NEWS FROM REPRODUCTIVE PARTNERS

Tests of Ovarian Reserve 
By Gregory Rosen, M. D.

The success rates of IVF and GIFT are related to many factors, but two very important factors are the age of the woman and the number of mature eggs and high quality embryos that are harvested/created. Because of these observations, many tests have been developed to attempt to assess who might be a better candidate for these procedures, i.e., who would be more likely to ripen more eggs, before starting an attempt at IVF or GIFT. 

Day 3 Follicle Stimulating Hormone (FSH) 

Follicle Stimulating Hormone is the hormone which travels from the pituitary gland to the ovaries to ripen eggs. Circulating levels of FSH start to rise a few days before menstruation and remain elevated for a few days after the period starts. The theory behind measuring an FSH on Day 2 or 3 of the cycle is simple. A woman of reproductive age who has the normal number of eggs remaining in her ovaries will only require a small amount of FSH to ripen those eggs and her Day 3 FSH will be low. Conversely, a woman who has fewer eggs left would require more FSH and her blood test will reflect a higher level of FSH. Estradiol, a form of estrogen made in the ovaries as a by-product of the eggs ripening, is measured at the same time to confirm that the measurement of FSH is accurate. 

In 1989, Dr. Richard Scott, who was then at the Jones Institute in Virginia, published a paper in which his group observed that women who had elevated levels of FSH on Day 3 of their cycles had less of a chance of getting pregnant in comparison to women whose levels of FSH were lower. Dr. Scott grouped patients into low, medium and high levels of FSH and he observed that the pregnancy rates were 17% in the low FSH group and only 9% and 4% in the medium and high FSH groups. 

This interpretation is very controversial. There are many physicians that feel that age is the primary predictor of pregnancy rate. To demonstrate this controversy, there are two larger studies that look at FSH and its affect on IVF outcome. Dr. Toner published the first study in 1991. The other study was published by Dr. Sharif in 1998. Both of these studies observed that women with higher FSH, in comparison to women with lower FSH, used more gonadotropins during stimulation, had higher cancellation rates (as many as 25% failed to ripen enough eggs to proceed), and their pregnancy rates were lower. There was, however, a major difference in the conclusions of the two papers. Toner interpreted his findings to show that increased FSH levels were more important than age in determining pregnancy outcomes. Sharif disagreed. He felt that age was the most important criterion. At Reproductive Partners it is our opinion that both age and FSH levels are of similar importance. 

Dr. Bassil published an article in 1999 where he looked at women only age 39 and older with an elevated FSH on Day 3. He observed that women with elevated FSH levels who had three or more eggs retrieved had an acceptable pregnancy rate (16%) compared with women who had fewer than three growing follicles. The pregnancy rate in this group was only 6%. His conclusion was that having an adequate ovarian response is essential to give a woman her age-adjusted chance of conceiving. He demonstrated that a significant number of women with elevated FSH levels were still able to ripen enough eggs to have a worthwhile attempt at pregnancy. 

One defect of Dr. Bassil's study and many other studies is that delivery rates were not evaluated. We now know that women with an elevated FSH have a high risk of miscarriage (probably at least 50%), which results in a low rate of delivery. When Bassil's data is evaluated in this light, the success rate in women with at least three eggs retrieved would be anticipated to be only about 8% and 3% respectively. It can be concluded from this study that there is a small but significant chance of delivery provided that least three or four follicles result from a moderate level of stimulation. 

In practice, patients seldom have a single Day 3 FSH level on which to base a decision. The prognosis appears to be poor in women with multiple abnormal levels and improved when multiple normal levels are observed in other cycles. 

Clomiphene Citrate Challenge Test (CCCT) 

The CCCT was first described in 1987 by Dr. Navot, two years before any information had been published on the usefulness of a Day 3 FSH. The CCCT measures an FSH and estradiol drawn on Day 3 of the cycle and then again on Day 10. In between, on Days 5 through 9, 100 mg of clomiphene citrate (SeropheneR or ClomidR) are administered daily. In a normal, non-medicated, ovulatory cycle, the FSH concentration on Day 10 should be significantly lower than on Day 3. The theory behind the CCCT is that an elevated FSH on Day 10 is an abnormal finding and indicates that either an increased requirement of FSH is necessary to stimulate the remaining follicles or that the remaining follicles are just less likely to respond to FSH. There has been much discussion in the medical literature as what is considered a normal or abnormal test, but overall, the following is in general agreement. If the Day 3 FSH or estradiol is abnormal, there is no reason to do a CCCT. An increase in FSH is expected from Day 2-3 to day 10 and the upper limit of this test on Day 10 should not exceed the upper limit of normal for a Day 3 FSH. 

A review of published studies on the CCCT show that as a woman gets older or if she has only one ovary she is more likely to have an abnormal CCCT. Women who smoke have an increased incidence of abnormal tests at a younger age. Women who responded poorly to gonadotropins (ripened fewer eggs than expected) have a high incidence of abnormal CCCT. Most studies agree that an abnormal CCCT indicates, just as with an elevated FSH on Day 3, that a woman will utilize more gonadotropins, produce fewer mature eggs and have a lower pregnancy rate than if her test is normal. More recent observations, however, have shown conflicting results. A significant number show that age remains the best way to determine who will get pregnant and who won't. An abnormal CCCT may only indicate that a woman's chances of conception are decreased because she is less likely to ripen enough eggs for her procedure. 

Ultrasound 

Another tool used to predict ovarian response utilizes transvaginal ultrasound to count the number of resting follicles seen early in the menstrual cycle. These resting follicles are also called antral follicles. Ovarian stimulation can only affect antral stage follicles. If enough of these are present, it might predict who would be more likely to have an adequate response to gonadotropins. 

Another View 

A 1999 article in Human Reproduction studied 22 previously fertile women over the age of 35 who were about to undergo a hysterectomy with removal of the ovaries. A Day 3 FSH, estradiol and CCCT were performed just prior to the procedure. The ovaries were examined and the number of eggs was estimated. The authors found no significant correlation between baseline or clomiphene stimulated FSH levels and the number of remaining follicles. They concluded that neither a Day 3 FSH or CCCT accurately reflects the true ovarian reserve, but the study was small. 

Summary 

The declining ability of a woman to conceive with advancing age is primarily attributed to the decline in the quality of her eggs and, only secondarily, to the decreasing number and accessibility to those eggs. A Day 3 FSH and estradiol or a clomiphene citrate challenge test can help to distinguish a subgroup of women who might ripen fewer or more eggs with gonadotropins. These tests are still extremely controversial. Individually, that is without knowing the woman's age and her past experience with gonadotropins, these tests allow a physician and patient to determine who might require more or less gonadotropins and who overall may ripen fewer or more eggs. The amount of gonadotropins that might be required is purely of financial interest, but egg number, especially in women who are older, is very important to success rate. 

The choice as to whether an attempt at ovarian stimulation should be carried out should be individualized according to all the available information. For women over age 38 with multiple abnormal FSH levels, particularly with only a few antral follicles visible on ultrasound, egg donation should be strongly considered. For a 30-year-old with a single abnormal FSH an attempt at stimulation clearly is warranted. Between these two extremes one must make a reasonable decision as to whether a trial of stimulation is reasonable. But to maximize the chance of success, a woman should have at least four to six follicles available for aspiration. 

NOW SHOWING: A LIFETIME OF HOPE IN JUST ABOUT 30 DAYS 

Reproductive Partners Medical Group, Inc. is pleased to announce the premiere of "A Lifetime of Hope in Just About 30 Days," a presentation utilizing the latest flash animation technology. In a "Lifetime of Hope" you will follow a patient through an IVF cycle, including all the visual elements from the ultrasounds monitoring follicle development, to the retrieval room and then to the laboratory, observing fertilization, embryo development and transfer. 

"A Lifetime of Hope" was produced by Reproductive Partners Medical Group, Inc. through an educational grant by Organon, Inc. and developed by Alan Dale Webmasters. Bookmark our home page (www.2reproduce.com), click on the "Lifetime" icon and attend the premiere of this exciting technical marvel.