The age-related decline in pregnancy rates begins in the '20s, becomes clinically significant in the 30's and reaches very low levels in the '40s. Recent data from oocyte donation programs suggest that the factors responsible for this decline involve the ovaries, not the endometrium. "Diminished ovarian reserve" is associated with follicular depletion and worsening oocyte quality with increasing age. Until recently the only indication of diminished ovarian reserve was chronological age. Because very low pregnancy rates have been noted in women with an elevated F. S. H. reading on day three of the cycle, this indication is now considered a better marker than age in predicting success rates with assisted reproduction. However, recent data suggest that relying on basal F. S. H. measurements can still cause clinicians to miss patients who have diminished ovarian reserve because the onset of an elevated level is highly variable.
Age is a factor
The associated between aging and decreased fecundity has been extensively reviewed. Results from donor insemination programs revealed that pregnancy rates decreased from 94% in women under 25 years of age to 57% in women between 36 and 40 and 36% in women between 40 and 45 after 12 months of well timed inseminations. This pattern suggest that age alone has limited predictive value in detecting diminished ovarian reserve. Additional results from oocyte donation studies show that pregnancy rates and miscarriage rates are similar to those of women of the same age as the donor or rather than those of the recipient.
F. S. H. and Estradiol
Early studies revealed that women with normal ovulatory cycles begin having subtle elevations FSH. in their early 30s and that levels tend to increase with age. In 1987 one group started screening IVF candidates with basal FSH. On day 3. Pregnancy rates were highest in women whose FSH. levels were below 15 IU/L.; the rate decreased to less than 5% in women with levels above 25 IU/L.. The investigators attributed this decline to diminished ovarian reserve because these patients developed fewer follicles, produced fewer oocytes and have fewer embryos available for transfer.
Another team examined basal FSH. levels, age, and IVF success rates in 1,478 cycles and found that FSH level was a better predictor of ultimate pregnancies than age. Evaluating the effect of previous oophorectomy on ovarian reserve, another group compared basal FSH. levels and IVF performance in 162 women who had one ovary and 1066 women who had two ovaries. Pregnancy rates were identical for both groups after controlling for basal FSH levels.
The value of FS H. screening in women over age 40 who are undergoing ovulation induction and intrauterine insemination was recently evaluated. Women aged 40-44 with a basal FSH below 25 IU/L. had a clinical pregnancy rate of 5.2% per cycle and a live birth rate of 1.9% compared with a clinical pregnancy rate of zero percent per cycle in cases in which either basal FSH was 25 or higher or patients were 44 years of age or older. Therefore, both age and basal FSH are important determinants of pregnancy rates. When cycle variability of FSH levels in consecutive IVF's was evaluated, women with normal basal FSH in one cycle and a higher level in subsequent cycle had poor pregnancy rates in both cycles. Thus, in women with intercycle variation in their FS H. levels, act on the high value rather than the normal level.
It is important to correlate the basal FS H. value with the estradiol level. Basal estradiol values above 50 decrease FSH levels through negative feedback on the pituitary. Basal estradiol readings above 50 have been associated with poor response to ovulation induction in assisted reproduction and with fewer pregnancies. When ovarian cyst are not actively producing estradiol, a premature estradiol elevation signifies earlier recruitment and is commonly seen in perimenopausal women. Therefore to interpret basal FS H. values correctly, is important that estradiol not be elevated.
Clomiphene Citrate Challenge Test
This test was originally used to assess ovarian reserve in women 35 years or older with unexplained infertility. It is simple to perform and involves measuring day 3 FS H. and estradiol, administration clomid from days 5-9 and, followed by repeat FSH on day 10. The test result is considered abnormal if either the basal or day 10 FSH are above 25 IU/L. The rationale behind the clomiphene citrate challenge test (CCCT)is that women with adequate ovarian reserve would have a developing cohort of follicles producing adequate estradiol and inhibin to overcome the effect of clomid on the hypothalamic-pituitary axis. The CCCT can help identify patients with diminished ovarian reserve that was not detected by basal FSH measurement. Few studies have dealt with the role of the CCCT in predicting response to ovarian hyper stimulation and assisted reproduction. In the original study, 51 women over age 35 with unexplained infertility were evaluated. All 51 women had normal FSH. levels. However, 18 had elevated day 10 values. Of those with abnormal CCCT., only one (6%) of the 18 conceived whereas 14 (42%) of the 33 with normal CCCT conceived.
In another study a 91 woman over age 35 with previous ovarian surgery or ovarian endometriosis, 37 (40.7%) had abnormal CCCT. None of the women with an abnormal test conceived, whereas 11% of those with a normal test did. Again, the value of the CCCT in predicting diminished ovarian reserve was underscored by the fact that twice as many women were identified when compared with those tested by basal FS H. alone. Recently, another group extended the use of CCCT to the general infertility population. The incidence of an abnormal CCC T was 3% when under age 30, 7% at 30-34, 10% at 35-39 and 26% over age 40 in 236 couples with no previous infertility workup. The incidence of abnormal CCC T., however, was highest (up to 50 percent) among couples with unexplained infertility regardless of age.
In another study there was a marked decrease in pregnancy rates with increasing age even in women with normal ovarian reserve. Therefore, other factors may be involved.
Gonadotrophin Agonist Stimulation Test
One group, extending earlier work in its institution, used the gonadotrophin agonist stimulation test (G. A. S. T.) to evaluate the change in estradiol level from cycle day 2 to 3 after subcutaneous administration of 1 mg leuprolide acetate (Lupron). The magnitude of the increase in estradiol correlated strongly with IVF success. This test has not been validated outside of assisted reproduction, and how it can be applied to infertile couples is unknown. However, the cost of the test may preclude its use for generalized screening. Similar tests using gonadotrophins (EFFORT) can be done, but usually do not add significant additional information.
Summary of Screening Recommendations
Basal FSH has been extensively evaluated in assisted reproduction and is currently the screening test of choice. The GAST has been validated in assisted reproduction but awaits further validation to confirm its predictive value. The CCCT is the best screening tool to detect diminished ovarian reserve and has been validated in assisted reproduction and in the general infertility population. It will probably become the test of choice for evaluating ovarian reserve. Based on current data, all infertile women over age 30 and younger women with unexplained infertility should undergo screening for diminished ovarian reserve. An abnormal test may be an indication for oocyte donation or adoption because of the dismal pregnancy rates noted in women with diminished ovarian reserve (even with assisted reproduction). In the current climate of cutting health-care costs and ever shrinking resources, the CCCT may become the screening test of choice to evaluate ovarian reserve.