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Ovarian Reserve and Infertility

Diminished ovarian reserve or function is an important cause of infertility. Women are born with a finite number of eggs, which peak at about 7 million five months into the pregnancy. Only one to two million are present at birth and about 400,000 at puberty. Ovulation will occur approximately 400 times during the reproductive life reaching menopause at about 51 years. Thus, there is a tremendous attrition rate for eggs. This plays a very important part in reproductive potential, that is, the ability to conceive. Diseases such as endometriosis, Turner’s Syndrome, and auto-immune ovarian failure may substantially decrease the reproductive potential. Considering the fact that many couples now delay childbearing into their mid to late 30s, we feel that it is important to have some assessment of ovarian reserve.

Age and fertility

While a 20 year old woman and a 40 year old woman ovulate the approximate same number of times each year, their monthly pregnancy rate, or fecundity, is much different. This is related to the above. When patients undergo In-Vitro Fertilization, there is an age-related decline in pregnancy rates. The following graph demonstrates the pregnancy rates for all patients in the USA that underwent Assisted Reproductive Technologies (IVF, GIFT, ZIFT) in 1998, as reported by the CDC. Actual delivery rates are a few percentage points below the pregnancy rates.

A woman's age not only affects the chances to conceive from ART, but also affects the risk of miscarriage. Most miscarriages (60 %) are due to numerical fetal chromosome abnormalities. The eggs a woman is born with have only partially completed the division of the chromosomes prior to ovulation. They may be in this suspended state for decades. If the chromosomes fail to completely separate, the resulting egg may have an extra chromosome. When fertilized by a normal sperm, the resultant offspring will have an abnormal chromosome number and likely miscarry. This is consistent with the increased risk of Down's Syndrome (trisomy 21, and extra chromosome 21).

The miscarriage rates for patients having ART in 1998 are shown below.

When women undergo egg donation, the dramatic decline in pregnancy rates associated with age is not seen, indicating the effects that age has pregnancy rates and egg quality. Older patients may stimulate less well in IVF and produce fewer total eggs. The may have lower estrogen levels, higher miscarriage rates, and lowers implantation rates. Women in their mid-thirties have been found to have elevated FSH levels, which may be the first sign of declining ovarian reserve.

The onset of the decline in reproductive potential is extremely variable. Therefore, ovarian reserve testing can be seen as a qualitative test to estimate where a person is in the process of depleting her ovarian reserve.

Tests of Ovarian Reserve

The basic concept of the menstrual cycle helps us to understand the various tests that have been developed to assess ovarian reserve. The pituitary gland secretes follicle stimulating hormone (FSH) which travels through the blood stream to the ovaries to stimulate the growth of follicles that contain eggs. The developing follicle secretes hormones which travel in the bloodstream back to the pituitary gland to decrease the FSH production. This is called negative feedback. Estradiol and inhibin are two hormones involved with this process. In a normal menstrual cycle, the FSH level is lower in the first few days of the cycle and then begins to rise as it stimulates the ovaries. A high FSH level on day 3 of the cycle indicates that the pituitary is attempting to stimulate an ovary that has diminished capacity to respond. This is a problem and a bad prognostic sign.

Tests of ovarian reserve:

  1. Cycle day 3 FSH. Many studies have shown that an increasing FSH level is associated with a decreased pregnancy rate. Women in their early 40s were found to have elevated FSH levels associated with accelerated follicular phases of the menstrual cycle compared to younger patients. Patients with high FSH levels that underwent IVF had granulosa cells in their ovarian follicles that produced less estrogen, were less viable in culture, had reduced mitotic index, and made less growth factors and inhibin than those from follicles than those of younger patients. In effect, they were less robust. There is an increased inter-cycle variability in patient’s FSH levels when elevated compared to normal levels. Some studies have added a basal estradiol level to the FSH. There is some controversy in the literature with some showing a significant effect of an elevated estradiol level on outcome and others showing no effect.
     
  2. Clomiphene Citrate Challenge Test. This simple test involves a day 3 FSH level, 100 mg clomid from day 5-9, and a day 10 FSH level. An abnormal test is an elevated day 10 FSH level. An elevated day 3 FSH is a positive test. This is a ‘provocative test’, which will unmask patients which might be missed with a day 3 FSH level. It is 2-3 times more sensitive than a day 3 FSH level. This may be the best screening test to date. A positive or abnormal test is associated with a poor chance to conceive (<5%).

FSH, MIU/ml

Protocol 1. FSH level day #3
2. Clomid 100 mg day 5-9
3. FSH level day #10
Results FSH <15 good
FSH >15<20 borderline
FSH >20 poor
  1. Serum inhibin levels. Inhibin is a protein that is secreted by the follicles of the ovary to inhibit FSH secretion by the pituitary. An ovary with decreased ‘reserve’ will secrete less inhibin and thus will have a higher day FSH level and worse prognosis. This blood test is done in research labs, at present.
     
  2. Ovarian volume/follicles. Several studies have shown that patients with decreased ovarian volume and baseline follicles have decreased reserve.

In summary, the assessment of ovarian reserve helps provide valuable information about the status of ovarian function. This may help a couple make a more informed decision concerning treatment options.
 

 

 

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