IVA AND THE GREAT FERTILITY REVOLUTION

Last week, a woman who suffered an early menopause gave birth. We report on the new frontiers of making babies.

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.

HIV IN CELLS ERADICATED WITH ANTIFUNGAL DRUG

New research by an international team finds that Ciclopirox, an antifungal cream used all over the world, completely eradicates HIV - the virus that leads to AIDS - in cultured cells, and the virus does not return when the treatment stops.

The study also found Deferiprone, a systemic drug used to remove excess iron from the body in people who have beta-thalassaemia major, has the same effect.
The researchers, including a team from Rutgers New Jersey Medical School, wrote about their findings in a paper published online. As both drugs are already approved for use in humans - both in the US and Europe - the researchers say this means the normally lengthy process of drug development should be less costly and time-consuming, bringing closer the prospect of global elimination of HIV and AIDS.

The cells of our body have a natural way of stopping this - they kill themselves. When the immune system detects the presence of a virus, it triggers a cell process called apoptosis that makes infected cells commit suicide. But the human immunodeficiency virus (HIV) has a way around this: it disables the host cell's ability to commit suicide, allowing it to continue to exploit cellular resources to fuel its growth and spread.

In this new study, the researchers found the drugs work against HIV in two ways: they inhibit expression of certain HIV genes, and they also jam up the host cell's mitochondria, the little powerhouses that supply them with energy. Both these effects reactivate the cell's suicide pathway. Healthy cells not infected with HIV were not affected. And remarkably, the virus did not bounce back when treatment stopped.

Thanks to these previous results confirmed in this new study, and the fact the systemic drug is already known to be safe in humans, testing the effectiveness of Deferiprone against HIV has already moved directly from cell culture to human trial in South Africa, bypassing the need for animal testing. Ciclopirox is not approved for systemic use, as it is a topical cream. But the discovery that both drugs, each well-tolerated in humans, are also able to eradicate HIV in cell culture renews hope that HIV and AIDS will one day, in the not too distant future, be wiped from the face of the Earth.

Written by Catharine Paddock PhD

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WHY PILING ON THE POUNDS MAY HELP YOU LIVE LONGER

It was Wallis Simpson who famously remarked that “you can never be too rich or too thin”. But the latest research suggests the former Duchess of Windsor got it wrong, at least where weight is concerned. The new study, the biggest on the topic to date, has found that those with a little extra padding are likely to outlive their slimmer counterparts.

The research, published in the Journal of the American Medical Association last week, found, as might be expected, that people who were very obese (a Body Mass Index of over 35) had 30 per cent higher mortality than those of a “healthy” weight (a BMI between 18.5 and 25). However, those who were just overweight (a BMI between 25 and 30) were around 6 per cent less likely to die during the study than those who fell into the “healthy” weight range. Even people usually classified as mildly obese (a BMI between 30 and 35) seemed to be at no risk of dying early.

While severe obesity is an established risk for conditions like heart disease and diabetes, some modest extra poundage is linked with increased longevity – a phenomenon known to experts as the “obesity paradox”. “We don’t fully understand why it occurs, but one explanation is that overweight people may be more likely to have health problems, like high blood pressure and diabetes, flagged up and treated,” says Paul Gately, professor of exercise and obesity at Leeds Metropolitan University. “Having a higher BMI seems to be protective for some chronic conditions like heart failure, too, and research is underway to explain this.”

What the latest research does highlight is the shortcomings of the BMI, a rough estimate of body fatness based on weight and height, as an overall gauge of health (to work yours out, divide your weight in kilograms by your height in metres squared – or use an internet BMI calculator). Although a BMI between 18.5 to 25 is regarded as the ideal, most experts now accept that those who carry a stone or two more can remain perfectly well, provided they eat a balanced diet and take some exercise to keep heart, arteries and blood glucose levels healthy.

BMI is also an imprecise tool because it does not take into account where body fat is deposited. Studies have shown that people who lay fat around their hips and thighs are at lower risk than those who deposit it around their stomachs (the apple shape), whatever their BMI, which is why doctors think waist measurement is key (the ideal being less than 32” for women and less than 37” for men). The measurement is also inaccurate for those with a muscular build who will register a high BMI despite being fit and healthy.

“What the latest research is telling us is that the biggest risks are with the very obese, and this is where we should be focusing our funding and research,” says Prof Gately.

Lucy Aphramor is a Coventry-based registered dietitian who has pioneered the Health at Every Size approach, which is based on the premise that good health is best realised regardless of weight. She argues it is healthier to be a little plump than pursue weight loss through yo-yo dieting – now thought to increase inflammation, a risk factor for heart disease. “A healthy weight is the weight you stabilise at when you have a healthy relationship with food and we can’t guess at that from numbers on a scale,” she says.

However Prof Gately warns against complacency. “You may be fine right now with a BMI of 27,” he says, “but a false sense of security can lead to your weight creeping up over time – which can become a problem.”

By Angela Dowden

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COCA-COLA RECOMMENDED AS 'MEDICAL CURE' FOR STOMACH BLOCKAGES

Doctors now commonly use the soft drink to treat patients with a nasty condition called gastric phytobezoar with a success rate of more than 90 per cent, a study said.

This is because the fizzy favourite has chemical ingredients that do a similar job to gastric acid while the bubbles help speed up the process, said researchers. Even the Diet and Coke Zero options work, because they have the same basic ingredients as the full fat version, said the report.

The researchers went through openly published academic papers that detailed 46 patients with the ailment who were treated with Coke in hospitals worldwide over the past 10 years.

A phytobezoar is a stomach blockage which, unless it is successfully removed or destroyed, can subsequently lead to a bowel obstruction. It is often caused by certain fruits which do not digest properly – for instance, in Asia many cases are a result of eating persimmons which are particularly prone to form blockages. A variety of treatments are available to treat it, from lasers and non-surgical endoscopies to the last resort of full surgery. But of the 46 cases patients given Coca-Cola, exactly half saw the drink destroy the blockage completely and a further 19 only needed non-invasive treatments as a result of Coke's help. Only four needed full surgery giving Coca-Cola a success rating of 91.3 per cent. They reported: "Coca-Cola administration is a cheap, easy-to-perform and safe procedure that can be accomplished at any endoscopy unit."

Coca-Cola has an acidity rating of 2.6 on the pH scale because it contains both carbonic and phosphoric acid.

The researchers added: "It resembles gastric acid, which is thought to be important for fibre digestion. "In addition the bubbles enhance the dissolving mechanism."

If the Coke does not completely destroy whatever is causing the blockage then it is likely to make it smaller and soften the phytobezoar making it easy to remove without the need for full surgery, the report said.

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DOCTORS SEEK COURT ORDER TO CARRY OUT ABORTION ON MENTALLY DISABLED WOMAN

The woman, who is not being named for legal reasons, suffers from sickle cell disease which has already caused her to have a string of strokes.

The medical team treating her say they are concerned that allowing her pregnancy to continue any further could endanger her life. They describe the situation as “urgent” and say that they must act quickly to reduce the risk.

Lawyers from an NHS trust in the south of England are due to take their case to the Court of Protection, sitting at the High Court in London later this week. The judge will be asked to make an order allowing doctors to treat the woman without her consent.

She is described as having a “significant learning impairment” and doctors believe she does not have the capacity to make a decision for herself.

Sickle cell disease is an inherited condition in which the red blood cells which supply oxygen to the body develop abnormally. The cells, shaped like a crescent sickle rather than being round, have a tendency to clog sections of blood vessels. The blockages, which can last for weeks at a time, can cause anaemia which leaves patients tired and breathless. In more severe cases, they can cause severe breathing problems and strokes.

Last year, the court effectively banned a young autistic woman from having sexual intercourse because she does not understand the risks involved. The judge said that the court had a responsibility to protect people’s freedom to make “unwise decisions” but must occasionally restrict it in their best interests.

Hospitals and councils have previously asked judges to force women to take contraception and undergo surgery. One woman with dementia was almost prevented from taking a cruise after social workers said it was too dangerous.

The latest case contrasts markedly with that of Savita Halappanavar, the Indian woman who died after allegedly being refused an abortion which it has been claimed could have saved her life by a hospital in Ireland.

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PARKINSON'S DRUGS LEAD TO COMPULSIVE GAMBLING & SHOPPING, NOT THE DISEASE ITSELF

Parkinson's disease, the neurodegenerative condition that can cause shakes and tremors, has been linked with alterations in behaviour in patients ranging from compulsive shopping and gambling to being obsessed with taking technical equipment apart, sorting objects or for taking long aimless walks.

Researchers have found that these side effects are caused by the drugs used to treat Parkinson's rather than the disease itself. In a small study, a group of newly diagnosed Parkinson sufferers who were not taking any medication, were asked about their compulsive behaviour and the results compared to a similar group of people who were healthy. It was found that one in five of both groups showed compulsive behaviour. "We've known for some time that these behaviours are more common in people taking certain Parkinson's medications, but we haven't known if the disease itself leads to an increased risk of these behaviours," said study author Dr Daniel Weintraub. "These results provide further evidence that impulse control disorders that occur in people with Parkinson's disease are related to the exposure to the dopamine-related drugs, not just the disease itself," he said. "More long-term studies are needed to determine if the 20 per cent of people who have some symptoms of these disorders are more likely to develop impulse control disorders once they start treatment for Parkinson's."

The symptoms can be controlled by altering doses of medication but drugs should not be changed or stopped without help from medical professionals. Experts have said the behaviours are particularly associated with drugs known as dopamine agonists, but can also affect people who take other Parkinson's drugs, in particular levodopa.

Parkinson's symptoms are caused by a decrease in the levels of the chemical in the brain, dopamine, due to the death of the nerve cells in the brain that make it. Dopamine agonists act in a similar way to natural dopamine in the brain and are particularly effective against the movement symptoms of Parkinson's.

Article by Rebecca Smith, Medical Editor of The Telegragh, UK.

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COMMON BLOOD PRESSURE DRUGS MAY LOWER RISKS OF DEMENTIA

It was found that people who had taken blood pressure drugs, particularly a class known as beta blockers, showed fewer changes in the brain linked to Alzheimer's disease.

Findings of a new study were presented at the American Academy of Neurology Annual Meeting in San Diego. Researchers examined the brains of 774 men after they had died, 610 of whom had been treated for high blood pressure. Aroound one in seven of those had been given only beta blockers, 18% had received beta blockers and another drug and the others had been given different drugs. It was found that the men who had received beta blockers as their only blood pressure medication had fewer abnormalities in their brains compared to those who had not been treated for their hypertension, or who  had received other blood pressure medications. Those who had been given beta-blockers in combination with other drugs also had fewer brain leisons and less shrinkage but not to the same extent at those who had used them alone.        

In 2011, more than 30m prescriptions were dispensed for beta blockers in England, showing that millions of patients have used the drugs. Lead researcher Dr. Lon White, of the Pacific Health Research and Education Institute in Honolulu, said: "With the number of people with Alzheimer's disease expected to grow significantly as our population ages; it is increasingly important to identify factors that could delay or prevent the disease; these results are exciting, especially since beta blockers are a common treatment for high blood pressure."     

Earlier research has shown that high blood pressure in middle age is a strong risk factor for dementia. The number of people with dementia is expected to explode to 1.7m by 2050. Dr. Simon Ridley, head of research at Alzheimer's Research UK, said: "Hypertension is a known risk factor for Alzheimer's and other causes of dementia, and keeping high blood pressure in check could be important for preventing these diseases; this study suggests a link between the use of beta blockers and fewer signs of dementia, but as the results of this study have yet to be published in full, it is not clear what caused this link; it is important to note that this study only looked at Japanese-American men, and these results may not be applicable to the wider population; while we cant conclude from this study that beta blockers can prevent dementia, a better understanding of the links between high blood pressure and dementia could be crucial for developing new treatments or approaches to prevention; with 820,000 people affected by dementia in the UK, and that number increasing, we urgently need to find ways to prevent the disease that causes it - that requires a massive investment in research."

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