Researchers examine 'fertility switch'

“High levels of a protein called SGK1 can cause infertility, but when there is not enough, women are more likely to lose a baby,” reported the Daily Mirror. The newspaper said that scientists hope “the discovery will lead to treatments to ensure women have the right levels of the enzyme in their womb lining.”

This report is based on a study performed on human womb cells and genetically engineered mice. High levels of this protein were found in the lining of the womb in women who were infertile. Meanwhile, reduced levels of the protein were found in the lining of the womb in women who had recurrent miscarriages.

Using a mouse model, the researchers demonstrated that producing high levels of SGK1 in the womb lining stops embryos implanting, meaning the mice did not get pregnant. Another mouse model showed that if the production of SGK1 was switched off, the mice became pregnant, but lost many of the foetuses.

This is complex research and appears to have been well conducted and carried out. The findings will help target future research into the role of the SGK1 protein in fertility and pregnancy. Eventually, these findings may lead to ways to manipulate the effects of this protein to increase the likelihood of successful pregnancies. However, this is early stage research and it may be a long time before we know if such a practical application of these findings will become reality.

Where did the story come from?

The study was carried out by researchers from Imperial College London, the University of Cambridge, the University of Manchester, Warwick University, and Tübingen University in Germany. Funding was provided by the Contraceptive Research Development Program Consortium for Industrial Collaboration in Contraceptive Research, the UK National Institute for Health Research Biomedical Research Centre and the Genesis Research Trust. The study was published in the peer-reviewed journal Nature Medicine .

This story was covered by the BBC and_ The Mirror._ The BBC coverage was accurate, and described both the potential applications of the findings and included a quote from experts stating that it will take time translate these findings to the clinic. The Mirror focused on how these findings could be used to combat infertility and miscarriage. This research is still at an early stage, however, and it is too soon to say what practical use these findings may have.

What kind of research was this?

This was a laboratory and animal based study that looked at the role of a protein called SGK1 in pregnancy and fertility. The SGK1 protein is produced in the lining of the womb (the endometrium), and the researchers thought it might play a role in embryo implantation in the womb and possibly in miscarriage.

The research used tissue and cells from women with proven fertility, women with unexplained infertility, and women with recurrent pregnancy loss. It also looked at what effect switching on or off the production of this protein would have on pregnancy in female mice. This was an appropriate study design to use, as the protein could not be manipulated in this way in humans.

What did the research involve?

The researchers looked at the levels of a protein called SGK1 in endometrial (womb lining) samples from women with proven fertility, women with unexplained infertility, and women with recurrent pregnancy loss (defined here as three or more consecutive miscarriages).

To determine the role of SGK1, the researchers genetically engineered mice so they produced a form of SGK1 that was always active, as well as mice that did not produce any SGK1. They then looked at what effect these changes had on the ability of the mice to get pregnant, and to have successful pregnancies that resulted in the birth of live offspring.

The researchers also analysed cells from the womb lining of women with recurrent pregnancy loss, and fertile women. They gave the cells a chemical stimulus to mimic the effects of pregnancy. They then looked at what effect a lack of SGK1 would have on these cells in the laboratory.

What were the basic results?

The researchers found that levels of SGK1 were higher in the womb lining of infertile women than fertile women. Levels of SGK1 were lower in the womb lining of women who had recurrent pregnancy loss than fertile women. The researchers also found that more of the protein was in its active state in infertile women than in fertile women, or women with recurrent pregnancy loss.

To determine the effect of these differences, the researchers genetically engineered mice to produce a form of SGK1 that was always active, to try to mimic what they had seen in the womb linings of women with unexplained infertility. They also genetically engineered mice to lack SGK1, to mimic the situation seen in the womb linings of women with recurrent pregnancy loss.

In mice that were engineered to produce the active form of SGK1, embryos could not implant into the womb lining, meaning the mice did not get pregnant. The mice that did not produce SGK1 were able to get pregnant similarly to normal mice, but had smaller litters as at least 30% of the foetuses were lost. There was also evidence of bleeding from the womb. The researchers concluded that lack of SGK1 triggers events similar to those seen during human miscarriage.

The researchers also analysed cells from womb lining in women who had recurrent pregnancy loss and fertile women. They found that in cells from fertile women, levels of SGK1 increased after a stimulus to mimic pregnancy was given. The increase in SGK levels was much less in cells from women who had recurrent pregnancy loss.

The researchers examined what effect a lack of SGK1 had on human womb lining cells. They found that some of the cells died when the pregnancy stimulus was given when SGK1 was absent.

How did the researchers interpret the results?

The researchers conclude that deregulation of a single protein, SGK1, is linked to both embryo implantation failure (infertility) and miscarriage. They say that continuous SGK1 activity in the womb lining leads to ‘complete infertility’. However, in pregnancy, SGK1 is required to protect the tissue lining the womb, and lack of the protein can increase the risk of miscarriage.

Conclusion

In this study, researchers have implicated the protein SGK1 in both infertility and recurrent pregnancy loss - two distinct causes of pregnancy failure. They found that this protein is produced at high levels in the womb linings of women with unexplained infertility, and a high proportion of the protein is in its active state. Using a mouse model, the researchers demonstrated that producing high levels of SGK1 in the womb lining stops embryos implanting, meaning the mice did not get pregnant.

The researchers also found that women who had a history of miscarriage (on three or more consecutive occasions), produced less SGK1 in the womb lining. They used another mouse model to investigate this, and found that in mice lacking SGK1, although embryo implantation did take place, some of the foetuses were lost.

This appears to be well conducted and well documented research. The use of mouse models and both human cells and tissue to investigate the role of this protein strengthens the likelihood that the findings may apply to human infertility and recurrent pregnancy loss. These findings will help target future research into the role of the SGK1 protein in fertility and pregnancy.

This research may eventually lead to ways to manipulate the effects of this protein to increase the likelihood of successful pregnancy. However, further research will take time and it is likely to be a while before we know if a practical application of these findings will become reality.