Sunday, 6 October 2013
IVA AND THE GREAT FERTILITY REVOLUTION
Even the late Prof Sir Robert Edwards, godfather of assisted reproduction, would be astonished by the experimental treatments that today’s fertility scientists keep coming up with.
Could the Nobel prizewinner who developed in-vitro fertility (IVF) treatment – which led to the birth of the first “test-tube baby”, Louise Brown, in 1978 – have imagined the latest leap forward? IVA, or in-vitro activation, seems to offer hope in the most impossible cases: women who have passed through the menopause. According to the Daisy Network, the support group for those who experience menopause prematurely, some 110,000 women in Britain between the ages of 12 and 40 are affected.
The Japanese-American team behind IVA announced last week that they have pioneered a technique that can find – like a needle in a haystack – primordial cells in the ovaries of women who have undergone menopause in their early thirties. These cells, which researchers from Stanford University School of Medicine in California and St Marianna University School of Medicine in Kawasaki, Japan, describe as “residual follicles”, contained immature eggs that could be nurtured into life, fertilised and then grown into embryos for implantation.
The study reported that the scientists’ work has already led to the birth of one baby boy, with another healthy pregnancy underway. Further case work is ongoing.
Truly no stone is being left unturned in the great fertility revolution. Every year seems to bring advances in this branch of gynaecology. Some are straightforward; for example, scientists at the University of Southampton, led by Nick Macklon, professor of gynaecology and obstetrics, have just discovered that a “choosy” uterus can reject poor quality embryos, preventing implantation. The team’s work could have a real impact on IVF success rates, Prof Macklon explains: “The big problem in IVF is still the low chance of getting embryos to implant. These new insights into how an endometrium (the lining of the womb) chooses an embryo may open new avenues to develop treatments.”
Other breakthroughs sound like science fiction – and are just as controversial. “Three-person IVF”, developed at the University of Newcastle, can create embryos from the genetic material of two women and one man to prevent life-threatening disorders. This technique aims to replace faulty mitochondria, the body’s tiny power stations, thus preventing the birth of children with mitochondrial disorder, which causes muscle weakness, blindness and heart failure. The technique already has ethical critics, and a team of scientists at the University of Sheffield, the University of Sussex and Monash University in Australia has warned that mixing DNA could lead to damaging side-effects for the baby, not least in its learning, behaviour and fertility in adulthood. Britain is set to be the first country to use three-person IVF as early as next year. Ministers are drawing up legislation in the face of condemnation from members of the Council of Europe, including eight MPs and peers, who liken the treatment to eugenics.
IVA, by comparison, is a more straightforward development. Women naturally have hundreds of thousands of primordial follicles, each containing one immature egg. Usually, only one follicle develops to maturity each month and releases an egg into the fallopian tube for possible fertilisation.
However, one in 100 women go through early menopause, also known as POI (primary ovarian insufficiency), meaning they can no longer produce eggs or support a pregnancy. Until now, their hopes for motherhood lay in egg donation, surrogacy or adoption.
But, in 2010, Prof Aaron Hsueh, professor of obstetrics and gynaecology at Stanford, found that blocking a protein called PTEN in mouse and human ovaries was enough to stir dormant follicles into producing mature eggs. Although it’s not known why follicles stop developing in women with POI, Prof Hsueh found that some patients still had smaller follicles but were not producing enough sex hormones for ovulation to occur. “Our treatment was able to activate or awaken some of the remaining primordial follicles and cause them to release eggs,” he says.
The procedure involves removing an ovary or piece of ovarian tissue, which is treated to stimulate follicle growth. When this is detected, the tissue is re-implanted into the woman’s body, and hormones used to encourage the egg to grow. When large enough, the eggs are collected as in any IVF procedure, fertilised and allowed to develop until big enough to re-implant. Hormone therapy for the mother supports the pregnancy to term.
Prof Kazuhiro Kawamura, of St Marianna University, who last week delivered the first baby conceived through IVA, said: “I could not sleep the night before the Caesarean operation, but when I saw the healthy baby my anxiety turned to delight. The couple and I hugged each other in tears. I hope IVA will be able to help patients with primary ovarian insufficiency throughout the world.”
Interestingly, a similar needle-in-a-haystack procedure is already being carried out in men who are classified as infertile and produce no sperm at all. It was developed in the 1990s by Dr Sherman Silber of the Infertility Centre of St Louis, a urologist and expert in cutting-edge IVF, who pioneered the ovarian-transplant techniques used in IVA. The “sperm retrieval” is allied with intra-cytoplasmic sperm injection (ICSI) – introducing a sperm directly into an egg to fertilise it.
Sperm retrieval requires a single gamete to be retrieved by microsurgery directly from the client’s epidydimus (the curved structure at the back of the testicle in which sperm matures). The procedure, which is available privately in Britain at a cost of around £2,000, is successful even in men who have been unable to ejaculate a single sperm normally or have a genetic disorder that would typically confer infertility. “If there are stem cells that might produce sperm,” Dr Silber explains, “they are found in tubules which connect the centre to the outer edge of the testis. So we don’t dissect the whole organ, but closely examine the periphery instead. This way, we find any sperm that might be 'hiding’ in the testis without doing any harm to it. Best of all, the patient can just get up and walk away painlessly when it is finished.”
According to Prof Dr Geeta Nargund, medical director of Create Health Clinics in London, “Essentially, IVA is an exciting new scientific development but it needs further productive randomised studies to see its effectiveness and ensure it is safe. At this stage, it is too early to say whether it is clinically applicable for treatment of patients.”
Prof Nargund, who is working with a Belgian team from the Genk Institute for Fertility Technology to simplify IVF techniques, dramatically reducing cost, is keen that false hope is not generated for those women who have undergone premature menopause. “Those who are at risk of early menopause,” she says, “due to genetic or other reasons should seriously consider freezing their eggs. There has been huge improvement in success rates using frozen eggs thanks to the introduction of vitrification – or fast-freezing – techniques.”
IVA will not be available in Britain for some years – and the experimental treatment won’t come cheap. Prof Kawamura explains: “In Japan, when the treatment becomes routinely available, it will cost around US$15,000 (£9,400) to harvest the egg, and more to have it fertilised using IVF.”
Inevitably, there is speculation that IVA could be used to extend the window of fertility for all women, not just those who experience early menopause. Could it benefit women who have passed through menopause in their early fifties?
Prof Hsueh is emphatic: “By 51 years of age, there are no follicles left. The IVA procedure does not correct for age-related increases in genetic defects, it only allows the possibility of getting more oocytes [immature eggs].”
So it seems our primordial cells don’t survive beyond “natural”, age-related menopause, but fade away in women with normal reproductive patterns. Older would-be mothers may have to wait a little longer for the next breakthrough in the great fertility revolution.