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How ovarian tissue freezing could prevent menopause–possibly forever

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How ovarian tissue freezing could prevent menopause–possibly forever


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,” Oktay said. 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.



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Early dark energy could resolve cosmology’s two biggest puzzles

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How ovarian tissue freezing could prevent menopause–possibly forever


A new study by MIT physicists proposes that a mysterious force known as early dark energy could solve two of the biggest puzzles in cosmology and fill in some major gaps in our understanding of how the early universe evolved.

One puzzle in question is the “Hubble tension,” which refers to a mismatch in measurements of how fast the universe is expanding. The other involves observations of numerous early, bright galaxies that existed at a time when the early universe should have been much less populated.

Now, the MIT team has found that both puzzles could be resolved if the early universe had one extra, fleeting ingredient: early dark energy. Dark energy is an unknown form of energy that physicists suspect is driving the expansion of the universe today. Early dark energy is a similar, hypothetical phenomenon that may have made only a brief appearance, influencing the expansion of the universe in its first moments before disappearing entirely.

Some physicists have suspected that early dark energy could be the key to solving the Hubble tension, as the mysterious force could accelerate the early expansion of the universe by an amount that would resolve the measurement mismatch.

The MIT researchers have now found that early dark energy could also explain the baffling number of bright galaxies that astronomers have observed in the early universe. In their new study, reported in the Monthly Notices of the Royal Astronomical Society, the team modeled the formation of galaxies in the universe’s first few hundred million years. When they incorporated a dark energy component only in that earliest sliver of time, they found the number of galaxies that arose from the primordial environment bloomed to fit astronomers’ observations.

You have these two looming open-ended puzzles,” says study co-author Rohan Naidu, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research. “We find that in fact, early dark energy is a very elegant and sparse solution to two of the most pressing problems in cosmology.”

The study’s co-authors include lead author and Kavli postdoc Xuejian (Jacob) Shen, and MIT professor of physics Mark Vogelsberger, along with Michael Boylan-Kolchin at the University of Texas at Austin, and Sandro Tacchella at the University of Cambridge.

Big city lights

Based on standard cosmological and galaxy formation models, the universe should have taken its time spinning up the first galaxies. It would have taken billions of years for primordial gas to coalesce into galaxies as large and bright as the Milky Way.

But in 2023, NASA’s James Webb Space Telescope (JWST) made a startling observation. With an ability to peer farther back in time than any observatory to date, the telescope uncovered a surprising number of bright galaxies as large as the modern Milky Way within the first 500 million years, when the universe was just 3 percent of its current age.

“The bright galaxies that JWST saw would be like seeing a clustering of lights around big cities, whereas theory predicts something like the light around more rural settings like Yellowstone National Park,” Shen says. “And we don’t expect that clustering of light so early on.”

For physicists, the observations imply that there is either something fundamentally wrong with the physics underlying the models or a missing ingredient in the early universe that scientists have not accounted for. The MIT team explored the possibility of the latter, and whether the missing ingredient might be early dark energy.

Physicists have proposed that early dark energy is a sort of antigravitational force that is turned on only at very early times. This force would counteract gravity’s inward pull and accelerate the early expansion of the universe, in a way that would resolve the mismatch in measurements. Early dark energy, therefore, is considered the most likely solution to the Hubble tension.

Galaxy skeleton

The MIT team explored whether early dark energy could also be the key to explaining the unexpected population of large, bright galaxies detected by JWST. In their new study, the physicists considered how early dark energy might affect the early structure of the universe that gave rise to the first galaxies. They focused on the formation of dark matter halos — regions of space where gravity happens to be stronger, and where matter begins to accumulate.

“We believe that dark matter halos are the invisible skeleton of the universe,” Shen explains. “Dark matter structures form first, and then galaxies form within these structures. So, we expect the number of bright galaxies should be proportional to the number of big dark matter halos.”

The team developed an empirical framework for early galaxy formation, which predicts the number, luminosity, and size of galaxies that should form in the early universe, given some measures of “cosmological parameters.” Cosmological parameters are the basic ingredients, or mathematical terms, that describe the evolution of the universe.

Physicists have determined that there are at least six main cosmological parameters, one of which is the Hubble constant — a term that describes the universe’s rate of expansion. Other parameters describe density fluctuations in the primordial soup, immediately after the Big Bang, from which dark matter halos eventually form.

The MIT team reasoned that if early dark energy affects the universe’s early expansion rate, in a way that resolves the Hubble tension, then it could affect the balance of the other cosmological parameters, in a way that might increase the number of bright galaxies that appear at early times. To test their theory, they incorporated a model of early dark energy (the same one that happens to resolve the Hubble tension) into an empirical galaxy formation framework to see how the earliest dark matter structures evolve and give rise to the first galaxies.

“What we show is, the skeletal structure of the early universe is altered in a subtle way where the amplitude of fluctuations goes up, and you get bigger halos, and brighter galaxies that are in place at earlier times, more so than in our more vanilla models,” Naidu says. “It means things were more abundant, and more clustered in the early universe.”

“A priori, I would not have expected the abundance of JWST’s early bright galaxies to have anything to do with early dark energy, but their observation that EDE pushes cosmological parameters in a direction that boosts the early-galaxy abundance is interesting,” says Marc Kamionkowski, professor of theoretical physics at Johns Hopkins University, who was not involved with the study. “I think more work will need to be done to establish a link between early galaxies and EDE, but regardless of how things turn out, it’s a clever — and hopefully ultimately fruitful — thing to try.”

We demonstrated the potential of early dark energy as a unified solution to the two major issues faced by cosmology. This might be an evidence for its existence if the observational findings of JWST get further consolidated,” Vogelsberger concludes. “In the future, we can incorporate this into large cosmological simulations to see what detailed predictions we get.”

This research was supported, in part, by NASA and the National Science Foundation.



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Plant-derived secondary organic aerosols can act as mediators of plant-plant interactions

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How ovarian tissue freezing could prevent menopause–possibly forever


A new study published in Science reveals that plant-derived secondary organic aerosols (SOAs) can act as mediators of plant-plant interactions. This research was conducted through the cooperation of chemical ecologists, plant ecophysiologists and atmospheric physicists at the University of Eastern Finland.

It is well known that plants release volatile organic compounds (VOCs) into the atmosphere when damaged by herbivores. These VOCs play a crucial role in plant-plant interactions, whereby undamaged plants may detect warning signals from their damaged neighbours and prepare their defences. “Reactive plant VOCs undergo oxidative chemical reactions, resulting in the formation of secondary organic aerosols (SOAs). We wondered whether the ecological functions mediated by VOCs persist after they are oxidated to form SOAs,” said Dr. Hao Yu, formerly a PhD student at UEF, but now at the University of Bern.

The study showed that Scots pine seedlings, when damaged by large pine weevils, release VOCs that activate defences in nearby plants of the same species. Interestingly, the biological activity persisted after VOCs were oxidized to form SOAs. The results indicated that the elemental composition and quantity of SOAs likely determines their biological functions.

“A key novelty of the study is the finding that plants adopt subtly different defence strategies when receiving signals as VOCs or as SOAs, yet they exhibit similar degrees of resistance to herbivore feeding,” said Professor James Blande, head of the Environmental Ecology Research Group. This observation opens up the possibility that plants have sophisticated sensing systems that enable them to tailor their defences to information derived from different types of chemical cue.

“Considering the formation rate of SOAs from their precursor VOCs, their longer lifetime compared to VOCs, and the atmospheric air mass transport, we expect that the ecologically effective distance for interactions mediated by SOAs is longer than that for plant interactions mediated by VOCs,” said Professor Annele Virtanen, head of the Aerosol Physics Research Group. This could be interpreted as plants being able to detect cues representing close versus distant threats from herbivores.

The study is expected to open up a whole new complex research area to environmental ecologists and their collaborators, which could lead to new insights on the chemical cues structuring interactions between plants.



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Folded or cut, this lithium-sulfur battery keeps going

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Most rechargeable batteries that power portable devices, such as toys, handheld vacuums and e-bikes, use lithium-ion technology. But these batteries can have short lifetimes and may catch fire when damaged. To address stability and safety issues, researchers reporting in ACS Energy Letters have designed a lithium-sulfur (Li-S) battery that features an improved iron sulfide cathode. One prototype remains highly stable over 300 charge-discharge cycles, and another provides power even after being folded or cut.

Sulfur has been suggested as a material for lithium-ion batteries because of its low cost and potential to hold more energy than lithium-metal oxides and other materials used in traditional ion-based versions. To make Li-S batteries stable at high temperatures, researchers have previously proposed using a carbonate-based electrolyte to separate the two electrodes (an iron sulfide cathode and a lithium metal-containing anode). However, as the sulfide in the cathode dissolves into the electrolyte, it forms an impenetrable precipitate, causing the cell to quickly lose capacity. Liping Wang and colleagues wondered if they could add a layer between the cathode and electrolyte to reduce this corrosion without reducing functionality and rechargeability.

The team coated iron sulfide cathodes in different polymers and found in initial electrochemical performance tests that polyacrylic acid (PAA) performed best, retaining the electrode’s discharge capacity after 300 charge-discharge cycles. Next, the researchers incorporated a PAA-coated iron sulfide cathode into a prototype battery design, which also included a carbonate-based electrolyte, a lithium metal foil as an ion source, and a graphite-based anode. They produced and then tested both pouch cell and coin cell battery prototypes.

After more than 100 charge-discharge cycles, Wang and colleagues observed no substantial capacity decay in the pouch cell. Additional experiments showed that the pouch cell still worked after being folded and cut in half. The coin cell retained 72% of its capacity after 300 charge-discharge cycles. They next applied the polymer coating to cathodes made from other metals, creating lithium-molybdenum and lithium-vanadium batteries. These cells also had stable capacity over 300 charge-discharge cycles. Overall, the results indicate that coated cathodes could produce not only safer Li-S batteries with long lifespans, but also efficient batteries with other metal sulfides, according to Wang’s team.

The authors acknowledge funding from the National Natural Science Foundation of China; the Natural Science Foundation of Sichuan, China; and the Beijing National Laboratory for Condensed Matter Physics.



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