Bad eggs as a cause of unexplained infertility

For about 10% of infertile couples we cannot determine what the reason for their infertility is. The diagnostic label we use for them is unexplained infertility, which just means that we cannot provide an explanation as to why they are infertile. For many of these couples , we have now found that the reason for their infertility is poor quality eggs. This can often be a difficult diagnosis to make; and it is one which is often overlooked by many gynecologists , especially when the woman is young and has regular cycles.

Some women with poor quality eggs have poor eggs because they have impaired ovarian reserve. Every woman is born with all the eggs she is ever going to have in her life; and as she gets older, she keeps on depleting her ovarian reserve until she becomes menopausal. However , for at least 10 years before reaching the menopause , her egg quality declines, so that she has enough eggs to produce enough hormones to get regular menstrual cycles, but not enough to make a baby. This is called the oopause. Since her cycles are regular , this lulls her - and her gynecologist - into a false sense of security. The good news is that we now have accurate tests to check ovarian reserve. These include a high-resolution vaginal ultrasound scan to check the antral follicle count; and a blood test to check the levels of AMH , or anti-Mullerian hormone. A low antral follicle count and a low AMH level both suggest poor ovarian reserve. In these cases the problem is that we have to technology to make the diagnosis but the diagnosis is not made properly because of a lack of awareness.

There is an other group of women , who have apparently normal ovarian reserve, but poor quality eggs. The group is much more frustrating to deal with. It is only when we do IVF or ICSI for these women , that we find out that they have an egg problem. Let me explain.

Some of these women will grow eggs poorly in response to superovulation. Such a poor ovarian response is a marker for poor ovarian reserve. Unfortunately, they have a normal antral follicle count and normal AMH levels, which means this diagnosis is made only after the IVF superovulation has started.

The third group is perhaps the most difficult. These are women who grow a sufficient quantity of follicles in response to superovulation ; and have high estradiol levels as well. Egg collection is usually uneventful ; and the doctor often retrieves 8 to 16 eggs for them. If IVF is done, when the fertilization check is performed the following day, much to the embryologist’s surprise and the patient’s dismay , it is found that the fertilization is very poor even though the sperm are fine and actively motile. If ICSI is being done, the embryologist often finds that the eggs are morphologically normal ; or are very fragile. For example, these eggs have granular cytoplasm ; or vacuoles in their cytoplasm ; or dark areas within the cytoplasm. Since normal eggs are simple spherical formless blobs, these subtle cytoplasmic abnormalities are often missed or overlooked. The embryologist may also noticed that the eggs are fragile, and the cell membrane offers little resistance to the injection pipette. Many of these eggs may die during the ICSI process.
Unfortunately , because egg morphology has not been adequately studied , we still do not have good descriptive terms , when talking about these abnormalities. Since the eye only sees what the mind knows, often these abnormalities are not picked up. The patient is often subjected to repeated IVF or ICSI cycles , with the same poor results each time.

Why is abnormal egg cytoplasm such a difficult problem ? In order to understand this, let's first review the important role the egg cytoplasm plays in embryo development. The most dramatic events during fertilisation occur in the nucleus, when the male and the female pronuclei fuse. However, the energy to drive this fusion comes from the mitochondria in the egg - the energy powerhouses of the cell, which power cleavage and cell division. One major problem is that there is no way of testing egg cytoplasmic quality - either clinically, or in the research lab at present. While electron microscopy studies have confirmed these eggs have cytoplasmic abnormalities, this is still an area which has not been adequately studied.

Of course, part of the problem in some labs is that the failed fertilisation is not because of an intrinsic egg problem,but because of poor lab conditions. How can you as a patient find out if the problem is a lab problem ; or a biological problem with your eggs ? This is why, if there are fertilisation problems, it's very important to ask the lab to document egg morphology with photographs and videos, which can then be reviewed later. It's also a good idea to repeat the treatment cycle in a better clinic, to eliminate the possibility that the poor results maybe an artifact created as a result of suboptimal lab conditions ( such as infection; poor quality culture medium; or an unskilled or inexperienced embryologist).

I also think it's time doctors coined new medical terms to describe these egg problems. We could borrow some of the terms we use at present to describe sperm problems ! Thus, if a patient has few eggs ( impaired ovarian reserve), this could be called oligo-ooctyosis ( = few eggs). If the eggs are abnormal, this would be terato-oocytosis ( = abnormal eggs) ; and if the eggs do not fertilise because of cytoplasmic problems, this would be astheno-oocytosis ( = weak eggs).

How do we tackle this problem in our clinic ? We trouble shoot, by checking if the problem is localised to just single patient; or if it's affect more than one ( which would suggest a lab problem rather than a patient problem). If we think the patient has abnormal eggs after egg retrieval, we take photographs of all these eggs , so the patient has adequate documentation. We prefer doing ICSI as compared to IVF for these patients. However it requires a skilled embryologist , because these eggs need to be handled with care and respect . If ICSI is done in the routine fashion , many of these eggs will die during the cytoplasmic aspiration.

If at the end of the ICSI cycle , we feel the patient has a problem with fragile eggs ; poor quality eggs; all eggs with cytoplasmic abnormalities, we explain this to the patient; and discuss their treatment options.

One possibility is that this was a one off phenomenon for unexplained reasons; and may not recur , if we try again. However , because we feel that the risk of recurrence is high , we change the superovulation protocol, with the hope that a change in medication may help to improve egg quality .

If this also fails , then the only realistic options are to consider either donor eggs or donor embryos. These can be very hard choices to make , especially for a young woman who felt she had normal eggs prior to starting the IVF treatment, because she had regular menstrual cycles , and a normal FSH and AMH level.
This is why we emphasize to patients that while the primary purpose of an IVF cycle is therapeutic , IVF cycles often reveal valuable diagnostic information , which can help us to pinpoint possible problems and create effective treatment solutions. These problems could never have been diagnosed unless IVF had been done !