About Fertility

Ovarian Reserve, FSH Levels, Clomiphene Challenge Tests, & Pregnancy Rates


What is ovarian reserve and why is it important?

Ovarian reserve may be defined as the youthfulness or health of the ovaries and the eggs (oocytes) they contain. Measurement of ovarian reserve, an important factor in female fertility potential, can only be approximated because precise tests are not currently available. Testing for diminished ovarian reserve gives couples the advantage of a more realistic estimate of the likelihood of fertility with treatment.


What factors commonly affect ovarian reserve?

Ovarian reserve decreases with age. Declining fertility with aging is not a new concept and low fertility rates with aging have been observed for centuries. The following table gives some indication of comparative fertility rates by age, with age 20-24 arbitrarily defined as 100%.


Relative Fertility Rates

fertrate

From: Maroulis GB, Semin Reprod Endocrinol 9: 165-75, 1991.
* This older data is likely to include substantial inaccuracies.


A compilation of IVF pregnancy rates from the French medical system provides important guidelines for patients and physicians. IVF is an important tool for studying reproductive physiology because IVF corrects many of the variables that potentially affect the occurrence of pregnancy, such as frequency and timing of coitus or sperm migration to the egg.

Average pregnancy rates decline gradually with age and do so more sharply after age 37. This is striking when one considers that menopause, the time when the ovary is effectively devoid of eggs, occurs on average at age 51. Therefore, for many women fertility begins to decline 15-20 years or more before the ovary is depleted of eggs. The actual degree and rate of decline varies from woman to woman. The aging of the eggs occurs because women make no new eggs after birth, in contrast to men who continue to make new sperm throughout adult life.

As fertility declines, the incidence of miscarriage also rises. Estimates for miscarriage rates are 10-20% under 35 years, 15-30% for 35-39 years, and about 35-60% for over 40 years.

This information implies that the functional capacity of the egg to create a live-born baby declines long before depletion of all eggs from the ovary.


How can ovarian reserve be estimated?

No perfect markers exist for ovarian reserve but Follicle Stimulating Hormone (FSH) levels under certain conditions provide the best currently available estimate. Two important concepts must be kept in mind:

  1. FSH levels predict low fertility when they are abnormal but they do not accurately predict high fertility when normal.
  2. The specific FSH assay system used in any laboratory affects the boundary between its normal and abnormal results.

Approximately 20 years ago, a classic study measured hormone values in peri-menopausal women between the ages of 48-53 years who continued to menstruate. FSH values in these subjects were generally elevated above the levels seen in young fertile women.

In the mid to late 1980's several investigations correlated early follicular phase FSH levels with pregnancy rates in IVF cycles. Women with the highest levels of FSH, similar to perimenopausal women, had the lowest average pregnancy rates and the highest miscarriage rates. Since the first reports of low pregnancy rates in women with elevated FSH levels, over 10 studies have confirmed this finding. We know of no reliable studies refuting this observation.

A variation of baseline FSH measurement (approximately day 3) is the Clomiphene Challenge Test (CCT), which may provide an earlier warning sign of diminished ovarian reserve than baseline testing alone. The CCT involves determination of the day 3-5 FSH level, administration of clomiphene 100 mg per day on days 5-9 and re-testing of the FSH level on day 10.

Clomiphene tends to elevate FSH levels but women with a normal response are able to return the FSH levels to baseline by day 10 while the day 10 FSH is often elevated in women with diminished ovarian reserve.

If the CCT is abnormal, an elevated FSH value is evident only on day 10 in about 65% of tests, and on day 3 or both days in about 35% of tests. Eventually, every woman reaches menopause and has highly elevated FSH levels throughout the menstrual cycle.

The assay kit used in the laboratory determines the FSH levels used to define an abnormal test, as in the following example.


fshlvl

Other tests such as early follicular estradiol (E2) levels, gonadotropin agonist stimulation tests, and inhibin levels are not as thoroughly studied as FSH values for predicting ovarian reserve. Elevated estradiol levels on day 3-5 sometimes imply lower fertility rates but the boundaries of normal values and interpretation of the results when FSH values are normal is uncertain. Similarly, the levels of inhibin, a hormone secreted by the ovary which suppresses FSH secretion, do not have sufficient clinical testing to currently recommend them as a routine assay.


What is the significance of an abnormal test?

Every study of ovarian reserve using FSH values found lower fertility in women with abnormal testing. The following graph [in preparation] demonstrates the relationship between CCT results, age, and fecundity after non-IVF treatments. When the CCT is abnormal, fertility is reduced regardless of age. However, even when the CCT is normal there is still an age-related decline in fertility independent of FSH levels.


If the FSH level is abnormal, should it be re-tested to confirm the result?

Generally, a single laboratory value should not be relied upon to make critical treatment decisions. However, FSH levels are stable and do not vary much with frequent measurement. The available evidence suggests that fertility estimates are more reliably based on the worst FSH value, not the best. A repeat abnormal FSH value generally does not substantially change the implications of prior abnormal values. The testing should be used as a guide to counsel patients about realistic expectations from therapy and to indicate when alternative treatments such as oocyte donation may deserve consideration as options.


Who should be tested?

We advise a CCT for patients with risk factors for diminished ovarian reserve. Examples would include most women of age 35 or above, unexplained infertility, single ovary, family history of early menopause, or prior chemotherapy or pelvic irradiation.


What are the reproductive options for couples with diminished ovarian reserve as indicated by an abnormal CCT or baseline FSH?

Three primary options exist, and there are others as well:

  1. Continue to attempt conception using the patient's eggs.  If preliminary testing is substantially abnormal, the probability of conception with IVF or ICSI is generally less than 5% per treatment cycle. The delivery rate is likely less than 1-2% per treatment cycle.
  2. Utilize Donor Egg IVF. This is an extremely effective therapy at experienced centers. Success rates can be found here.
  3. Use of donor embryos, if available.