The Daily Telegraph

The menopause is reserved

By Roger Highfield, Science Editor

SCIENTISTS have reserved the menopause for the first time in a treatment that could revolutionise the lives of women. The medical breakthrough raises the prospect of ovary banks being set up to extend female fertility into old age.

A little over two decades after Britain opened a new chapter of reproductive medicine with Lonise Brown, the world’s first test-tube baby, an Anglo-American team has carried out the first successful ovarian graft.
This is a new kind of transplant which promise to have a more profound effect on human fertility than IVF. It could be used to:

  • Treat sterility caused by premature menopause;
  • Protect fertility in patients having cancer treatment;
  • Delay the menopause so that woman in their 70s could conceive;
  • Even help to ameliorate the effects of ageing and prolong the active life of women.

The grafts could also be a better, and safer, substitute for the widely-used hormone replacement therapy
The operation on a 30-year-old American that paved the way to these developments was to masterminded by the leading figure in the field, Prof Roger Gosden, of Leeds University. He will report on his success today at the annual meeting of the American Society for Reproductive Medicine in Toronto.
The pioneering operation on Margaret Lloyd-Hart was carried out last February at New York Methodist Hospital by Dr Kutluk Oktay, who had worked with Gosden.
The graft was used to put back her own ovary tissue, which had been previously removed and frozen. But the procedure opens up the way to ovary transplants from another donor, whether the victim of a fatal accident on an aborted foetus.
“This is proof of the principle that the ovary grafts could be used to rescue fertility,” said Prof Gosden. “There is no reason why ovaries could not be stored for decades.”
After a graft, “there is a good prospect the ovary would continue to function long after the menopausal age”. The ovaries produce the female sex hormones oestrogen and progesterone and contain cavities, called follicles, in which eggs develop.
Ovary grafts have a number of medical uses but the longer-term applications will rekindle ethical debate of the kind that greeted the news six years ago that women in their fifties and sixties had become pregnant after egg donation.
The ability to use grafts to restore the fertility of middle-aged or even elderly women will rise the  the question of when woman is too old to bear children.
Babies born to older women would be brought up by people of grandparent age, and would face being orphaned early, while the mothers are the greater medical risk.
The work also raises more extraordinary, and speculative, possibilities: the use of ovarian tissue from an aborted foetus could restore the fertility of an elderly woman, though any children she bore would have the foetus as their biological mother.
Ovary grafts lie outside the control of the Human Fertilisation and Embryology Authority, which is concerned only with mature eggs and sperm, while ovaries contain immature eggs.
However, Prof Gosden said efforts were under way to set out voluntary guidelines on the use of ovary grafts. Five years ago the possible use of foetal ovaries for restoring fertility was banned by Parliament.
As well as curbing the unethical use of ovary grafts, Prof Gosden in keen to prevent profiteering, for instance by inexperienced teams of doctors who could demand hefty charges to store tissue with no real guarantee that they had the expertise to reverse the operation.
The hope is that one day ovarian tissue from women suffering cancer will be routinely removed before they are given chemotherapy or radiotherapy, which cause sterility.
The “rind” of ovaries,
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Scientists hail success
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the cortex containing the eggs, would be frozen and then replaced some time – even years – afterwards.
Hundreds of cancer patients have had ovarian tissue banked. However, none has had ovarian tissue re-implanted. It is possible that this will place early next year in Britain, after studies suggest that certain disease, notably Hodgkin’s, do not involve the ovaries.
“With this technology, women who need chemotherapy or radiation therapy for cancer treatment and want to preserve their fertility will be able to bank their ovarian tissue and have it transplanted when their cancer treatment is complete,” said Dr Oktay, who carried out the operation.
“It will also enable patients to prolong their reproductive life span, as banked ovarian tissue does non ‘age’,”
Ovary grafts may even help arrest ageing. Hormone replacement therapy for women has become part of mainstream medical practice, preserving healthy arteries and bones. The advantages for sustaining an active life are concerns about weight gain, pre-menstrual tension and breast cancer.
Some experts have asked whether an ovarian graft could be better than boosting levels of the female sex hormone oestrogen to premenopausal levels with pills. Patches and implants.
Another possibility would be ovary transplants from a donor. “I have already encountered the case of an overseas woman doctor who had a child born with Turner’s syndrome, which causes sterility,” said prof Gosden.
“The mother now hopes to store part of her own ovary so that the daughter might one day have the option of becoming pregnant with her mother’s eggs.”
Transplants could raise another extraordinary possibility: the transplant of ovarian tissue from an aborted foetus to restore female fertility. Foetal ovaries are the best source of foreign tissue because the older the donor the fewer the eggs, and  because there may be fewer rejection problems because foetal tissue is better tolerated.
Such a transplant could benefit women who had not stored their own tissue. How not stored their own tissue. However, a woman who had received foetal tissue would not have children who were genetically her own: they would be result of the combination of genes from the father and the aborted foetus.

How to beat the biological clock

Reports by
Roger Highfield
Science Editor

OVARY grafts not only offer a way to treat infertility but may also enable healthy woman to conceive in old age and even help them stay youthful.
However this research raises important issue from the cut-off age, beyond which it is unethical to allow a woman to conceive, to the use of foetal ovary tissue to maintain fertility – an issue that embroiled Prof Roger Gosden in controversy three years ago and led to a ban on a related research in Britain.
His two clinics in Leeds already receive the occasional call from single women in their late 30s who want to keep their reproductive options open as their biological clock runs down.
As a result of the ovary graft on Margaret Lloyd-Hart, he expects these calls to become more numerous. “There is always someone out there who wants to push things faster and harder than doctors,” he said.
The ovary ages more rapidly than any other organ. Within a few years in is likely that a test will be developed to assess a woman’s complement off eggs so that she knows how close she is to running out, which in when the menopause occurs.
Once women are aware of this “ovarian age”, ovarian tissue could be stored and returned to the body after menopause to restore fertility and maintain a “youthful” hormone balance, rather than use hormone replacement therapy.
Prof Roger Gosden said: “Personally, I have always regarded these techniques as primarily for fertility conservation, but I know that some see them as an opportunity to provide women with more choice about hormones.”
Prof Gosden doubts that all women would want to postpone the menopause. “Some are doubtless glad when its advent releases them from the monthly ‘curse’ and constant worries about contraception.
“Others would regard any interference with natural events as abhorrent. But for some women ‘the change’ is traumatic, mentally and physically.”
He adds that the medical postponement of menopause would be reversible by surgery to remove the ovaries.
But that still leaves the question of at what age does it become unethical to have children. Using eggs donated from younger women scientist have already enabled women in their 50s and 60s to conceive.
While the public is uneasy about tampering with the “natural course of events”, doctors are concerned by the medical risks faced by a pregnant 60-year-old. There are other issue, not least how the children face being orphaned early.
“We are unlikely to see any pregnancies among 70-year-olds, although contraceptive precautions would be advisable for those who are sexually active,” Prof Gosden added.
But in middle age, the advantages would be clear for this career conscious society. “The boom of his treatment, mainly, would be for women in their 40s, more of whom nowadays seeking a late pregnancy, but finding this difficult or impossible,” he said.
An ovary graft would increase their chances and – provided better egg quality matched the greater quantity – the risk of miscarriage or genetic defects in the foetus could be reduced. If the eggs were stored while she was still young they would not have “aged”, he points out.
Protecting their ovaries from the ravages of time emancipates women – giving them the same control over their fertility that men have, particularly since women are now living longer and staying healthier than ever before. “Why shouldn’t they enjoy free rein over their biological capital?” argues Prof Gosden.
As for ovary grafts helping to ameliorate the effects of ageing, Hormone Replacement Therapy has become part of mainstream medical practice, preserving healthy arteries and bones to prolong active life.
The advantages are undeniable but there are concerns about weight gain, premenstrual tension, a higher risk of breast cancer and so on.
Ovary grafts could render it unnecessary because older women would retain fully functioning ovaries, and so not need oestrogen supplements to protect them from osteoporosis, Alzheimer’s and heart disease.
Another issue is how to provide fertile ovaries for young women who were born without them (for instance, sufferers of Turner’s syndrome).
Ovarian tissue for donation is rare, said Prof Gosden. “Hence the logical conclusion to consider using tissue from foetuses (and possibly from young accident victims) because of greater abundance.”
While at the University of Edinburgh School of Medicine, Prof Gosden studied the possibility of removing the ovaries from female foetuses that have been aborted and transplanting them into infertile women.
If this were to work, the transplanted ovary would start producing its own eggs under the influence of the woman’s hormones and conceptions could then take place in the normal way – although any children that resulted would be the genetic offspring of the foetus.
The idea met stiff opposition when it was raised in 1994. Dame Jill Knight, the Conservative MP, successfully moved a motion in the House of Commons to make further research along these lines a criminal act. “It is totally repugnant,” she said, “That an unborn child – a child deliberately prevented from being born – should be plundered to facilitate the birth of another child.
“I want to send a message out to scientists that there is no point in spending any more time on this type of research… Aborted human eggs will simply not be allowed to be used for fertilization purposes.”
The House concurred, when the vote was taken in the dead of night. The “Aye” lobby quickly filled with at least 300 MPs and, with only 15 in the opposing lobby, there was no point in even sending in the tellers.
Prof Gosden’s view at the time was that the Commons had “made an ass of itself”.
“Although I was never passionate about the practical application of foetal tissue for fertility treatment (realizing the ethical minefields), I am about the free do of intellectual endeavour and the pursuit of science,” he said.
“Calling a halt on technique that might never work was farcical. The episode provided an opportunity for anti-scientific forces to vent their wrath on those who struggle for human progress.”

Being diagnosed gave ‘terrible feeling of isolation’

MONIQUE Francis regards herself as one of the more fortunate sufferers of premature menopause. She already had one child, her son Edward, before being affected at the age of 34. But at the time she was trying for another.
Mrs Francis heads the Daisy Network, a group which offers advice and support for sufferers, who are defined as those affected by menopause before the age of 40, when the ovaries cease to produce eggs and hormone levels change.
She initially blamed her loss of periods on diet and mood swings on being “a bad-tempered person.” But once she had ended her diet, her periods reappeared only fleetingly. When she was diagnosed as menopausal the next year – the result of an autoimmune response – she experienced “a terrible feeling of isolation”.
“I wouldn’t have minded it happening a little later,” she said. “But it came when I was desperate for another baby.”
There are, of course, options such as surrogacy and adoption. Modern science has also offered up egg donation as another way to achieve pregnancy.
In all cases, the fact that any resulting child will not be genetically related to the mother is a profound issue. In the case of Mrs Francis, her doctor recommended egg donation and her 33-yerar-old sister, Diana Hamilton, offered to help.
“That helped, as she is as close to me genetically as anyone will get,” said Mrs Francis. However, she gave up after four attempts.
Premature menopause effects one woman in every 100 so that, in Britain alone, there are around 110,000 affected.
There are many causes. These including genetic factors, notably an abnormal X chromosome, as with sufferers of Turners’s syndrome. In two thirds of case, the body turns on the ovaries, a so-called autoimmune response, perhaps while fighting an infection. And in many other cases the ovaries are damaged by surgery or cancer treatment.
For those women who Know they are at risk, there is the option of egg freezing.
However, Prof Gosden points out that the success rates – one live born baby for every 100 eggs that are frozen – are poor.
Now ovary storage and grafts offer a new option. “I have come across people who have frozen embryos but not frozen ovarian tissue, which is still in an early stage of development,” said Mrs Francis, who is now 39.

My hunt for the one man able to help me

NOTHING could have prepared Margaret Lloyd-Hart for misery that followed a simple operation. She had already had one ovary removed at 17 because of cysts and last year she lost the other on the advice of her doctor, to deal with a hormone-related medical complaint.
Mrs Loyd-Hard, 30, a professional dancer, then suffered the devasting effects of surgically menopause. Fortunately, partly because of her interest in science fiction, she had had her ovarian tissue cryogenically preserved – frozen.
This decision eventually led her to doggedly surf the Internet and then make a phone call to track down Prof Roger Gosden, the only scientist capable of masterminding an operation to reimplant her ovary issue.
She said: “I wonder how many women out there have any idea how rough the transition to being surgically menopausal is. It is vastly worse than a natural menopause.”
Even doctors – usually male – often “have no idea” of what the effects are on their patients, she said, adding: “It was nothing less than horrifying to find, at 29, that I did not have any more energy. I could not sleep I had constant dark circles under my eyes. As a professional dancer my energy and enthusiasm went through the floor.”
With help from her home computer, Mrs Lloyd-Hart has become the first woman to have undergone an ovary graft in an attempt to reverse these effects.
She lives in Tucson, Arizona, and met her British husband, Michael, in America in 1986.He returned to Oxford University but now works as an astrophysicist at the Steward Observatory, University of Arizona, where Mrs Lloyd-Hart once studied dance.
She said that until recently, she had an “active schedule” as a dancer. She explained: “Most of my early training has been in western dance form, ballet, modern and jazz, but then I got into Middle Eastern, and that is what I do professionally.”
She said that she would not have agreed to the second operation in she had realized that it would result in the loss of her supply of hormones and “surgical menopause”.
Of her decision to have the ovary tissue stored she said: “I thought there may be a chance, somewhere down the road, where I wanted to have children. If it was possible not to burn a bridge, then I would rather not.”
At that time her doctor doubted the technology existed to reverse the operation. But her view was: “This was my last ovary and I did not like the idea of just throwing it away.”
Before she had the operation a hunt on the Internet revealed that one of the few centres capable of cryopreservation was on her door step. A building affiliated to the University of Arizona was used to store her tissue. Before the operation, “I was an energy pack. I danced for hours a day. I played bagpipes and I also Painted, which I did professionally.” But a week after, she felt she “did not have a life anymore”.
Mrs Lloyd-Hart added: “I did not sleep well. The sleep you get is really thin, not a deep sleep. There were nightmares, called doom dreams, and tingling in my extremities.”
She also suffered hot flushes, a sensation of her flesh crawling, and had lost her energy and sense of well-being. Her emotions ranged from depression to anxiety and panic attacks.
To compensate for the loss of her remaining ovary, her doctor had prescribed hormone replacement therapy. But Mrs Lloyd-Hart said that she had not found a combination that did much to alleviate misery.
Last summer she discussed her predicament with a new doctor. He told her that he knew of experimental ovary crafts on sheep that had been carried out by Prof Gosden.
“It sounded like it was worth following up,” she said.
A hunt on the Internet tracked him down to Leeds General Infirmary. One morning, she plucked up the courage to telephone him.
She was anxious but it turned out that she was exactly the patient Prof Gosden was looking for, after years of honing his methods in animal studies. Mrs Lloyd-Hart said: “I was so pleased by his manner. He is a sweet, gentle guy.”
The overall aim of Prof Gosden’s work is to develop ways to bank ovaries for women who would otherwise be sterilised by cancer treatment. But a stumbling block was the theoretical risk that the operation would reintroduce tumour cells in the body. This risk did not exist whit Mrs Lloyd-Hart’s tissue as she had not suffered cancer. The operation could help her and pave the way for a technique by which cancer patients could “bottle” their fertility.
Prof Gosden is not a surgeon and had to find one to reimplant her tissue. He put her in touch with Dr Kutluk Oktay in New York, who was not only on the right side of the Atlantic, but a former colleague in whom he had confidence.
For eight weeks, Mrs Lloyd-Hart an Dr Oktay exchanged e-mails to reassure her on each stage of the operation, tackle issues, such as where to reintroduce the tissue, and discuss the risk. “We had some intense questions to tackle,” she said. “He was a delight.” She opted to have her stored ovary tissue returned to the original site. “My feeling was that we have enough obstacles in doing this for the first time. I thought it would be most reasonable to eliminate any variables and put it back in the original location.” The operation was scheduled for Feb 18 and was funded by a research grant. She was, understandably, nervous when being prepared. Her husband was by her side.
Under the influence of general anaesthetic, a keyhole technique was used to replace the graft. She made a quick recovery from the immediate effects of surgery.
She now feels different, though the impact has been subtle. The full effect is expected to take nine months, though it is already altering the way she reacts to hormone replacement therapy.
Hard evidence that the graft has “taken” has come from a test of her transplant. In response to injections of a fertility hormone, her restored ovarian tissue produced an egg. Mrs Lloyd-Hart said: “It was four and a half months after the surgery we saw a follicle [egg sac] develop. That was a good sign. It has kicked in earlier than we thought and the blood supply is looking excellent.
“I am still waiting for my own body to kick in and to have my cycle. That is when I will feel good again.”
She has summoned up the energy to choreograph dance. Now she is waiting for the day she can perform again in public.


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