Possible cause of IVF failure in some women identified
IVF only has around a 25% success rate, largely due to the high rates of failure when embryos try to implant. Some women suffer from recurrent implantation failure, where the embryo is transferred but fails to attach to the endometrium - the mucus membrane of the uterine wall. This is a significant cause of the failure of IVF as most embryo losses occur at this early stage.
Women who repeatedly suffer this failure have been shown to have altered levels of microRNA in their endometrium, so the researchers at The University of Manchester’s Institute of Human Development decided to experiment with varied levels of microRNA-145 and its target, the receptor for insulin-like growth factors (IGF1R).
They found that IGF1R has a previously unknown role to play in the attachment process and that when it is reduced there is a higher probability that the embryo won’t attach.
Professor John Aplin, who led the study said: “When an embryo is ready for implantation, its replacement is carefully timed to coincide with the window of maximal receptivity in the uterus.
“This window is open for no more than four days. Our study suggests that the presence of IGF1R during this period is required for the embryo to stick to the uterus.”
MicroRNA-145 has a role to play in this process as over-expression inhibits the growth of IGF1R. The lab research conducted by the team showed that varying this level had a direct effect on IGF1R.
Causes of IVF Failure
1. Egg Quality
2. Sperm Quality
3. The Stimulation Protocol
4. The HCG Injection
5. The Endometrium
6. The Embryo Transfer
7. The IVF Laboratory
After investing an enormous amount of time, emotion, and financial resources, a negative result can be devastating. The post-IVF meeting allows the physician and patient to review the cycle, answer questions, and hopefully, come up with a better treatment plan for the future. At IVFMD, we analyze the following factors to find the causes of IVF failure:
1. Egg Quality
The egg is the first and most important factor to be considered during the analysis for the causes of IVF failure. The egg provides the majority of the ingredients required for successful fertilization and embryo development. Once the sperm enters the egg, it triggers a series of biochemical reactions that lead to the formation of the male and female pronuclei, which then fuse to combine the the parents’ genetic material to create the embryo. The single cell embryo subsequently divides into daughter cells through a process regulated by the organelles that reside within the cytoplasm of the egg. As the cells divide, the chromosomes from the original cells migrate along special pathways (the mitotic spindles) into the daughter cells. With time, these migrating tracts can become defective resulting in abnormal separation of the chromosomes. The result is an embryo with an abnormal number of chromosomes that, depending on the severity of the error, may stop growing at an early stage in the lab or eventually ends as a biochemical pregnancy or first trimester miscarriage.
Age has a great impact on the egg. After age 30 egg quantity and quality begin to decline and the rate accelerates after age 35, so that by age 40 only about 10% of a woman’s eggs are normal. The decrease in egg number, when combined with poor egg quality, often translates into a lower chance of creating a normal embryo with IVF.
Although they acknowledge that more research is needed to confirm the findings - particularly in the difficult-to-observe human uterus at the time of implantation - they believe that developing treatments to suppress microRNA-145 could lead to improved rates of attachment.
Professor Aplin said: “This is one of the hardest groups of women to treat in fertility science and rates are still very low across the board. Repeated IVF cycles are stressful and can be expensive too. Greater understanding of the mechanisms which control success or failure can lead directly to treatments to make IVF cycles more efficient so that infertile couples can start their families.”
Abnormal Sperm
Although abnormal sperm appear to be a less common factor affecting the success of an IVF cycle, they nevertheless play an important supporting role. Sperm do not merely bump into an egg and cause fertilization. Rather, the process of fertilization itself is very complex. In order for sperm to migrate to the egg, they must be motile; in other words, the tail of the sperm must be able to propel the sperm through the female reproductive tract to the egg. There are specific receptors on the surface of a sperm head that bind to specific receptors on the outer membrane of an egg allowing for sperm/egg interaction. Once this happens, enzymes are released from the sperm head that enable digestion of a hole in the outer membranes of the egg. The sperm eventually penetrates the egg where the nucleus of the sperm opens, releasing the sperm DNA. At that point, the chromosomes from the sperm and the chromosomes from the egg combine, producing a fertilized egg (which is actually a very early embryo). Studies suggest that the incidence of chromosomal abnormalities in sperm is far greater than that seen in eggs. However, whereas a chromosomally abnormal oocyte may lead to a chromosomally abnormal pregnancy, chromosomally abnormal sperm appear to not be able to successfully fertilize an egg.
Intracytoplasmic sperm injection (ICSI) was developed to enable men with very low sperm counts, low motility, or very few normal sperm to be able to achieve fertilization and pregnancy. Over the past few years, ICSI has evolved to the point that it is now routinely performed in cases of severe male factor, resulting in fertilization rates comparable to those achieved with normal sperm. In addition, data from long term studies suggest that the incidence of chromosomal abnormalities in the offspring from IVF cycles in which ICSI was utilized do not exceed those found in nature.
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The full paper: miR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R’, published in the Journal of Cell Science can be read here.
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Jamie Brown
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44-016-127-58383
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University of Manchester
Journal
Journal of Cell Biology