Wednesday, 15 March 2017

The Crazy Plan to Restore a Woman's Fertility—and Defy the Limits of Nature Sam Woolley/Gizmodo

Over the course of seven years, Sezenia Tzeni endured seven rounds of in vitro fertilization. Typically, women undergo only three or four IVF treatments before either getting pregnant or giving up. But for Tzeni and her husband, conceiving a child was more important than almost anything else.
“My mother and friends told me to do an adoption,” 36-year-old Tzeni told Gizmodo. “But I wanted to feel it, to feel the feeling of pregnancy and the moving in my belly.”
Each time, though, the cycle of hope and disappointment became more devastating. After the seventh round, finally, she stopped trying.
Then, in 2015, a friend told Tzeni, who lives on a small island in Greece, about a clinic in Athens called Genesis. There, a gynecologist named Konstantinos Sfakianoudis claimed to have found a way to rejuvenate aging ovaries with a blood treatment typically used for healing wounds. So far, Sfakianoudis says, the technique has helped nine women nearing menopause who were having difficulty conceiving to get pregnant via IVF. In pre-clinical trial data provided by Sfakianoudis, 11 of 27 menopausal women saw menopause reversed, with hormone levels returning to those associated with fertility, and menstruation beginning again. Two of those women were able to generate healthy eggs, and one of them got pregnant, though she has not yet given birth.
In another case study, a menopausal German woman treated by Genesis got pregnant and gave birth, according to information Sfakianoudis provided to Gizmodo.
Now, the group is planning to bring its treatment to the US. Genesis is currently in the process of enrolling 50 patients in a clinical trial in collaboration with scientists from UC Berkeley and a La Jolla IVF practice. But the clinic’s work has engendered plenty of skepticism. Its bold claim suggests it has managed to reverse a milestone event in a woman’s life—in a sense, to undo the process of aging itself. But other than a brief presentation at a conference last summer, Genesis has yet to publish its findings. And even if its technique works, some wonder, is reinstating fertility in women well into their fifties and sixties something we should even really be doing?
“We were skeptical, too, when it started to work,” Sfakianoudis told Gizmodo, via phone from Greece. “Now I could not be more optimistic.”
This seemingly miraculous treatment contradicts what has been considered fact since the 1950s: That women are born with all the eggs they will ever have. Estimates suggest that from the time she is born, a woman loses about 1,000 egg cells, called oocytes, a month. At puberty, oocytes begin to mature, and during each cycle of ovulation, usually just one ripens to maturity. Eventually, at some point, conventional wisdom holds that a woman’s supply of oocytes runs out. Her ovaries stop producing the hormones needed to maintain fertility, and she enters menopause.
Over the past decade or so, though, a small trickle of research has challenged this picture. In 2004, a reproductive biologist then at Massachusetts General Hospital named Jonathan Tilly published a paper suggesting that in mice, oocytes were regularly replenished by stem cells. If he was right (and if the finding held true in humans) it meant that stem cells could be harnessed to produce new eggs, perhaps even reverse menopause. His work was—and still is—controversial. But since then, new research by Tilly and others gave the idea more credibility. A year after his initial study, Tilly announced that he had identified bone marrow as the source of those egg-producing stem cells. In 2009, a team in China reported that they had similarly isolated “female germline stem cells” in the ovarian tissue of mice, which they then transplanted into infertile mice. Eventually, the mice were able to give birth.

The Greek group’s work is rooted in this idea, that a woman’s ovaries might just need a boost—from stem cells, or something else—to kickstart egg production again. Instead of stem cells, though, Genesis turned to a blood treatment known as platelet-rich plasma (PRP). It’s an old practice typically used to help muscle and tendon injuries heal faster, though just how effective it is for healing remains unclear. The idea is to spin down a sample of a person’s blood in a centrifuge to isolate molecules that help trigger tissue and blood vessel growth, then inject this enriched blood back into the body, hopefully stimulating tissue regeneration to help a wound heal faster. Bone marrow transplants and (the far less invasive) PRP transfusions contain similar growth factors, so Genesis put two-and-two together and began offering their clients transfusions of PRP.
Genesis’ idea isn’t totally without precedent. At least one fertility clinic in New York offers PRP as a “ovarian rejuvenation treatment” for a cool $3,500, citing, accompanied by many asterisks, a single case study presented at a conference of a postmenopausal woman who gave birth after being treated with PRP. A 2015 Chinese study of five infertile women with thin uterine linings all became pregnant after PRP infusions stimulated that lining to grow thicker. A similar trial is currently underway at UCSF. Meanwhile, OvaScience, a biotech startup founded by Tilly, is working to rejuvenate egg cells from older women by adding new cytoplasm and mitochondria.
In 2015, the Greek clinic began treating patients past and nearing menopause with PRP, as well as younger women who had other conditions like uterine scarring that made it difficult to conceive. They found that in all three scenarios, PRP seemed to stimulate egg production. Additionally, and notably less scientifically, they concluded that “the overall state of feminine mental and physical health appeared to improve significantly with the restoration of youthful hormone levels.”
Last July, Sfakianoudis’s team presented early results at the European Society of Human Reproduction and Embryology annual meeting in Finland. More recently, the clinic partnered with a biotech firm with transhumanist leanings, Ascendance Biomedical, to spin the treatment off into a company, Inovium.
The US trials are an effort by the company to gather more data to back up their findings and lend it legitimacy. The trial will be held at the Center for Advanced Genetics in Carlsbad, CA and supervised by Michael and Irina Conboy, a husband and wife research team at UC Berkeley known for their pioneering work studying aging and rejuvenation in mice.
Still, it’s hard not to raise an eyebrow at a company that mixes up the name of the scientist who supposedly inspired its work on the “science” tab of the company website. (Inovium referred to scientist Jonathan Tilly as “Dr. Roger Tilley.” When Gizmodo pointed this out, the company edited the page, but still spelled Tilly’s name incorrectly.) More troublingly, Inovium and Genesis are offering women that are desperate for children and willing to pay a very high price a treatment for which they still have published no peer-reviewed data, have done very small studies, and have little more than untested theories to explain how it all actually works.
“I would be very cautious proceeding with such a clinical investigation,” said Christos Coutifaris, president-elect of the American Society of Reproductive Medicine. “Infertility patients are very vulnerable,” he added, referring to the emotional toll that fertility treatments can take.
Genesis is the biggest private fertility clinic in Greece. Fertility is big business—the industry is expected to surpass $30 billion by 2023—and Genesis’ founder, Kostas Pantos, envisioned turning Greece into a hub for medical tourism in this fast-growing market. Since opening in 1995, the clinic has often been at the forefront of fertility technology, with early forays into genetic screening of embryos and research identifying which embryos are most likely to make it to term.

So far, more than 60 women who were either past menopause or having trouble getting pregnant have received PRP treatment at Genesis, including Tzeni, according to Sfakianoudis. In over 75 percent of those cases, the clinic claims that hormone levels (AMH, FSH, LH, and Estradiol) returned to “youthful levels.” The nine women who ultimately wound up pregnant after undergoing PRP and IVF were between 36 and 54, and experienced no complications.
“We’re still in the very early process of trying to figure out when it works, how it works and why it works,” Sfakianoudis said.
Ultimately, the end goal is to publish the results of the US trial in a peer-reviewed journal.
Michael and Irina Conboy, the Berkeley scientists who have signed on as advisors and researchers on the project, said that while it’s plausible the treatment works and early data is promising, a proper pilot study is needed before anyone can really judge anything.
“What I like most about this trial,” Michael Conboy told Gizmodo, “is that it sounds very unlikely it will harm anyone.”
Unlike traditional PRP transfusions, which require donor blood, the Greek clinic’s procedure uses a patient’s own genetic material, removing their blood plasma, enriching it, and then injecting it back into the ovaries in a relatively noninvasive procedure. The study will look at menopausal and perimenopausal women looking to conceive, and follow them through IVF treatment and, if all goes well, birth.
The Conboys said that they were enticed by the clinic and spin-off company seeking to back-up its wild-sounding claims with actual science.
“They specifically mentioned that they don’t want to be another Ambrosia,” Irina Conboy said, referencing the Silicon Valley startup that offers blood transfusions to youth-seekers based on questionable science. “All of this needs to start with a study,” she added.
The Conboy’s own lab has found that old blood can be damaging to younger mice, and that young blood is not as effective at rejuvenation as fans of the theory, like billionaire Peter Thiel, have hoped it would be. The couple’s work, though, has also indicated that regulating certain blood proteins that change with age to maintain youthful levels can allow stem cells to more effectively repair the body, as they do in youth.
“The idea is that the stem cells themselves are not too old, but it’s the environment around them that suppresses them,” Conboy said.
PRP, he speculated, could be sending signals to stem cells in the ovaries that produce oocytes to regenerate.
The trial is still in its early stages—basic details, like whether or not UC Berkeley will officially oversee it, are still being worked out.

Even if the trial does indicate Inovium’s treatment is effective, though, it is not likely to quell all detractors. The treatment raises questions of whether women at or nearing menopause should be having children at all. Because risks of pregnancy complications increase with age, most IVF clinics have an upper age limit under 45 years of age. In some countries, like Israel, performing IVF over a certain age is illegal. Most of the women Sfakianoudis’s team have treated so far have been between 45 and 64.
For Tzeni, Sfakianoudis concluded that her pregnancy woes were due to chronic inflammation in the lining of her uterus.
At first, the clinic tried treating the inflammation with several different antibiotic pills. Still, there was significant inflammation. Then they tried PRP. The inflammation disappeared.
“He told me, ‘Now it’s perfect to have embryos success,’” she said of Sfakianoudis. “He told me, ‘Don’t worry, you will have children and I’m sure you will have twins.’”
After another round of IVF, on September 17, 2016 she gave birth to twins.

New Scientist THIS WEEK
20 July 2016

Menopause reversal restores periods and produces fertile eggs

Women who have already passed through the menopause may be able to have children following a blood treatment usually used to heal wounds
Mother holding baby
Never too old?
Peter Dazeley/Getty
MENOPAUSE need not be the end of fertility. A team claims to have found a way to rejuvenate post-menopausal ovaries, enabling them to release fertile eggs, New Scientist can reveal.
The team says its technique has restarted periods in menopausal women, including one who had not menstruated in five years. If the results hold up to wider scrutiny, the technique may boost declining fertility in older women, allow women with early menopause to get pregnant, and help stave off the detrimental health effects of menopause.
“It offers a window of hope that menopausal women will be able to get pregnant using their own genetic material,” says Konstantinos Sfakianoudis, a gynaecologist at the Greek fertility clinic Genesis Athens.
“It is potentially quite exciting,” says Roger Sturmey at Hull York Medical School in the UK. “But it also opens up ethical questions over what the upper age limit of mothers should be.”
Women are thought to be born with all their eggs. Between puberty and the menopause, this number steadily dwindles, with fertility thought to peak in the early 20s. Around the age of 50, which is when menopause normally occurs, the ovaries stop releasing eggs – but most women are already largely infertile by this point, as ovulation becomes more infrequent in the run-up. The menopause comes all-too-soon for many women, says Sfakianoudis.
The age of motherhood is creeping up, and more women are having children in their 40s than ever before. But as more women delay pregnancy, many find themselves struggling to get pregnant. Women who hope to conceive later in life are increasingly turning to IVF and egg freezing, but neither are a reliable back-up option (see “The pregnancy pause“).
The menopause also comes early – before the age of 40 – for around 1 per cent of women, either because of a medical condition or certain cancer treatments, for example.
“It offers hope that menopausal women will be able to get pregnant using their own genetic material“
To turn back the fertility clock for women who have experienced early menopause, Sfakianoudis and his colleagues have turned to a blood treatment that is used to help wounds heal faster.
Platelet-rich plasma (PRP) is made by centrifuging a sample of a person’s blood to isolate growth factors – molecules that trigger the growth of tissue and blood vessels. It is widely used to speed the repair of damaged bones and muscles, although its effectiveness is unclear. The treatment may work by stimulating tissue regeneration.
Sfakianoudis’s team has found that PRP also seems to rejuvenate older ovaries, and presented some of their results at the European Society of Human Reproduction and Embryology annual meeting in Helsinki, Finland, this month. When they injected PRP into the ovaries of menopausal women, they say it restarted their menstrual cycles, and enabled them to collect and fertilise the eggs that were released.
“I had a patient whose menopause had established five years ago, at the age of 40,” says Sfakianoudis. Six months after the team injected PRP into her ovaries, she experienced her first period since menopause.
Sfakianoudis’s team has since been able to collect three eggs from this woman. The researchers say they have successfully fertilised two using her husband’s sperm. These embryos are now on ice – the team is waiting until there are at least three before implanting some in her uterus.
Older mothers
The team isn’t sure how this technique works, but it may be that the PRP stimulates stem cells. Some research suggests a small number of stem cells continue making new eggs throughout a woman’s life, but we don’t know much about these yet. It’s possible that growth factors encourage such stem cells to regenerate tissue and produce ovulation hormones. “It’s biologically plausible,” says Sturmey.

Fertilised eggs

Sfakianoudis’s team says it has given PRP in this way to around 30 women between the ages of 46 and 49, all of whom want to have children. The researchers say they have managed to isolate and fertilise eggs from most of them.
“It seems to work in about two-thirds of cases,” says Sfakianoudis. “We see changes in biochemical patterns, a restoration of menses, and egg recruitment and fertilisation.” His team has yet to implant any embryos in post-menopausal women, but hopes to do so in the coming months.
PRP has already been helpful for pregnancy in another group of women, says Sfakianoudis. Around 10 per cent of women who seek fertility treatment at his clinic have a uterus that embryos find difficult to attach to – whether due to cysts, scarring from miscarriages or having a thin uterine lining. “They are the most difficult to treat,” says Sfakianoudis.
But after injecting PRP into the uteruses of six women who had had multiple miscarriages and failed IVF attempts, three became pregnant through IVF. “They are now in their second trimester,” says Sfakianoudis.
Fertility aside, the technique could also be desirable for women who aren’t trying to conceive. The hormonal changes that trigger menopause can also make the heart, skin and bones more vulnerable to ageing and disease, while hot flushes can be very unpleasant. Many women are reluctant to take hormone replacement therapy to reduce these because of its link with breast cancer. Rejuvenating the ovaries with PRP could provide an alternative way to boost the supply of youthful hormones, delaying menopause symptoms.
Ovarian follicle
More eggs, please
Steve Gschmeissner/SPL
However, Sfakianoudis’s team hasn’t yet published any of its findings. “We need larger studies before we can know for sure how effective the treatment is,” says Sfakianoudis.
Some have raised concerns about the safety and efficacy of the procedure, saying the team should have tested the approach in animals first. “This experiment would not have been allowed to take place in the UK,” says Sturmey. “The researchers need to do some more work to make sure that the resulting eggs are OK,” says Adam Balen at the British Fertility Society.
To know if the technique really does improve fertility, the team will also need to carry out randomised trials, in which a control group isn’t given PRP.
Virginia Bolton, an embryologist at Guy’s and St Thomas’ Hospital in London, is also sceptical. “It is dangerous to get excited about something before you have sufficient evidence it works,” she says. New techniques often find their way into the fertility clinic without strong evidence, thanks to huge demand from people who are often willing to spend their life savings to have a child, she says.
If the technique does hold up under further investigation, it could raise ethical questions over the upper age limits of pregnancy – and whether there should be any. “I lay awake last night turning this over in my mind,” says Sturmey. “Where would the line be drawn?”
Health issues like gestational diabetes, pre-eclampsia and miscarriage are all more common in older women. “It would require a big debate,” says Sturmey.

Sperm home test kit