Category Archives: Human Reproduction

A long-held belief about women and fertility is that each woman has a set amount of eggs in her lifetime and that when those eggs are depleted at menopause, so are her chances at having a biological child. However, research out of Massachusetts General Hospital questioning that view. Using stem cells taken from human ovaries, scientists have produced early-stage eggs, which brings up all sorts of questions about possible new methods for treating infertility. Nicholas Wade, writing in the New York Times, adds, "The ability to isolate stem cells from which eggs could be cultivated would help not only with fertility but also with biologists’ understanding of how drugs and nutrition affect the egg cells."

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Jonathan Tilly, the director of Mass General's Vincent Center for Reproductive Biology and leader of the new research, had reported in 2004 that ovarian stem cells in mice could create new eggs "similar to how stem cells in male testes produce sperm throughout a man’s life." His new study attempted to prove this with humans. Researchers took healthy ovaries from patients having sex reassignment surgery, and injected stem cells from the ovaries into human ovarian tissue grafted under the skin of mice: "Within two weeks, early stage human follicles with oocytes had formed." Ryan Flinn writes in Bloomberg Businessweek that this could potentially point at "new ways to aid fertility by delaying when the ovaries stop functioning." 

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Dr. Tilly has long been a proponent of the belief that women might be able to produce new eggs, and has said the 50-year belief otherwise is based on lack of evidence rather than on data proving that it's impossible. In 2005, he reported that women have a "hidden reserve of cells in the bone marrow that constantly replenish the ovaries with new eggs," though other researchers have not been able to confirm his finding. 

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Along with opening new doors to understanding the incredibly complex human egg cell, this new research could eventually have very practical implications for the 10 percent of child-bearing age women in the U.S. who have fertility problems. More philosophically, it opens up a new way of thinking about the hard-stop in women's lives for having kids. While fertility technologies like in-vitro and egg freezing are happening to some extent, Tilly's team is exploring the way this new knowledge could improve in-vitro -- IVF involves a limited number of eggs -- and also looking into possibility of developing an ovarian stem-cell bank with eggs that could be "cryogenically frozen and thawed without damage, unlike human eggs." 

“The problem we face with IVF is we don’t have many eggs to work with,” said Tilly. “These cells are renewable. If we are successful -- and it’s a big if -- in generating functioning eggs from these cells, we can generate as many eggs as we need to on a per patient basis.”

Researchers warn that there's a ways to go before there are any real applications to this, if ever. Female reproduction expert David Albertini said it's still unclear whether the egg cells yielded actually could be used in human fertility. Cells grown in laboratories are more likely to develop abnormalities; even if they are proven viable, it's a given that there will be numerous social and political aspects that factor in down the road. Nonetheless, evidence that women's eggs may not be the finite commodity we all thought they were seems poised to make a huge impact across many aspects of contemporary life. What would if mean, for instance, if the old ticking "biological clock" no longer applied -- or applied to women and men more equivalently? 

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As Tilly said in a recording released to the press, "If we can guide the process correctly, I think it opens up a chance that sometime in the future, we might get to the point of actually having an unlimited source of human eggs. A woman could come in, have a small biopsy taken from her ovary for us to retrieve these cells. Once we get these cells out, we can take a hundred of them and make a million of them. If we can get to the stage of generating functional human eggs outside the body, it would rewrite essentially human assisted reproduction."

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Brave new world? Maternity ages stretching into the 50s and 60s? Or simply another step toward the prediction some have made that sex will be just a recreational activity in another 10 years?

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New Stem Cell Research Could End the Hard Stop of Female Fertility

SUNDAY, Feb. 26 (HealthDay News) -- Researchers report that they've isolated stem cells from adult human ovaries that can mature into eggs that may be capable of fertilization.

The lab findings, which upend longstanding scientific theory, could potentially lead to new reproductive technologies and possibly extend the years of a woman's fertility.

It was long believed that women were born with a lifetime supply of eggs, which was depleted by menopause. But a growing body of research -- including a new paper from Massachusetts General Hospital -- suggests egg production may continue into adulthood. The study is published in the March issue of Nature Medicine.

"Fifty years of thinking, in every aspect of experiments, of interpreting the results, and of the clinical management of ovarian function and fertility in women was dictated by one simple belief that turns out to be incorrect," said lead study author Jonathan Tilly, director of the hospital's Vincent Center for Reproductive Biology. "That belief was the egg cell pool endowed at birth is a fixed entity that cannot be renewed."

Dr. Avner Hershlag, chief of the Center for Human Reproduction at North Shore-LIJ Health System in Manhasset, N.Y., said the study is "exciting" but emphasized the work is still very preliminary.

"This is experimental," Hershlag said. "This is a beginning of perhaps something that could bring in new opportunities, but it's going to be a long time in my estimation until clinically we'll be able to actually have human eggs created from stem cells that make babies."

The same team at Mass General caused a stir in 2004 when it published a paper in Nature reporting that female mice retain the ability to make new egg cells well into adulthood.

In both mice and humans, the vast majority of egg cells die through a process called programmed cell death, or apoptosis, the body's way of eliminating unneeded or damaged cells. For humans, that process is dramatic. Female fetuses have about 6 to 7 million eggs at about 20 weeks' gestation, a little more than 1 million at birth, and about 300,000 by puberty.

Studying mice egg cells and follicles, the tiny sacs in which stem cells become eggs, the Mass General researchers discovered something that didn't make mathematical sense.

Most prior research had focused on counting the healthy eggs in the ovaries, and then made assumptions about how many had died from that, Tilly said. But his lab looked at it the opposite way and focused on cell death.

"We found far too many eggs were dying than could be accounted for by the net change in the healthy egg pool," Tilly said. "We reasoned that maybe the field had missed something." They wondered if stem, or precursor cells, were repopulating the ovaries with new eggs.

Initially, the findings were met with skepticism, according to the study authors, but subsequent research bolstered the conclusions.

Those included a 2009 study from a team in China, published in Nature Cell Biology, that isolated, purified and cultured egg stem cells from adult mice, and subsequently introduced them into mice ovaries that were rendered infertile. The infertile mice eventually produced mature oocytes that were fertilized and developed into healthy baby mice.

Studies showing that women had the same capacity as mice were lacking, however.

In this study, Tilly's team used tissue from Japanese women in their 20s and 30s with gender identity disorder, who had their ovaries removed as part of gender reassignment surgery.

The researchers isolated the egg precursor cells and inserted into them a gene from a jellyfish that glows green, then inserted the treated cells into biopsied human ovarian tissue. They then transplanted the human tissue into mice. The green fluorescence allowed researchers to see that the stem cells generated new egg cells.

Tilly said the process makes evolutionary sense. "If you look at this from an evolutionary perspective, males have sperm stem cells that continually make sperm. Because species propagation is so important, we want to make sure it's the best sperm, so don't want sperm sitting around for 60 years waiting to get used," he said. It makes no sense from an evolutionary perspective that "females will be born with all the eggs they will have and let them sit there," he noted.

Hershlag, meanwhile, said much remains to be overcome.

"Ultimately, in our field only one thing counts," he said, "and that is if you can make an egg that can make a healthy baby."

More information

The U.S. National Library of Medicine has more on how human embryos develop.

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Stem Cell Finding Could Expand Women's Lifetime Supply of Eggs

An experiment that produced human eggs from stem cells could one day be a boon for women who are desperate to have a baby, according to a study published on Sunday.

The work sweeps away the belief that a woman has only a limited stock of eggs and replaces it with the theory that the supply is continuously replenished from precursor cells in the ovary, its authors said.

"The prevailing dogma in our field for the better part of the last 50 or 60 years was that young girls at birth were given a bank account of eggs at birth that's not renewable," said Jonathan Tilly, director of the Vincent Center for Reproductive Biology at Massachusetts General Hospital, who led the research.

"As they become mature and become a woman, they use those eggs up (and) the ovaries will fail when they enter menopause."

Tilly first challenged the "bank account" doctrine eight years ago, suggesting female mammals continue producing egg-making cells into adulthood rather than from a stock acquired at birth.

His theory ran into a firestorm.

Other scientists challenged the accuracy of his experiments or dismissed their conclusions as worthless, given that they had only been conducted on lab mice.

But the new work, said Tilly, not only confirms his controversial idea, but takes it farther.

In it, his team isolated egg-producing stem cells in human ovaries and then coaxed them into developing oocytes, as eggs are called.

Building on a feat by Chinese scientists, they pinpointed the oocyte stem cells by using antibodies which latched onto a protein "handle" located on the side of these cells.

The team tagged the stem cells with a fluorescent green protein -- a common trick to help figure out what happens in lab experiments.

The cells were injected into biopsied human ovarian tissue which was then grafted beneath the skin of mice.

Within 14 days, the graft had produced a budding of oocytes. Some of the eggs glowed with the fluorescent tag, proving that they came from the stem cells. But others did not, which suggested they were already present in the tissue before the injection.

Tilly said "the hairs were standing up on my arm" when he saw time-elapse video showing the eggs maturing in a lab dish.

Further work needs to be done to test the viability of the eggs, and little is known about the hormones or other mechanisms by which oocytes emerge from the stem cells.

But the impact could be far-reaching, Tilly said.

"If we can guide the process correctly, I think it opens up a chance that sometime in the future, we might get to the point of actually having an unlimited source of human eggs," Tilly said in a video recording released to the press.

"A woman could come in, have a small biopsy taken from her ovary for us to retrieve these cells. Once we get these cells out, we can take a hundred of them and make a million of them.

"If we can get to the stage of generating functional human eggs outside the body, it would rewrite essentially human assisted reproduction."

According to a press release issued by Massachusetts General Hospital, Tilly's team are already exploring the idea of banks where oocyte stem cells can be frozen and stored, and then retrieved when a woman wants to have a baby.

Human eggs are extremely delicate and likely to suffer damage when frozen and thawed, but this risk does not apply to the egg cells that make them, it said.

Previous work has shown that around one in 10 women of reproductive age is at risk of premature ageing of the ovaries, a finding with repercussions in societies where women opt ever later to become mothers.

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Pioneering lab work aims to smash women's fertility barrier

Study Suggests Women May Be Able to Make More Eggs as They Age

Feb. 26, 2012 -- Scientists say they have found a way to use ovarian stem cells to perhaps one day help infertile women get pregnant -- or add years to a woman’s reproductive cycle.

In a study published in Nature Medicine, researchers report finding egg-producing stem cells in human ovaries. They also report being able to make some of those ovarian stem cells grow into immature eggs that may someday be useful for reproduction.

At this point, such “seed” eggs can’t be fertilized by sperm. But if scientists are able to entice them to mature and can prove they can be fertilized and grow into embryos -- a feat that has been reported in mice -- it would overturn a long-held scientific belief that women can’t make new eggs as they get older.

“What it does is really open a door into human reproduction that 10 years ago didn’t even exist,” says researcher Jonathan L. Tilly, PhD, director of the Vincent Center for Reproductive Biology at Massachusetts General Hospital, in Boston.

Outside experts agree. They say the findings could have profound importance for reproductive medicine and aging, allowing doctors not only to restore a woman’s fertility but also to potentially delay menopause.

“I think the significance of this work is like reporting that we found microorganisms on Mars,” says Kutluk Oktay, MD, who directs the Division of Reproductive Medicine and the Institute for Fertility Preservation at New York Medical College in Valhalla, N.Y.

Still, It’s a Long Way to Mars

“It’s a proof of principle that they could do it,” says David F. Albertini, PhD, director of the Center for Reproductive Sciences at the University of Kansas Medical Center in Kansas City, Kan.

“The world wants to know today if we’re ready to restore fertility in women, whether they’ve aged or been treated for cancer or whatever,” Albertini says, adding that he doesn’t think that’s on the horizon. “This is an extremely rare event, at best.”

The egg-generating stem cells the researchers were able to extract from ovaries were very rare. The researchers only came across one for every 10,000 or so ovarian cells that they counted.

But when they took those cells and implanted them back into human ovarian tissue, they divided and essentially made young eggs.

Tilly says his team stopped short of trying to make one of the eggs functional because “for a lot of reasons, as it should be,” it is illegal in the U.S. to experimentally fertilize human eggs.

“We think the evidence provided clearly indicates that this very unique, newly discovered pool of cells does exist in women,” he says.

A Lot of Potential

“It’s a really exciting result,” says Evelyn Telfer, PhD, a cell biology expert at the University of Edinburgh in Scotland.

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Future Fertility Fix? Egg-Producing Stem Cells Found in Human Ovaries

In research that could have far-reaching implications for female fertility, U.S. scientists have isolated stem cells from human ovarian tissue that give rise to what appear to be normal egg cells.

The finding, published Sunday in the journal Nature Medicine, builds on earlier landmark papers by the Boston researchers, which suggest that female mammals continue producing egg cells, known as oocytes, into adulthood.

Since 2004, the scientists at Massachusetts General Hospital have produced a series of papers based on work in laboratory mice, which challenge the long-held belief that female mammals are born with a finite number of eggs that run out at a certain point in the life cycle.

The team was able to isolate stem cells from ovarian tissue taken from mice, from which they grew fully functional egg cells in the lab, which could then be fertilized and even produce healthy offspring.

"The primary objective of the current study was to prove that oocyte-producing stem cells do, in fact, exist in the ovaries of women during reproductive life, which we feel this study demonstrates very clearly," said lead author Jonathan Tilly, director of the Vincent Center for Reproductive Biology at Massachusetts General.

In their experiments, the team isolated the stem cells from ovarian tissue that had been removed from women in their 20s and early 30s.

When put in culture dishes in the lab, these stem cells gave rise to cells with the characteristic features of oocytes, including the physical appearance and gene expression patterns of those seen inside human ovaries.

"They spontaneously generate eggs in the dish," Tilly said in a phone interview, noting that they proliferate so well that a small number of stem cells could easily spawn a million egg cells in the lab.

The researchers next took stem cells they had genetically manipulated to glow green and injected them into snippets of human ovarian tissue. These prepared tissue bits were then grafted beneath the skin of specially bred mice, which have no immune system that can cause rejection of human tissue.

Within two weeks, researchers discovered the implanted ovarian tissue in the mice contained numerous immature human follicles with egg cells that originated from the injected stem cells. Follicles are small sacs within the ovary which contain maturing eggs.

Tilly said they knew the eggs cells had arisen from the injected stem cells "because they were all green."

Among the many potential clinical applications the researchers are exploring is whether these stem cells could produce oocytes that could play a role in in-vitro fertilization, as well as other applications to improve the outcomes of IVF and other infertility treatments.

"Can we use these cells for fertility reasons to maximize the opportunity for patients who are experiencing infertility to have different options available to them to have a genetically matched child?" asked Tilly.

"I think it's a fairly good possibility that at some point in the not-too-distant future there will be clinical protocols developed using some aspect of these cells or their properties that will have a significant impact on human reproduction."

Among them is the idea of extracting structures responsible for energy production in cells — called mitochondria — from the stem cells and injecting them into a woman's eggs at the time of in-vitro fertilization, with the hope of boosting the chances of conception and a successful birth.

But Tilly said another idea is to see whether these ovarian stem cells could be used to delay menopause — and the myriad health effects that can develop as women age.

"I've always been intrigued by the prospects of what if you could slow the rate at which the egg cell pool goes away and end up keeping an ovary functioning long past its normal time of failure," he said.

"With these egg stem cells, it raises the prospect that by harnessing the power of those cells, perhaps we can control the rate at which that precious reserve of egg cells is depleted and maybe even delay it ... And if you could achieve that, what would happen? Would we truly see a benefit or would there be unforeseen bad effects?"

More than a decade ago, Tilly's lab created a mouse through genetic manipulation that did not experience ovarian failure with age and was able to maintain an adequate reservoir of eggs.

"So it didn't undergo the equivalent of menopause," he said, or "mouseopause" as the scientists have dubbed it.

While normal mice as they reach old age experience health problems similar to those of postmenopausal women — including declining eyesight and hearing, hair loss, osteoporosis, diminished cognitive function and reduced muscle mass — these genetically modified mice did not. Nor did they have an increased risk of cancer.

So could these stem cells one day be used as the basis for an anti-aging treatment?

"There would be some pretty significant health benefits that would come out of it," said Tilly, if that were the case.

Even though every aspect of the human oocyte-producing stem cells have so far matched what the researchers have found in their mouse equivalents, Tilly conceded that "mouse is mouse — and perhaps human will be different."

"We don't know" if eggs generated from human ovarian stem cells will be normal and healthy, he said. "We will have to be very careful if and when we get to that stage."

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Human ovarian stem cells may hold promise for treating infertility: study

BACKGROUND

The Internet has revolutionized fertility care since it became a popular source of information and support for infertile patients in the last decade. The aim of this scoping review is to map (i) the main categories of patient-focused Internet interventions within fertility care, (ii) the detailed composition of the interventions and (iii) how these interventions were evaluated.

METHODS

A literature search used various ‘Internet’ and ‘Infertility’ search terms to identify relevant studies published up to 1 September 2011. The selected studies had to include patients facing infertility and using an infertility-related Internet intervention. We charted data regarding categories of interventions, components of interventions and evaluation methodology. We categorized the stages of research using the UK's Medical Research Council framework for evaluating complex interventions.

RESULTS

We included 20 studies and identified 3 educational interventions, 2 self-help interventions, 1 human-supported therapeutic intervention, 9 online support groups and 2 counselling services. Information provision, support and mental health promotion were common aims. Few interactive online components were present in the online programmes. Three studies were in the pilot phase and 17 were in the evaluation phase.

CONCLUSIONS

Several categories of patient-focused Internet-based interventions in fertility care are primarily applied to provide support and education and promote mental health. The interventions could be improved by using more interactive and dynamic elements as their key components. Finally, more emphasis on methodological standards for complex interventions is needed to produce more rigorous evaluations. This review shows where further development or research into patient-focused Internet interventions in fertility-care practice may be warranted.

Source:
http://humupd.oxfordjournals.org/rss/current.xml