menopause. The advantage is greater if the follicle loss after transplant can be minimised. As an example, the delay in menopause (D) for a woman with a median ovarian reserve who cryopreserves 25% of her ovarian cortex at the age of 25 years and for whom 40% of follicles survive after transplantation would be approximately 11.8 years, but this extends to 15.5 years if the survival is 80%. As another novel finding, spreading the same amount of tissue to repetitive transplants significantly extends the benefit. For example, for the same 25-year-old woman with a median ovarian reserve, 25% cortex removal, and 40% follicle survival, fractionating the transplants to 3 or 6 procedures would result in the corresponding delay in menopause (D) of 23 or 31 years. The same conditions (3 or 6 procedures) would delay menopause as much as 47 years if post-transplant follicle survival is improved to 80% with modern approaches. An interactive Web tool was created to test all variables and the feasibility of ovarian tissue freezing and transplantation to delay ovarian ageing.
Conclusion
Our model predicts that with harvesting at earlier adult ages and better transplant techniques, a significant menopause postponement and, potentially, fertile life span extension can be achieved by ovarian tissue cryopreservation and transplantation in healthy women.
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