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'Reawakened' ovaries and infertility cure claims

“A baby has been born through a new technique to ‘reawaken’ the ovaries,” is the intriguing story on the BBC News website.

The news is based on the work of a team of researchers who have developed a technique that could potentially treat some women with a type of infertility called primary ovarian insufficiency (POI) – also known as premature ovarian failure.

In cases of POI, women have problems with their follicles – the small sacs in the ovaries in which eggs grow and mature. They run out of working follicles or have some follicles remaining in the ovaries that are not working properly. As a result they develop menopausal symptoms early, before they reach 40 years of age, and many are unable to have children. This condition affects around 1 in every 100 women.

In the current study, researchers surgically removed the women’s ovaries, split them into fragments, and then treated them with drugs designed to stimulate tissue growth. The fragments were then grafted back into women. In some women, rapid follicle growth occurred, and some mature eggs were retrieved. In one woman, these eggs were used for in vitro fertilisation and embryo transfer, and she has given birth to a healthy baby.

This research provides proof-of-principle that this technique can work for women with POI. However, further research will be required before this technique could become widely available. Researchers also say that although this technique could be used on women with other causes of subfertility, it does not overcome the possibility of age- or environment-related defects in eggs. 

Where did the story come from?

The study was carried out by researchers from St Marianna School of Medicine, Akita University, Kinki University and the IVF Namba Clinic in Japan; and Stanford University, US. It was funded by the National Institutes of Health, National Institute of Child Health and Human Development, California Institute for Regenerative Medicine, Grant-In-Aid for Scientific Research, and funds from The Uehara Memorial Foundation, The Naito Foundation, Terumo Life Science Foundation, Astellas USA Foundation and Mochida Memorial Foundation.

The study was published in the peer-reviewed journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The story was generally well reported in the media. Although the Daily Express’s headline – “Mothers ‘could give birth at 60 plus’” – is misleading.

As BBC News points out, this technique is unlikely to help women have children at older ages, as at older ages egg ‘quality’ becomes an issue. Its story includes a quote from an infertility expert, Professor Nick Macklon, who says: “Quality and quantity [of eggs] are two very different things.”

What kind of research was this?

This was research on mice and a group of 27 women with primary ovarian insufficiency (POI). In this condition a woman’s ovaries stop working normally before she reaches the age of 40, which is earlier than menopause would usually occur.

Many women with POI do not get monthly menstrual periods (amenorrhoea) or they have them irregularly.

Resulting problems with ovulation may make it difficult for women with POI to get pregnant. POI is related to problems with follicles, the small sacs in the ovaries in which eggs grow and mature.

The first part of the research used animal studies to determine how specific treatments (called ovarian resection and drilling) worked for polycystic ovarian syndrome – another condition that can cause infertility.

The techniques involve removing or destroying parts of the ovary, but they can also trigger ovulation. They investigated this using mice. The researchers then developed a method for re-activating ovaries, and tested whether it would work in women with POI.

This research aimed to provide proof-of-principle that this technique can work for women with POI. Larger studies would be needed to assess how frequently this technique works, how effective and safe it is compared to existing treatments and whether it could be used to treat other types of infertility.

What did the research involve?

The researchers initially determined how ovarian resection and drilling treatments might work and performed a number of experiments on mice.

The researchers then applied their findings to women.

The researchers removed the ovaries from 27 women with POI. In the laboratory they cut the ovaries into strips and analysed some to see whether there were any residual follicles present.

They then froze the strips. After thawing, they fragmented the strips further into cubes of 1 to 2 mm2 and treated them with a specific type of drug for two days.

These drugs had previously been shown to be able to activate dormant follicles in mouse ovaries. They then transplanted the treated ovarian cubes back into the women.

The women were monitored by ultrasound, and serum oestrogen levels were measured to assess whether the follicles were growing (a sign they might be becoming active). When follicle growth was detected, the women were treated with hormones to promote egg maturation, and eggs collected from the follicles. These eggs were then fertilised in the lab with the husband’s sperm using in vitro fertilisation, and embryos were transferred back into the mother.

What were the basic results?

The researchers found that if they fragmented ovaries before transplanting them into mice that the ovaries grew more, and that follicle (the small sacs in the ovaries in which eggs grow and mature) growth was promoted.

This is in line with the findings that ovarian resection and drilling treatments can be used for polycystic ovarian syndrome. They found that ovarian fragmentation disrupted a signalling pathway called “Hippo”, which the bodies of mammals use to regulate the size of organs. Disrupting this pathway could help stimulate tissue growth that would otherwise not occur. (Signalling pathways are specific ways in which cells “communicate” with each other).

The researchers found that fragmented ovaries produced oocytes (egg cells) after being transplanted back into mice, which had been treated with several hormones. These oocytes could then be collected and fertilised in the laboratory. The resulting embryos were transferred into surrogate mothers, who gave birth to healthy pups.

The researchers then found that stimulating another signalling pathway, called Akt, with Akt-stimulating drugs produced additional follicle growth.

The researchers then tested whether ovarian fragmentation (disrupting Hippo signalling) and Akt stimulation could work as an infertility treatment for women with POI.

Of the 27 women with POI, 13 had residual follicles. After transplantation of the drug-treated ovarian cubes, follicle growth was detected in eight women, all of whom had residual follicles. Mature oocytes (eggs) were collected from five women.

They carried out in vitro fertilisation and transplantation of embryos in three women. One woman had two embryos transferred, but no pregnancy occurred. One woman had two embryos transferred and is currently pregnant. One woman had two embryos transferred, became pregnant and gave birth to a healthy baby. 

How did the researchers interpret the results?

The researchers conclude that they have demonstrated “additive increases in follicle growth when ovarian fragments containing secondary and smaller follicles were treated with Akt stimulators. Using this in vitro activation method for infertility treatment of [primary ovarian insufficiency] patients, we successfully promoted the growth of residual follicles in autographs and report a viable birth following oocyte retrieval and in vitro fertilization (IVF)-embryo transfer”.

The researchers go on to say that “the ovarian fragmentation-in vitro activation approach is not only valuable for treating infertility of [primary ovarian insufficiency] patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve”.

Conclusion

This study has developed a technique that can reactivate ovarian tissue from women with primary ovarian insufficiency as long as they have residual follicles (the small sacs in the ovaries in which eggs grow and mature).

It should be noted that the researchers point out that women without any residual follicles will not respond to this technique. They also point out that although this technique could be used on older women, it does not overcome age- or environment-related increases in defects in eggs. So the Daily Express’s fanciful claim that this technique could lead to women in their sixties giving birth is almost certainly not going to happen.

It is also important to bear in mind that not all women with primary ovarian insufficiency have residual follicles, and the technique did not work in all of the women who did have them.

This research provides proof-of-principle that this technique can work for women with primary ovarian insufficiency. Larger studies will be needed to get a better estimate of the success rate of this approach, and to test the technique in women with other causes of subfertility.

Due to the highly experimental nature of this research it is impossible to predict when, or indeed if, this type of treatment becomes available on the NHS.

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