Aneuploidy Versus Chaotic Mosaicism

It should be clear by now that the majority of human eggs are abnormal. They are either chromosomally abnormal, having too few or too many copies of specific chromosomes, or developmentally abnormal in the way they progress from stage to stage. This problem with human embryos, which is not seen anywhere else in the animal kingdom, is caused, for the most part, by intrinsic problems in the egg, and these problems increase in severity and frequency with increasing age.

There is a fourfold increase in chromosomal aneuploidy that occurs from a woman’s late twenties and early thirties until her late thirties and early forties. This fourfold increase in chromosomal abnormalities is simply related to the aging of the egg, and it is superimposed on a background incidence of chromosomal abnormalities seen in the human that is unprecedented in any other animal. The background rate of chromosomal abnormality unrelated to the wife’s or husband’s age is related either to an intrinsic defect in her eggs or to an intrinsic defect in his sperm.

With aneuploidy, the chromosomes get stuck in their tracks, so to speak, and an extra chromosome may be left behind in the egg via a process called nondisjunction. Thus, not all of the chromosomes move to their proper positions in the process of reducing the chromosome number from forty-six to twenty-three. With aneuploidy, almost every cell in the developing embryo suffers from having an incorrect number of a particular chromosome. Three copies of chromosome 21, which results in Down syndrome, or three copies of chromosome 16, which results in an early miscarriage, are classic examples of aneuploidy, where there are just one or two chromosomes in error, and they are uniformly in error in every cell of the embryo. The rest of the chromosomes of the aneuploid embryo are normal. Aneuploidy is a uniform problem in all the cells of the embryo and is specifically caused by the aging of the egg.

However, chromosomal abnormalities can be much more complex, involving more than just one chromosome, and can be different in different cells of the embryo. This is called mosaicism. Mosaicism can be caused by either an intrinsic egg problem or by a defect in the sperm. In this kind of problem there may be several different chromosomes that have only one copy, or three copies, rather than the normal two copies. Furthermore, which chromosomes have an abnormal number of copies may be different in different cells of the embryo. These are very abnormal embryos that would not ever be likely to implant, or else would lead to an extremely early miscarriage. This more complex kind of chromosomal error is not due to aging, and is caused by an intrinsic problem either in the egg, or in the sperm, unrelated to the biological clock.

The first couple who helped us discover the role of the sperm in normal embryo development was a twenty-five-year-old woman married to a twenty-eight-year-old man who were celebrating their fifth anniversary when they first saw me. He had no sperm in his ejaculate. We were, however, able to find a small number of sperm in his testicles using TESE, and we injected them into his wife’s eggs in an IVF cycle. Twenty-three eggs (out of twenty-six) were fertilized and subjected to PGD. From those twenty-three fertilized eggs, only three embryos were chromosomally normal, two boys and one girl. We replaced all three of those chromosomally normal embryos into her uterus, and she delivered healthy twins nine months later, one boy and one girl.

The fascinating discovery stemming from this couple was that in such a young woman, in whom the only problem was the infertile male, you would not expect to find such a huge number of chromosomally abnormal embryos. The embryos exhibited a complex, chaotic array of errors that had to be occurring during the course of cell division in the developing embryo, rather than originating in a nondisjunction event in the egg prior to fertilization. Such a large number of embryos with chromosomal abnormalities in this young patient was more likely caused by the sperm than the egg.

These chaotic abnormalities had to develop out of an improper structural system for cell division in the early embryo caused by a sperm centrosome defect. The motor that directs the whole system for cell division comes from the sperm centrosome. This is the little circular structure at the neck of the sperm that joins the head and the tail, and helps propel the sperm tail and gives the sperm its movement. This centrosome of the sperm is also what becomes the centriole of the fertilized egg, which controls cell division for every cell in your body. In fact, every single cell in your body (which all have to divide) derives its centriole from your father’s sperm. Chromosomally chaotic embryos can also develop from an intrinsic problem in a particular woman’s eggs, but even then it is not related to aging of the egg.

Table 14.2 depicts the results of a thirty-eight-year-old woman using normal donor sperm for IVF. Only three of the embryos from twenty-two fertilized eggs were chromosomally normal. All of the abnormal embryos, except for number nine, were simple aneuploidies in otherwise normal-appearing embryos. This is the type of chromosomal error that is found in the normal-appearing embryos of aging eggs.

The chromosomal defects associated with aging eggs result in normal-appearing embryos. Chromosomal abnormalities associated with severely deficient sperm result in abnormal-appearing embryos. But even when the sperm centrosome is normal, a certain percentage of eggs (unrelated to aging) will be chaotic mosaics, abnormal in appearance and intrinsic to that particular woman’s eggs at any age.

A couple who demonstrated this dilemma came to us because the husband had moderately low sperm production. The wife was young (twenty-nine years old) and healthy. During their first ICSI cycle, we were able to obtain many eggs, and there was a consistently high fertilization rate. With more than twenty-five embryos examined by PGD in each of three separate ICSI/IVF cycles, every single embryo had some sort of complex, chaotic abnormality, with poor cell division. So we tried using donor sperm in two subsequent cycles, thinking that perhaps a defect in the sperm centrosome was causing this poor result. But after several cycles with donor sperm, we continued to obtain only large numbers of chromosomally chaotic, abnormal-appearing embryos.

After much soul-searching, we decided the problem was the wife’s eggs (even though she was young and produced many eggs). So for the next IVF cycle, we used the husband’s sperm rather than donor sperm, but now employed donor eggs. This was a relatively bold step to take in view of the fact that she was young and healthy, and had produced so many eggs in every IVF cycle. As soon as we switched to donor eggs, there were quite a few chromosomally normal embryos, and she became pregnant immediately with twins.

The type of egg defect she exhibited (chaotic mosaicism) was not related to her age. Two percent of even young women are infertile, and this is usually because of an intrinsic problem with their eggs that has nothing to do with their biological clock. These two exemplary cases demonstrate that repeatable defects in embryo development causing consistent failure to get pregnant with ICSI and IVF may be the result of a defect in the sperm (which might be expected in view of the very low sperm production rate), or may be due to a defect in the eggs (despite the wife being young and having many eggs).

What relates to the biological clock is the more simple chromosomal errors called aneuploidy, which increase dramatically with the woman’s age and with the decrease in her ovarian reserve. The number of embryos that appear abnormal does not seem to increase with a woman’s age or her biological clock. What increases with the age of her eggs is the number of normal-appearing embryos that are actually chromosomally abnormal. Miscarriage is caused, for the most part, by the more simple chromosomal errors (aneuploidy) that increase in frequency with the age of the woman, and that result in completely normal-appearing embryos.

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