Fertility Associates of Memphis

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Ovarian Reserve: The Egg Factor in Infertility

Ellie Haddad
Raymond Ke, MD
Kutteh Ke Fertility Associates of Memphis, PLLC.
Division of Reproductive Endocrinology
University of Tennessee Health Science Center

Despite technological advances in the management of infertility, a significant number of infertile couples do not present with an obvious cause and are usually given the frustrating diagnosis of unexplained infertility. Many of these patients may be suffering from diminished ovarian reserve or what many experts refer to as the “egg factor.”

While there is a well known decline in female fertility with age, it is clear that age is not the best measure of a woman’s ovarian reserve and is often an unreliable predictor of successful pregnancy. Accordingly, it would be a mistake to assume that diminished ovarian reserve is a phenomenon that only ‘older’ women experience. There are some obvious risks to ovarian reserve such as smoking, prior chemotherapy or pelvic radiation treatment, but in most cases, there are no early warning signs that this is occurring until she experiences infertility.

To understand ovarian reserve, two important concepts in ovarian function must be understood. First, women are born with all of the eggs they will ever have. Although there are approximately six to eight million eggs at birth, many of these are lost during childhood so that by the time a female begins her periods she only has about 300,000 to 500,000 eggs left. During the typical menstrual cycle 10-30 eggs are recruited for growth on a daily basis, but only one of these dominates to become a mature follicle ready for fertilization. The rest die off resulting in the loss of hundreds of eggs per month. This loss continues month after month until the egg pool is nearly exhausted leaving a woman with only 100-500 eggs per ovary resulting in menopause. But the rate of egg depletion is not uniform throughout life and usually accelerates around age 35 or when a woman has about 25,000 eggs left.

The second concept to understand is that not all the eggs in the ovaries are equal. In fact, most of the stored eggs are not capable of achieving a successful pregnancy. Of these, many are not genetically normal and will either not fertilize with sperm or result in an abnormal embryo that rapidly dies. Some may also have defects in their cellular organs and enzymes that limit embryo growth. It is believed that women tend to ovulate their best eggs when they are younger. This concept of quality is more important for eggs than it is for sperm whose basic job is to deliver its’ half of DNA material safely into the egg. An egg must not only provide its’ half of the DNA but all of the necessary “machinery” for the effective development of the early embryo. Therefore, ovarian reserve is not just about how many eggs are left but also more accurately, how many “good” eggs.

Looking for Good Eggs

A ‘good’ egg has two features: it has normal chromosomes (genetic material) and it must let those chromosomes join with those from a sperm cell and subsequently divide in an efficient fashion. Unfortunately, we have no perfect test for egg quality. Although quality declines as women get older, age is not a very good measure. Two women at the same age can have vastly different possibilities of conceiving on any given month and the differences are particular wide in the 35-43 year old age group. And unlike sperm, it is difficult to directly inspect eggs for their quality.

We have to look for our clues to egg quality in indirect ways. One possible way is by observing the menstrual pattern. As women age, their cycles shorten. Unfortunately, this is such a late phenomenon in a woman’s reproductive career and most women’s cycles vary somewhat month to month that observing menstrual patterns is a very insensitive method of determining egg quality. Determination of estrogen or other hormone levels have been studied but have proven to be inconsistent. Ultrasound measurement of ovarian size and the number of small cysts (egg follicles) has some promise but are not predictive on their own.

FSH: The Cruelest Number

So far, the best simple test is a blood measurement of FSH that stands for follicle stimulating hormone. It is one of the more important ways in which the brain talks to the ovaries. Every month, the brain releases FSH when it wants the ovaries to release a mature egg. The ovaries respond by communicating ‘message received’ to the brain and then initiating the ovulation process – a two week process where the ovary recruits and selects the best egg available for release. As ovarian reserve diminishes, the brain has to send stronger FSH signals to the ovary each month in order for ovulation to occur. This breakdown in the communication between the eggs and the brain correlates with a high FSH level and poor pregnancy rates in infertility treatment.

While finding an elevated FSH is the simplest method to diagnose decreased ovarian reserve, it is not perfect. An abnormally high value is not good but a normal FSH test is not completely reassuring and has less predictive value. This is because the release of FSH occurs in pulses and catching a pulse at the wrong time can give a falsely low value. One month the result may be a 7 and the next month it may be a 13. For a while, we thought that it might be possible to wait for a month with a better level and improve the odds that a given cycle would work. Unfortunately, we learned that the intermittent high FSH is just as bad – even in months where the test may be normal. To decrease the variability, the test should always be drawn early in the cycle immediately after a spontaneous period – by convention on cycle day 3. If a woman does not have spontaneous periods or has taken hormone medication to start her period then the FSH test is not reliable.

What is an abnormal FSH level? That depends on the laboratory doing the testing. It may be difficult to fathom but different laboratories may report different results on the same specimen. In the past, this small difference was not important. But the diagnosis of decreased ovarian reserve depends on the ability to evaluate small differences within what was previously thought to be the normal range. For this reason, many fertility centers will insist on FSH test be performed at their designated lab whose results have been correlated with actual pregnancy statistics. This is the only way clinics can give their patient useful prognostic information. Most experts agree that cycle day 3 FSH values above 15 mIU/ml is not good news while values below require careful correlation with pregnancy data and age.

In an attempt to increase the sensitivity of the FSH blood test to detect diminished ovarian reserve, fertility experts often perform a clomiphene citrate challenge test (CCCT). After taking clomiphene citrate (aka Clomid) on days 5 to 9, the FSH should not rise if ovarian reserve is adequate. A high FSH level on day 10 is as bad as a high level on day 3 and can help distinguish a true negative test from a false one. The CCCT is often combined with other tests such as ultrasounds and estradiol measurements to further help its predictive value.

Is it Hopeless?

What makes this diagnosis so exasperating is that there is no known method to improve a woman’s ovarian reserve. Furthermore, women feel so normal - they are menstruating regularly and all the other tests are perfect. The most important aspect of treatment following the diagnosis of diminished ovarian reserve is a thorough discussion with a reproductive endocrinologist that encompasses not only the treatment options but also risks to the mother and fetus if she should conceive, especially if she is over the age of 40. Even if the problem appears borderline, the infertile couple needs to know all of their alternatives since time will not be on their side.

But all is not lost. Even in a women with a high FSH, the possibility of pregnancy with her own eggs remains. Depending on the degree of ovarian reserve depletion, the success rate for any given infertility treatment is decreased and there may be an increase in the miscarriage rate. Because it is generally recognized as the treatment with the highest success rate, in vitro fertilization (IVF) will often be recommended. Usually, it is the only therapy with any significant chance of success over what the couple can accomplish on their own. Results with intrauterine insemination (IUI) and ovulation induction (OI) are not very spectacular with a pregnancy rate of less than 5% with each attempt. Unfortunately, even IVF is not very helpful when the FSH is very high, there is a poor response to ovarian stimulation, or if the woman is over the age of 37.

IVF with egg donation remains the treatment of choice for egg factor infertility due to its’ high success rate. This makes sense since we are replacing the patient’s eggs with a ‘good’ egg from a healthy donor. IVF techniques are used to fertilize the donor’s eggs with the patient’s husband’s sperm and the resulting embryo(s) will be transferred to the patient. The success rate approaches 80% per attempt and is dependent mainly upon the ovarian reserve and age of the donor.

While oocyte donation offers many couples an excellent and fulfilling way to bypass the problem of diminished ovarian reserve, it is not for everyone. Hopefully, advances in our ability to either increase ovarian reserve or to ‘fix’ the egg quality problem without resorting to another woman’s eggs will be forthcoming soon. Meanwhile the message for all infertile women of any age is to be aware of their ovarian reserve as a factor when considering therapy.