Women are faced with the harsh reality that as they age their chances of having a child that is genetically their child become less and less. At a relatively young age by today’s standards, they will lose the ability to have children so that by age 41, as much as 50% of Caucasian females with be unable to have their own child.
Enter Ovarian Reserve Testing. A number of tests have been proposed to identify the at-risk women. The three most commonly used tests for ovarian reserve today are the antral follicle count done using ultrasound, day three hormone determinations for FSH, LH, and estradiol, and AMH.
However, the tests themselves are only part of the picture.
So where is the problem and how do eggs factor into this?
Oocytes (eggs) contribute half of the genetic material that is required to make a human. The other half comes from the male and thus for many of the instructions for how to build a human, there are two identical sets of plans. Thus if there is an error in one set, the other set compensates and a child is born. Instructions for building a human are called genes and the genetic material is condensed into sausage – like structures called chromosomes. People have 23 sets of chromosomes with the 23rd set being the sex-determining chromosome: the X and/or the Y (female=XX; male= XY). The other 22 sets are numbered 1-22. A clinical example of a person with an abnormal number of chromosomes is a Down person who has three chromosome 21s instead of the usual 2.
Oocytes have a set of chromosomes and sperm have a set of chromosomes so that when the sperm fertilizes the oocyte, the resulting embryo has the correct number of chromosomes. The process of creating an oocyte that has a single set of chromosomes is called meiosis and is frequently done incorrectly. An early oocyte starts with two sets of chromosomes, just like any other cell in the body, but must go through a process which reduces this number to one set of chromosomes. This process is very mechanical. The oocyte has a system of small fibers much like a rail system that the chromosomes attach to. The oocyte can then pull the two sets of chromosomes apart leaving a single set of chromosomes as this early oocyte divides to form the oocyte that can be used for sperm to fertilize. As an oocyte ages, these microfilaments can break and thus too many chromosomes go with one daughter cell and not enough go with the other daughter cell. There are energy- generating structures within the oocyte called mitochondria which produce energy. Older mitochondria produce less energy than younger mitochondria. The oocyte has proteins which it uses to do its work, and these become less effective as the oocyte ages.
The bottom line is that for an embryo to create a human, it must have the correct number of chromosomes. For this to happen the oocyte must be structurally normal. The common parlance of “bad egg” refers to oocytes that are structurally abnormal and a “good” egg is a structurally normal oocytes.
The underlying physiology of the aging problem starts with the fact that women stop producing oocytes 5 months into the process of gestating inside their mothers. They produce 6-7 million oocytes but by the time they are born, they are down to 2-3 million oocytes. By age 20 women have 300K – 400K oocytes. The ovary recruits a large number of oocytes each month. A 20-year-old recruits approximately 1000 oocytes per month and this recruitment goes on incessantly until there are no more oocytes to recruit. The pool of oocytes has been called a reserve. Since oocytes are not created, this pool of oocytes represents the total reproductive potential for a woman. Age decreases the pool, or reserve, and thus there is a constant reduction in the ovarian reserve. Women would be best served if there was a way to track the status of the reserve so that if it became dangerously low she could elect to preserve her fertility by undergoing fertility preservation where multiple oocytes are simulated to develop and then these are removed after which they are frozen for use in the future. Unfortunately, no accurate test has been devised.
A critical and frequently under appreciated subtlety of this process is that the pool of oocytes is really composed of two groups of oocytes: one group is structurally normal and can create embryos with the correct number of chromosomes. The other group of oocytes are structurally damaged and cannot create embryos with the correct number of oocytes. The ovary has a nasty tendency to use the normal oocytes first. Thus, as a woman ages her pool of normal oocytes diminishes and more and more of the remaining oocytes are structurally damaged and create embryos with an incorrect number of chromosomes. The clinical example of this is the increased miscarriage rate as women age and the increased chance for the birth of child with Down syndrome trisomy 21). At some point, all oocytes are structurally abnormal even though there are still oocytes present in the ovary.
A concept called “reduced ovarian reserve” has evolved. Reduced ovarian reserve is used to describe the effect of age on the ability of the oocytes in the ovary to create embryos with the correct number of chromosomes. While this seems like a logical concept, there is a subtle problem with this. Suppose that 10 oocytes are retrieved from a fertile, 20-year-old female. Testing embryos from oocyte donors has demonstrated that as many as 30% of the oocytes create embryos with the incorrect number of chromosomes. From 10 oocytes, 7 would be normal. Now consider 10 oocytes from a 40-year-old female. Studies have demonstrated that up to 90% of these oocytes will be abnormal. However, both the 10 oocytes from the 20-year-old and the 10 oocytes contain at least one oocyte that can potentially create normal, Thus, knowing the number of oocytes would not help identify which woman is at risk of soon having no more normal oocytes and will be functionally sterile.
Age alone warns a woman that her reserve is being reduced. If a woman wants to freeze some of her oocytes for fertility preservation, she needs to do that at a young age. She may never need the use the frozen oocytes, but if she waits too long, fertility preservation through oocyte freezing will be too late. Freezing oocytes at a young age (< 35 years old) provides an insurance policy that she may never need to use.
Testing for ovarian reserve for women is extremely useful for both older women and for younger women. Not all young women had a normal ovarian reserve and not all older women are out of normal oocytes. Unfortunately, some young women will have fewer oocytes than other women her own age. Furthermore, in rare circumstances a young woman may have oocytes that cannot create normal pregnancies. It would be extremely useful if there was a simple test to help identify the group of women with fewer normal oocytes. For younger women, this would help identify those women who at a young age would benefit from oocyte freezing for fertility preservation. For older women, accurate reserve testing would help to identify those women who still have a chance to have their own genetic child so that they could be aggressive in becoming pregnant. It would also help to identify those women who unfortunately no longer have any normal oocytes and could avoid countless cycles of heart-breakingly unsuccessful cycles of IVF and move on to other resolutions for their infertility.
However, it is extremely important to remember that there is no highly accurate test for ovarian reserve that will tell a person if she can have a child that is genetically her own. This warning is critical to avoid unnecessary and ineffective treatment. The tests are useful to create a picture of where problems MIGHT lie when trying to conceive.