Over the course of seven years, Sezenia Tzeni endured seven rounds of in vitro fertilisation. 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 ageing 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 scepticism. 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 ageing itself. But other than a brief presentation at a conference last winter, Genesis has yet to publish its findings. And even if its technique works, some wonder: Is reinstating fertility in women well into their 50s and 60s something we should even really be doing?
"We were sceptical, 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 1000 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 $US3500 ($4550), 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 ageing 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 $US30 billion ($39 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 per cent 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 17 September 2016 she gave birth to twins.