More and more women are having their first child after the age of 35. This time also coincides with the biological decline in fertility potential. One of the most challenging clinical scenarios is the impact of the aging egg on pregnancy chances. This decline in fertility potential, or "ovarian reserve", is the natural consequence of the aging process on human eggs.

The human ovary has two major functions. One is the reproductive function or production of eggs (oocytes). The second is the steroidogenic function or production of hormones, mostly estrogens. The reproductive function of the ovary has a much shorter lifespan that the steroidogenic function. Therefore fertility potential declines in the late 30s to early 40s, even though menopause occurs in the late 40s to early 50s. Each woman is born with a set number of eggs, predetermined before birth. This pool of eggs is never replenished. A female fetus will have the greatest number of eggs around 16-20 weeks of pregnancy (6-7 million); at birth this number decreases to about 2 million, and by puberty to about 300,000. This constant and dynamic process of decline continues until menopause, and is not interrupted by birth control pills, pregnancy, or ovulation. From this reservoir of eggs, fewer than 500 eggs will ovulate during a woman's reproductive years.

Lower pregnancy rates and higher miscarriage rates are both the consequences of the aging process, and reflective of a decline in egg quality (Table 1). Women ovulate their healthiest eggs during their 20s and early 30s. By the mid 30s the remaining eggs are of lower quality, and by the early 40s only eggs with very low fertility potential are available for ovulation or ovulation induction. This phenomenon is a normal biological process, which neither fertility medications nor lifestyle changes can halt. A healthy egg has two functions necessary for a successful pregnancy. First, it must have normal chromosomes, and second, it must be able to combine its chromosomes with those of the sperm in a correct and efficient manner to produce a normally dividing and growing embryo.

What happens to the egg that makes these functions go awry? From the time of birth to just prior to ovulation, all the eggs are "suspended in time". They began the process of chromosome duplication prior to birth and are now waiting for possible selection as the dominant egg. From this pool of eggs, one is selected every month. Once one egg is selected as the dominant egg for a particular menstrual cycle, the LH surge occurs and triggers completion of the duplication process. Now the egg can be fertilized. The length of time the egg waits for selection as a dominant egg corresponds to the chronological age of the woman. During this waiting interval, the paired chromosomes are fragilely attached to each other and are very susceptible to injury. The longer the wait, the greater the chance of injury. Therefore, eggs from older women are more likely to have incurred an injury to the chromosomes. These injuries produce abnormal separation of the chromosomes, resulting in chromosomally abnormal embryos. These embryos are more likely to result in either no pregnancy, or a chromosomally abnormal pregnancy leading to a miscarriage (Table 1). Some chromosomally abnormal pregnancies can lead to a live birth with defects such as Downs syndrome.

Besides using age to determine pregnancy chances, we can use hormonal testing to gain insight into egg quality. The first of these tests is the basal FSH (Follicle Stimulating Hormone) and Estradiol. This blood test is performed on the second or third day of the menstrual cycle (by convention, the first day of flow is cycle day 1). For most laboratories currently using chemiluminescent assays, an FSH value above 10 mIU/ml is elevated and an Estradiol value above 70 pg/ml is elevated. An elevation of either one of these values bodes poorly for pregnancy chances. There is some monthly biological variation in these values, but we know that the strategy of trying to "pick a better month" for infertility treatment does not work. When assessing chances of pregnancy based on a series of lab results, the most predictive value is the highest value (whether highest FSH or Estradiol value). While an elevated value indicates diminished ovarian reserve, a normal value indicates that one can expect age-appropriate fertility chances.

For some patients, we may recommend a Clomid Challenge Test (CCCT), which is a more sensitive test for assessing ovarian reserve. For this test we assess FSH and Estradiol values on cycle day 3, then administer Clomid (Clomiphene Citrate 100 mg/day) from cycle days 5-9, and then reassess the FSH value on day 10. All three blood test results must be in a normal range for the overall test result to be normal. Any abnormal value indicates an abnormal Clomid Challenge Test. The FSH value on cycle day 10 should be less than 10 mIU/ml, and if elevated indicates diminished ovarian reserve.

Various strategies for improving egg quality have been suggested, and some have been tested. These fertility treatment techniques include transferring donor cytoplasm to an egg (cytoplasmic transfer), transferring the nucleus of an egg into a donor enucleated egg (nuclear transfer), or freezing eggs at a younger age for use much later (oocyte freezing). Unfortunately these strategies have not shown improvements in pregnancy rates, and none are clinically available. Egg freezing technology will probably show improvements over the next 5-10 years, but this possibility does not help our patients who are currently in their mid 30s to 40s, and facing the challenge of infertility.

We questioned for years whether age-associated decline in fertility was caused primarily by the aging egg or the aging uterus, or a combination of both. We now know that it is the result of the aging egg. With the advent of egg donation (a recipient mom achieving pregnancy through the use of young donated eggs) we have been able to achieve pregnancies for women even into menopause. Egg donation programs produce high pregnancy rates, and for patients with declining ovarian reserve, provide an option for pregnancy that may not otherwise be possible.

If fertility treatment is unsuccessful based on a diagnosis of diminished ovarian reserve, patients can explore other options besides infertility treatment such as egg donation, adoption, or choosing to live childfree. While these decisions may be difficult, it is comforting to know that there are options available, as well as support to assist you in achieving your goal of building a family.

Table 1: