Evaluation of Ovarian Reserve

Annette Lee,M.D.
Reproductive Endocrinologist
RMA New Jersey

None of the elements of the classical "basic infertility workup" (HSG, BBT, semen analysis, post-coital test, endometrial biopsy) will diagnose an increasingly common cause of infertility: diminished ovarian reserve. With patients 30 and over now comprising the majority of infertility patients, evaluation of ovarian function should be considered early in the diagnositc process.

By menarche, the average female has lost more than 90% of her original 7 million eggs. Each month of her life, hundreds of primordial follicles containing immature eggs will undergo atresia. With age, both the quality and quantity of the remaining oocytes will decrease. Classic studies on populations that do not use birth control have shown the effect of age on fertility; the incidence of infertility rises from about 10% at age 30 to 90% at age 45.

Studies of ovarian reserve have included tests such as the GnRH stimulation test, serum measurements of inhibin B and three-dimensional measurements of ovarian volume. But in practice, the most useful measures have been the "day 3 FSH level" and the clomiphene citrate challenge test (CCCT).

DAY 3 FSH and ESTRADIOL

The physiological basis for this test is that as ovarian function declines, so does granulosa cell production of inhibin B (which inhibits FSH secretion), resulting in subtle elevations of basal FSH and estradiol levels in the early follicular phase, years before cycle irregularity sets in. Most centers previously used a cutoff of FSH> 20 International Units/ml to denote poor ovarian reserve. This is half the menopausal level, usually >40 International Units/ml. The most widely used assays have recently been changed and the new cutoff is level may be lower (12-14 International Units/ml at IVFNJ). So it is very important to verify with each laboratory their particular range of "normals'. Estradiol levels should be <70 pg/ml but may be higher in women <35. We recommend measuring day 3 FSH and estradiol in ANY infertility patient because a high estradiol level may artificially suppress FSH secretion, resulting in a "normal test" in a patient who actually does have poor reserve.

Elevated day 3 FSH levels are a very poor prognostic factor REGARDLESS OF AGE. Prospective studies of IVF cycles have demonstrated low pregnancy rates (0-8%) in this group, high miscarriage rates, and a large proportion of aneupliod oocytes. Although the day 3 FSH level may vary from month to month, a single elevated day 3 FSH denotes a poor prognosis for pregnancy.

THE CLOMIPHENE CITRATE CHALLENGE TEST

Although women with elevated day 3 FSH levels almost always have a poor prognosis, women with normal levels may also have diminished ovarian reserve. In order to improve detection rates, the more sensitive Clomiphene Citrate Challenge Test (CCCT) can be used. There are 3 steps to the CCCT; first, measure day 3 FSH and estradiol levels and performing a baseline ultrasound to exclude any patients with ovarian cysts. Second, give 100 mg of clomiphene days 5 -9 and third, measure FSH and estradiol levels on day 10. Again, each laboratory uses a different cutoff level for FSH, above which either a day 3 or day 10 level indicates a poor prognosis. The data on estradiol levels is less clear. The main utility of measuring estradiol is to confirm that the day 3 FSH level is not artificially suppressed by elevated E2 levels. Some investigators have advocated measuring day 10 progesterone levels (greater than 1.1 ng/ml being associated with poor reproductive performance). We recommend performing a CCCT in any patient in which the index of suspicion for diminished ovarian reserve is high, including:

• age 35+
• history of endometriosis
• family history of early menopause
• history of menstrual irregularity
• previous ovarian surgery
• failed treatment with clomiphene or gonadotropin
• unexplained infertility
• smokers
• history of chemotherepy or radiation treatment

Contraindications for the CCCT: allergy or intolerance of clomiphene (visual changes, severe headache, etc), ovarian cysts or unexplained abnormal bleeding and of course, pregnancy.

COUNSELING THE PATIENT WITH ELEVATED DAY 3 FSH LEVELS OR ABNORMAL CCCT

Patients with the diagnosis of diminished ovarian reserve should be told that the prognosis for pregnancy is poor, but not zero. Spontaneous albiet rare pregnancies HAVE occurred in these women. In general, success rates for any treatment including I VF in this population will not exceed 5%.

In 1998, the only practical options for patients are donor egg and adoption. At IVF New Jersey, the delivery rate is about 50% per donor egg cycle. Of course, the initial diagnosis can be an emotionally devastating event and grieving reactions such as anger and denial are normal. Counseling should be offered to patients with this diagnosis and often there may be a grieving period before the patient can consider alternatives such as adoption or donor egg.

Day 3 levels have been uses as in informal "screening test" for women who are concerned about their "biological clocks" but are not yet ready to conceive. However, studies examining their predictive value have largely been done in IVF patients and it is unknown whether their predictive value extends to the general population.

Annette Lee, MD
Susan Treiser MD, Ph.D
Michael Darder MD
193 Rt. 9 South Manalapan, NJ 07726
(732) 577-6500 1527
Hwy. 27 Somerset NJ 08873 (732) 220-9060