Thursday November 29 2007
In vitro fertilisation
“A class of drugs under development to treat cancer could be useful for treating infertility too” The Daily Telegraph reports today.
The newspaper goes on to explain that a gene "central to many cancers" also appears to play a role in fertility. The gene p53 is responsible for a protein that holds tumours in check by stopping damage to DNA.
This study in mice found that litter size was significantly increased and the pregnancy rate was raised to 100% when both parents had the p53 gene on both chromosomes. Mice that didnt have a working copy of the gene had a reduced embryo implant success rate and consequently smaller litters. By injecting these mice with a protein that is usually produced by the p53 gene, and was therefore lacking, the successful mice pregancy rate and litter size were improved nearly to the level of those with the p53 gene on both chromosomes.
The Daily Telegraph mentioned that the authors are working to “test these ideas” with a fertility clinic in New York. It is not clear what this means and at what stage this research is at, but results from human studies reflect treatment effectiveness better than studies on mice. Usually it is years between studies in animals and meaningful studies in humans.
Where did the story come from?
Doctor Wenwei Hu and colleagues from the Cancer Institute of New Jersey in the US conducted the research which was supported by grants from the Breast Cancer Research Foundation and the National Cancer Institute. The study was published in the peer-reviewed medical journal: Nature.
What kind of scientific study was this?
This was an animal study that investigated the effect of the p53 gene on fertility in mice. The p53 gene codes for protein 53, a protein that suppresses tumours and can trigger the body’s defense against cancer. People with faulty copies of the gene are more likely to get a variety of cancers.
The researchers bred two strains of mice that had one of four different genotypes. They either had the p53 gene on both chromosomes (homozygous), on one of either of the chromosomes (heterozygous) or did not have the p53 gene at all (p53 negative). The mice were mated and the litter size and pregnancy rates were compared between the groups to see whether there was any effect of p53 on fertility.
To ensure that any defect in reproduction was due to the loss of the p53 gene rather than other differences in the genetic background of the mice, the mice were bred within each strain, and also interbred with mice from other strains. In this way, the researchers were able to say that the smaller litter sizes were dependent on the loss of the gene rather than the genetic background of the mice.
The researchers also tested the theory that the absence of the p53 gene affects reproduction through its affect on a protein called the "leukaemia inhibitory factor" (LIF). This protein is a cytokine (a substance used by cells as a signaling compound) that allows cells to communicate with each other and which eventually affects cell growth and development.
LIF is involved in gene encoding and has been found to be critical to the implantation of the developing embryo in the uterus. The researchers thought that the gene p53 regulates the amount of LIF being produced and wanted to test whether injecting LIF into the mice with no p53 gene had an effect on the litter size and pregnancy rates. If they were correct in their interpretation of the mechanism, they expected that adding LIF to p53 negative females who had mated with p53 negative males would increase the litter size.
What were the results of the study?
The researchers found that when male and female mice that had two copies of the p53 gene were mated, an average of over six embryos implanted successfully in the mice uterus at the same time (referred to as litter size) and all the mice became pregnant - the pregnancy rate was 100%.
When neither the male nor the female mice carried the p53 gene on either chromosome, the average number of embryos implanted was less than one and the pregnancy rate was 27%. The difference in number of embryos and pregnancy rate were statistically significant.
The results for the tests of the effect of LIF on pregnancy rates and litter size showed that when mice with no p53 gene mated and the females were injected with LIF on the fourth day of pregnancy, the litter size increased to an average of five embryos and a 100% pregnancy rate was achieved.
What interpretations did the researchers draw from these results?
The researchers noted that the most common cause of unsuccessful human in vitro fertilisation is a failure of the embryos to implant in the uterus. They also say that low LIF protein levels have been reported in infertile women.
They claim that their results show a new function for the p53 gene in maternal reproduction in mice through regulation of the LIF protein. They propose that p53 may have a similar function in humans.
What does the NHS Knowledge Service make of this study?
This animal study used recognised techniques and reported on its results and methods appropriately.
As mentioned in the media reports, more research is required to discover precisely how p53 regulates maternal reproduction in humans before it is possible to confirm whether these types of treatments offer any hope for improving human fertility.
Sir Muir Gray adds…
There will be a long and winding road before an infertility treatment becomes available - if ever. Animal studies carry no guarantee of human benefit, particularly when a treatment for one condition is considered for use for another.