Ovarian stimulation undertaken by women over 35 years of age who are receiving fertility treatment may be disrupting the normal pattern of meiosis - a critical process of chromosome duplication - and leading to abnormalities of chromosome copy numbers (aneuploidy). This can result in IVF failure, pregnancy loss or, more rarely, the birth of affected children with conditions such as Down's syndrome. The findings about meiosis disruption were presented yesterday at the annual conference of the European Society of Human Reproduction and Embryology today.
The findings come from an analysis of polar bodies, the small cells that are the by-product of oocyte (egg) development. "We were able to examine the copy number of all 23 pairs of chromosomes, in all three products of female meiosis in over 100 oocytes with abnormal numbers of chromosomes," said fertility researcher Alan Handyside. "What happens in female meiosis is that the 23 pairs of chromosomes duplicate and each pair of duplicated chromosomes comes together and the four single chromosomes, or 'chromatids', become 'glued' together along the whole length of each chromosome. This actually occurs before the woman is born and is the stage at which DNA is swapped between the grandparents' chromosomes."
But sometimes, decades later, just before ovulation, the glue "dissolves" first between the two duplicated chromosomes and finally after fertilization between the two individual chromosomes. This enables pairs of chromosomes to segregate in the first meiotic division producing the first polar body. In the second meiotic division the second polar body is produced, resulting in a single set of chromosomes in the fertilized oocyte which, when combined with the single set in the fertilizing sperm, restores the 23 pairs.
The researchers believe that ovarian stimulation may be disturbing this process in older women because the chromosomes are becoming unglued prematurely, particularly the smaller ones like chromosome 21. Ovarian stimulation uses hormonal medication to stimulate the ovaries to release a larger number of oocytes than normal, in order to provide enough good quality oocytes for fertilization in vitro.
Following natural conception in older mothers, Down's pregnancies are predominantly caused by errors in the first female meiotic division. "Our evidence demonstrates that, following IVF, there are multiple chromosome errors in both meiotic divisions, suggesting more extensive premature separation of single chromosomes resulting in more random segregation, which in turn results in multiple chromosome copy number changes in individual oocytes," explained Professor Handyside.
"We need to look further into the incidence and pattern of meiotic errors following different stimulation regimes including mild stimulation and natural cycle IVF, where one oocyte per cycle is removed, fertilized and transferred back to the woman. The results of such research should enable us to identify better clinical strategies to reduce the incidence of chromosome errors in older women undergoing IVF," he concluded.
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Source: European Society of Human Reproduction and Embryology