A decreased ovarian reserve indicates that there is a significant reduction in the amount of eggs that are able to mature within the ovaries. A "significant" reduction in ovarian reserve can be defined as one that results in a reduced fertility rate. One important question is "what test results for ovarian reserve suggest a reduction in fertility?"
Unfortunately, the tests currently available for ovarian reserve have predominantly been studied only in the context of controlled ovarian hyperstimulation (using FSH containing medication) with either inseminations or Advanced Reproductive Technologies (such as In Vitro Fertilization). Very little is known about the incidence of abnormal (testing for) ovarian reserve in the general infertility population or the fertile population.
Women with regular menstrual cycles generally have eggs that will mature and ovulate.
Counseling women with regular menstrual cycle intervals who are found to have a decreased ovarian reserve (using available tests) is difficult due to the lack of information correlating these test results with fertility rates in the fertile and general infertility populations. At this time, the most accurate advice appears to be that COH and ARTs have (known) decreased success rates for women with a decreased ovarian reserve. Focusing infertility treatments on male factor or pelvic factor issues might be particularly useful for this population of women, allowing these women to produce their one (presumably normal and healthy) egg each month. Intrauterine inseminations may be appropriate if there is a suggestion of a (mild or moderate) male factor or a sperm mucus interaction problem (abnormal postcoital test). Pelvic evaluation (laparoscopy and possibly hysteroscopy) to optimize the pelvis for reproductive success should also be considered in this infertile population.
A womanís reproductive potential (ability to conceive and carry a pregnancy to term) is related to her age (decreasing reproductive potential with advancing maternal age) and her ovarian reserve (defined as the number of eggs remaining in the ovaries that have the potential to mature). Be aware that some infertility experts use the term ovarian reserve to describe both the number of remaining eggs and their inherent (egg) quality.
Tests available to determine ovarian reserve include
The "cycle day 3 FSH" blood levels can be drawn at anytime of the day on cycle day 2, 3 or 4 (the first day of a full flow being cycle day 1). Research suggests that the difference in FSH concentration between cycle day 2, 3, and 4 is small so that the patient can have a sample drawn on the most convenient of these days. The study demonstrating this used only a small number of women (20 women under 40 years of age) and reports a less than 20% coefficient of variation between FSH values determined for the same women over the course of these days. A second study from another infertility center confirmed these findings.
Multiple reports since 1989 have correlated the cycle day 3 FSH concentrations to pregnancy rates at the time of In Vitro Fertilization. IVF success (pregnancy rate) is reported to be independently associated with both the womanís age and the cycle day 3 FSH concentrations. In other words, both are important. The early classic studies from the Jones Institute in Norfolk, Virginia revealed a 17% success rate per IVF cycle (very high at that time) when the cycle day 3 FSH concentration was less than 15 IU/L, 9% when 15-25 IU/L and 4% when greater than 25 IU/L. Generally, a cycle day 3 FSH level of less than 15 IU/L (using the Lee Co assay, see discussion below) is considered reassuring.
A womanís cycle day 2-4 FSH levels vary from cycle to cycle. Generally, the amount of variation is low (up to 20%) if the FSH level is within the "encouraging" range and may be much greater (40% or higher) if the FSH level is in the "discouraging" range.
Interest has focused on whether fertility is greater for a woman (with a discouraging FSH concentration) in cycles in which her basal FSH level is lower. In one clinical trial comparing paired high and low FSH cycles of controlled ovarian hyperstimulation (use of FSH containing fertility medication) the ovarian response was not significantly different in terms of number of eggs retrieved or fertilization rates. This report suggests that serial FSH levels have little clinical value. The bulk of the other clinical studies available support this finding.
Younger women with only one ovary may also have a decreased ovarian reserve. The basal FSH concentration in these women may be discouraging and a common concern is whether this reduction in ovarian reserve suggests a significant decrease in reproductive potential. The research in this specific area is scanty but what is available does suggest a reduced reproductive potential with basal FSH concentrations in the "discouraging" range.
The cycle day 3 FSH concentration depends on (is critically dependent upon) the assay used to determine its value.
In the USA there are several different assays, including the Lee Co (now BINAX, the assay on which most available research data is based), Becton Dickenson (a newer ELISA assay system which reports values about 40% as high as the older Lee Co assays), and immulite by DPC (a popular assay system purchased by many ART programs since it is small and relatively inexpensive with values fluctuating depending on the reagents provided, making close contact with the company and its standards important). Each of these different assays uses different standard solutions to perform the test, and therefore give different results for the same samples.
When compared head to head in one preliminary report, the Lee Co assay yielded values 2.4-2.5 fold higher than the Becton Dickenson assay at three different points (concentrations) along the standard curve in the range expected for reproductive age women. Therefore, a value of 25 IU/L on the Lee Co assay correlates roughly to 10 IU/L on the Becton Dickenson assay. This has led to confusion and occasionally misinterpretation of results. The system used in the early studies on cycle day 3 FSH concentrations is the Lee Co assay and has a normal range of 5-20 IU/L. The Becton Dickenson assay has a normal range of 1.5-6.3 IU/L. The immulite DPC assay has a normal range that has fluctuated widely with the different reagents that have been supplied.
Many infertility centers have their own office based assay systems for determining commonly ordered hormone levels. Each of these centers should be able to suggest the encouraging, discouraging and borderline levels for their particular assay system.
In 1995, the "cycle day 3 estradiol" concentration was reported to predict success (pregnancy rates) at IVF. As with most hormonal assays, knowledge of the assay used is critical since the available estradiol assays are varied and appear to give different values for the same samples. The physician must become familiar with the assay that (s)he uses to establish clinically relevant cutoff values.
The report introducing estradiol as a useful parameter in assessing ovarian reserve (from one of the most successful IVF centers in the USA) found no pregnancies (in 600 IVF cycles) in women (undergoing IVF) if the "estradiol concentration on their assay was greater than 75 pg/mL" or if "the FSH was greater than 17 IU/L and the estradiol was greater than 45 pg/mL." Since the estradiol assay used in this study was established in their own hospital the comparison to other assays may show significant differences. Once standard data within a lab system is established the estradiol level may be a predictable and valuable parameter helping to predict fertility treatment (especially ART) outcome and ovarian reserve.
The literature on basal estradiol concentrations has some conflicting reports. The largest study to date reports no difference in pregnancy rates in women with normal basal FSH concentrations based on the basal estradiol concentration. This report suggests that the estradiol concentration may be useful in determining whether the woman was truly around cycle day 3 (to help determine the meaning of the FSH concentration) but that otherwise the basal estradiol concentration has little clinical utility.
It will be interesting to see how this literature settles out as more data becomes available.
The clomiphene citrate challenge test uses this fertility medication (100 mg per day for cycle day 5 to 9) to provoke a hypothalamic, pituitary and ovarian response. The test usually involves checking hormone levels (such as FSH, estradiol, progesterone) on cycle day 3 and again on cycle day 10. The clomiphene challenge test is a provocative test that measures the response of the reproductive axis to a stressor (clomiphene citrate) and thereby appears to be far more sensitive than the basal FSH concentration (alone) at identifying women with decreased ovarian reserve.
Most often, it is the FSH response to clomiphene citrate that is used to determine ovarian reserve. In several reports from a diverse number of infertility centers, an abnormal FSH concentration on cycle day 3 or 10 heralds poor success with controlled ovarian hyperstimulation (and lower fertility rates during these stimulated cycles). The FSH concentrations that should be used for cutoff values are not well standardized, with some large groups using 10 IU/L on the Becton Dickenson assay (equivalent to roughly 25 IU/L on the Lee Co assay).
Progesterone has also been proposed as another predictive variable in the clomiphene citrate challenge test. One report on this challenge test demonstrated no pregnancies in women whose progesterone concentration was greater than 1.1 ng/ml on cycle day 10 compared to a 19% pregnancy rate if the progesterone concentration was less than 0.9 ng/ml on this day. It seems that these findings remain to be confirmed and standardization must still be established for this test to gain widespread acceptance.
Available literature uniformly suggests a low (possibly zero) success at In Vitro Fertilization if the clomiphene citrate challenge test is abnormal (the reduction in fertility depends on the cutoff levels used to define an abnormal result). The incidence of abnormal test results in the normal fertile population and general infertility populations is not clearly established, so the value of the clomiphene citrate challenge test is primarily within the context of controlled ovarian hyperstimulation.
A decreased ovarian reserve using the basal FSH concentration or the clomiphene challenge test suggests a poor prognosis (in terms of fertility) at In Vitro Fertilization and probably controlled ovarian hyperstimulation with intrauterine inseminations.
It seems that the number of recruitable follicles per cycle is dramatically reduced if the ovarian reserve is decreased. Therefore, one might expect up to 20 mature eggs to develop simultaneously with these fertility medications if the ovarian reserve is high while only 1-3 might develop if the reserve is low.
One large clinical series that examined women with a discouraging ovarian reserve reports that some (a small percentage) of these women have a good response to FSH containing medications. However, the pregnancy rates for these women with a reduced ovarian reserve and a good response to fertility medications remained very low. This report suggests that the number of eggs matured with fertility medication is not clinically important in the presence of a decreased ovarian reserve. More information on this important issue would be useful.
If a woman with a decreased reserve is very committed to pursuing Advanced Reproductive Techniques (such as In Vitro Fertilization) using her own eggs, a frank discussion with an experienced infertility specialist should focus on the likelihood of success given the findings from her ovarian reserve evaluation. Age should also be (independently) considered.
There are no good clinical reports in the literature describing the value of any of these tests (of ovarian reserve) in spontaneous (natural) cycles. The diminished ovarian reserve really has only been shown to suggest that a woman will most likely not respond well to ovulation enhancing medication. The importance of determining a reduction in ovarian reserve in the general infertility population is therefore unclear.
If one of my patients ovulates regularly, has a decreased ovarian reserve, and is highly motivated then I often suggest aggressive management of any identifiable male factor or pelvic factor infertility problem. This will allow the couple to optimize their fertility success by treating all identifiable problems without resorting to the use of (very expensive) fertility medications.
Donor egg programs are becoming increasingly available and are an alternative that some women might want to consider if their own ovarian reserve is very low. The fertility rate is roughly predicted by the donorís age, and the recipient carries the pregnancy from the time of embryo transfer (prior to implantation). An experienced donor egg program will most likely have the type of support and counseling often found helpful in this situation.
The in vitro maturation of immature eggs (harvesting immature eggs from the ovaries and maturing these eggs to the point of becoming fertilization capable in culture = in vitro) has been the subject of a great deal of recent discussion and research. Although there have been a few pregnancies that have carried to term with this technique (in 2002 I believe there have been only 3 liveborn deliveries from this technique in the world literature), the technique is still in its infancy. Once the "bugs have been worked out" of this technique, the in vitro culturing of immature eggs will most likely revolutionize IVF. It is possible that at that stage, infertility specialists will also be able to select the few best eggs from thousands of eggs matured in culture from ovaries with decreased ovarian reserve and improve the fertility of these couples.