Researchers hope to help even more childless couples

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Four million test-tube babies have now been born thanks to British scientist and Nobel Laureate Robert Edwards' tireless and innovative work on in vitro fertilisation, yet many couples still suffer from infertility. Researchers at Karolinska Institutet are trying to find out more about the causes of infertility with the aim of finding new and more effective treatments.

An estimated 10-15% of couples of childbearing age who want to have children are infertile, defined as not having conceived after a year of regular unprotected sex. This infertility is equally likely to be due to either partner, but in around 10% of cases no cause is found. Often infertility leads to an existential crisis, and treatment is both physically and mentally demanding.

Bild på Outi Hovatta.The most common cause of infertility in women is problems with ovulation due to hormone changes. This can be treated with various hormones to stimulate the maturation of follicles in the ovaries and bring about ovulation. However, hormone therapy carries a number of risks, and regular ultrasound examinations are needed to avoid overstimulation and multiple pregnancies.

"The most serious risk is ovarian hyperstimulation syndrome, with damaged ovaries, cysts, fluids in the abdomen and coagulation disorders, which can be life-threatening, so we're very careful with stimulation," explains Outi Hovatta, professor of obstetrics and gynaecology specialising in assisted conception from the Department of Clinical Science, Intervention and Technology at Karolinska Institutet, and consultant at the fertility unit at Karolinska University Hospital Huddinge.

"The most serious risk is ovarian hyperstimulation syndrome, with damaged ovaries, cysts, fluids in the abdomen and coagulation disorders, which can be life-threatening, so we're very careful with stimulation," explains Outi Hovatta, professor of obstetrics and gynaecology specialising in assisted conception from the Department of Clinical Science, Intervention and Technology at Karolinska Institutet, and consultant at the fertility unit at Karolinska University Hospital Huddinge.

Hovatta's research group is looking to develop simpler treatments with fewer side effects for women undergoing hormone therapy and in vitro fertilisation. They are also trying to learn more about the factors that control the development of the eggs and ovaries. One day, she hopes, it will be possible to replace hormone therapy altogether with a technique called in vitro maturation. This involves taking immature eggs from the woman's ovaries and maturing them in the laboratory. The method's success rate is relatively low at present, with only 23% of women becoming pregnant at the first attempt, which means that multiple attempts have to be made. On the other hand, the treatment period is shorter, and the high costs of hormone therapy are avoided.

Hovatta and her colleagues have also developed groundbreaking methods for fertility preservation. She was the first to publish a revolutionary method for freezing ovarian and testicular tissue back in 1996, and her research group now faces a key challenge: getting the least developed egg cells to mature from frozen ovarian tissue. And they are almost there.

"It looks like it could soon work, but there are still a few things that we need to resolve. We've identified a gene that keeps eggs inactivated in the ovaries, and we've found a mechanism that can prevent this inactivation and get the egg to mature outside the body."

The method may help some women and children with cancer who undergo ovary-damaging chemotherapy to regain the ability to have children later in life.

Unexplained miscarriage

Another cause of infertility is recurrent miscarriage. This may be due to problems with hormone balance or the immune defence, malformation of the womb, or a genetic disorder. When it comes to missed miscarriages, where a dead foetus is not spontaneously ejected from the womb, 40% of cases are a result of chromosome defects. But some miscarriages are still unexplained.

Bild på Kristina Gemzell Danielsson."There's still much that we don't know - even if the woman's hormone balance is OK, there may be a local problem in the lining of the womb which causes a breakdown in communication between mother and unborn child from the very outset," explains Kristina Gemzell Danielsson, professor of obstetrics and gynaecology from the Department of Women's and Children's Health at Karolinska Institutet and consultant at the women's clinic at Karolinska University Hospital Solna.

Among other things, Danielsson is looking at the function of the lining of the womb and the role it plays in infertility. Even as the egg passes through the Fallopian tube to the womb, there is an exchange of signalling substances between the fertilised egg and the mother. Successful implantation of the embryo in the womb requires synchronisation between the embryo and the lining of the womb.

The goal for Danielsson's research group is more effective prevention and treatment of problems such as pre-eclampsia and miscarriage, which can be due to defective implantation. The interaction between the embryo and the lining of the womb is difficult to study directly in humans, and so they are using cells from the Fallopian tubes and the lining of the womb and embryos donated by healthy fertile women.

"We've developed a unique 3D model of the lining of the womb which includes all of its cell layers," says Danielsson. "This enables us to test the role of various factors, such as cytokines, in implantation."

After many years of hard work, the research group has managed to find the right materials, conditions and techniques for dealing with the cells in the model. They have now found, for example, that if leukaemia inhibitory factor is absent, or present in excessive concentrations, the lining of the womb does not respond to signals from the embryo, even if the embryo appears viable. Implantation will then fail. In the longer term, the group hopes to be able to replace the factors or signalling substances that are missing.

"So far this is only at the research stage, but the aim is to improve the treatment of infertility," says Danielsson.

Swedish doctors generally use only gentle instruments in cases of miscarriage and abortion, but the hard instruments used in large parts of the world can cause scarring and blockages in the womb.

Danielsson is also looking into whether it might be possible to use endometrial stem cells to repair damage to the lining of the womb and get it to function again. The mechanism is believed to be the same as when the lining of the womb repairs itself after menstruation, because then there is no scarring despite the bleeding. Research also shows that the lining of the womb can be damaged by hormone stimulation.

"We must therefore be careful with IVF treatments. Sweden is already a world leader in IVF, but perhaps we can get even better results if we change the use of hormone stimulation."

Old eggs can cause infertility

It is becoming more and more common for women to put back having children until later in life, which means that more are having problems conceiving and need help. Old eggs are one of the causes of infertility, as the egg cells make more mistakes when they divide.

Bild på Christer Höög.Christer Höög is a professor at the Department of Cell and Molecular Biology at Karolinska Institutet. His research group is trying to find out why the complex molecular mechanisms that control how the chromosomes are distributed when the sex cells divide do not always work properly.

Using a special strain of mice, they have been looking at how egg cells distribute their chromosomes, and what happens at a more advanced age. Together with Outi Hovatta, they are now trying to switch from mice to humans to discover what it is that goes wrong in the female sex cell.

"Progress in this field is relatively slow," says Höög. "It's hard to conduct research on human eggs, because we only have access to a small number. We are therefore using mice, but the results need to be tested on human eggs too."

As women get older, their eggs are less able to distribute their chromosomes correctly. This results in too many or too few chromosomes, known as aneuploidy. Research shows that by the age of 40 women have defects in 80-90% of their eggs. In men, the risk of aneuploidy does not increase particularly with age, because new sperm are constantly being produced from stem cells. Women, on the other hand, are born with a pool of germ cells that have already divided once, and maturation may not be completed for another 20 years. This means that these cells spend a very long time in a very delicate state.

"These germ cells are sensitive to age, and we're trying to find out why," says Höög. "One possible hypothesis for why things go wrong is that some of the cohesins - proteins that hold the chromosomes together until they need to be used during fertilisation - break down. They don't seem to be sufficiently stable."

Text: Helena Mayer, Published in Medicinsk Vetenskap (Medical Science) no 4, 2010

Cell and Molecular BiologyGynaecologyObstetricsReproductive Medicine