Fertility Blaze
Fertility Blaze 2014 › Fertility Blaze Vol-2, No-1, 2014

Ovarian reserve testing

Ovarian reserve

A delay in childbearing is strongly associated with age-related decline in fertility potential.1   The age-related reduction in fecundity is a result of the presence of a limited pool of oocytes in human ovaries.2   This eventually increases the incidence of infertility among couples trying to conceive.1

“Ovarian reserve”   denotes the functional potential of the ovary that is expressed as the number and quality of oocytes within it.3   The age-related impairment in a woman’s ability to achieve and maintain pregnancy, both through natural and assisted techniques, may be attributed to the age-related changes within the ovary, i.e. a reduction in the number of oocytes available for ovulation or retrieval and an ongoing decline in the capacity of these oocytes to form viable embryos.4   As early as 31 to 35 years of age, spontaneous cumulative pregnancy rates begin to decline. At 35 to 39 years of age, one-third of women experience difficulty achieving pregnancy and by 40 to 44 years of age, one-half of women have impaired ability to reproduce. The cumulative success rates with donor insemination have also been seen to decline with increasing age of women (Figure 1).4

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Diminished ovarian reserve (DOR) or reduced ovarian reserve is a state of reduced ability of the ovary to produce oocytes owing to advanced age or congenital, medical, surgical and idiopathic causes.5

Rationale for measuring ovarian reserve

Although the decline in oocyte pool and quality with age is a universal phenomenon, fertility potential may still vary among women in the same age group. It therefore becomes essential to understand the reason behind the reduced fertility potential or the decreased ovarian reserve. Also required are a series of tests, known as the ovarian reserve tests that may assist in determining the ovarian reserve to predict the outcome. Ovarian reserve tests are aimed at adding value to the counseling process for couples opting for infertility treatments. These tests are an indirect estimate of a woman’s remaining follicular pool. An ideal test is the one that is easy to perform and reproducible. These tests help differentiate women with normal and poor ovarian response.  6   Ovarian reserve testing helps identify women at increased risk of exhibiting a poor response to ovarian stimulation or those with very low odds of becoming pregnant through in vitro fertilization (IVF). The tests also help identify those who still produce enough oocytes to have a fair chance of becoming pregnant even if the age is advanced.1

Measures of ovarian reserve

Ovarian reserve tests include biological, biochemical, biophysical, and histological tests. Chronological age, a biological parameter of measuring ovarian reserve, is known to be associated with decreased ovarian reserve. Histological assessment of ovarian reserve includes ovarian biopsy. Although projected as a potential tool for assessing the ovarian reserve, ovarian biopsy was found to have no significant role in the routine assessment of ovarian reserve.7

This article focuses on the biochemical and biophysical tests of ovarian reserve (Figure 2) and aims to put forth all that is new in the field of ovarian reserve testing. The biochemical testing is further subdivided into static and dynamic tests.

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Static tests: follicle-stimulating hormone (FSH), estradiol, inhibin B, and antimullerian hormone (AMH)

Dynamic tests: clomiphene citrate challenge test (CCCT) and exogenous follicle stimulating hormone ovarian reserve test (EFORT)

Biophysical tests include the ultrasonographic assessment of ovarian volume and antral follicle count (AFC).

Application of ovarian reserve tests

Ovarian reserve testing has enjoyed diverse application in the field of reproductive medicine. The tests were initially intended to be used as an aid to examine patients prior to the initiation of a cycle of IVF. Eventually, only those patients falling within a normal range as specified by each center were treated. However, subsequent studies included heterogeneous patient populations and outcome measures leading to obscure interpretation of these tests. The tests have also been used to segregate women with good prognoses from those with poor prognoses despite their similar age groups.2

Although ovarian reserve tests are used to identify patients with DOR, the entity DOR itself has had diverse explanations and/or definitions. DOR can be explained both as reduced ability to achieve pregnancy as well as a poor ovarian response to gonadotropin stimulation.8   Additionally, studies evaluating the outcomes of ovarian reserve testing have included heterogeneous populations. Therefore, the application of these tests should be carefully individualized according to the patients.

Principles of screening tests

Screening tests are aimed at identifying individuals who are most likely to develop a disease. Ovarian reserve tests, likewise, help identify infertility patients who are at risk for DOR, who are more likely to exhibit a poor response to gonadotropin stimulation and those who have an imperceptible chance of achieving pregnancy with assisted reproduction, particularly IVF.

A screening test has four main characteristics that change with the diagnostic threshold. These include sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). An ideal screening test has validity, i.e. the ability to classify a person who has disease (DOR in case of ovarian reserve test) as test positive (highly sensitive) and the one without disease as test negative (highly specific). Therefore, a highly sensitive test would identify patients with DOR while a highly specific test would identify those without DOR. The sensitivity and specificity of different thresholds of a diagnostic test may be plotted as receiver operating characteristic (ROC) curves to establish the cutpoint that maximizes sensitivity and specificity. PPV and NPV undergo change with the prevalence of disease (DOR) in the study population. PPV suggests the possibility that a woman with a positive test actually has DOR while NPV is the probability that a woman with a negative test has normal ovarian reserve. The hallmarks of an ovarian reserve test are its predictive values rather than sensitivity or specificity.
Figure 3 illustrates the characteristics of an ovarian reserve test.2

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Major ovarian reserve tests

FSH

The significance of cycle day 3 FSH levels as predictive of pregnancy outcome and stimulation characteristics in IVF was reported more than 20 years back by Scott and colleagues.9   A basal or day 2-3 FSH is used to determine ovarian reserve and levels >10 IU/L are often used as a cut-point for further investigations.10     van der Steeg and his colleagues investigated the predictive value of basal FSH on spontaneous ongoing pregnancy in subfertile ovulatory women and reported that a basal FSH level ≥8 IU/L was associated with decreasing fecundity, independent of female age and cycle length. Routine testing of basal FSH was not recommended in subfertile couples.11

Esposito and colleagues12   evaluated whether a moderately elevated [10-11.4 mIU/ml, World Health Organization 2nd International Standard (IRP 78/549)] and elevated FSH (>11.4 mIU/ml, conversion factor to SI units, 1.00) could determine the ability to achieve pregnancy through IVF and embryo transfer, both independently, and after controlling for confounding variables such as age, diagnosis, and response to gonadotrophins. The sensitivity of a moderately elevated and elevated FSH value in predicting IVF failure ranged from 6.7-19.5%. Specificity of moderately elevated and elevated FSH concentrations for all age groups ranged from 90.1-100%. The PPV of a moderately elevated FSH concentration ranged from 60-100% while for an elevated FSH, the PPV was 100%. It is evident that cutpoints that have high specificity (80%-100%) end up having low sensitivities (10%-30%). Interpretation of this test is difficult owing to lack of consensus in defining an elevated FSH concentration and a change in the assays.12

Four hundred and thirteen infertile women aged 23 to 40 years, who underwent 523 cycles of IVF, were analyzed to identify the critical FSH values that would best predict grim chances of success in IVF program. Each woman was subjected to a CCCT within 1 year of each IVF cycle. The overall live birth and implantation rates were 43% and 24%, respectively. The critical values for day 3 and day 10 FSH levels were 14.1 and 16.9 mIU/mL, respectively, with a 0% live birth rate and a 5% implantation rate above these levels. It was deduced that medical centers offering IVF should determine their critical FSH values in order to identify patients most unlikely to benefit from IVF.13   Roberts and colleagues14   have shown that a history of elevated basal FSH levels in patients <40 years of age predicts a lower oocyte yield in IVF cycles with normal basal FSH levels; however it does not predict either lower pregnancy or implantation rates. Patients aged >40 years with elevations in basal FSH levels in the past, present with compromised ovarian response and embryo quality in comparison to those with normal FSH levels.

To summarize, the clinical significance of testing for basal FSH is restricted to a minority of patients and therefore this test should not be included in the routine testing for the prediction of IVF outcome.15

Estradiol

Estradiol is a less helpful indicator of a woman’s follicular reserve.16   Estradiol levels during cycle days 2, 3, 4 and 5 are not constant and therefore, have poor reliability.17,18      Penarrubia and colleagues17   have reported that FSH shows comparatively less intra-cycle variability than estradiol serum concentrations. Data suggest that dynamic endocrine tests may be better than basal evaluation of estradiol in predicting ovarian response.19

Frattarelli et al20   have shown that patients with basal estradiol levels <20 pg/mL or ≥80 pg/mL have an increased risk for cancellation. However, the levels neither predicted pregnancy outcome nor correlated with ovarian response in those patients not canceled. It was pointed that irrespective of basal estradiol levels, patients who produce more than three maturing follicles in response to stimulation have adequate ovarian reserve as evidenced by their pregnancy rates. Ranieri et al,21   on the other hand, reported that simultaneous evaluation of basal levels of FSH and of the response of estradiol to gonadotrophin-releasing hormone agonist (GnRHa) stimulation was the best predictor of ovarian reserve and a sensitive predictor of response to ovarian stimulation.

Basal estradiol thus does not have any significant role in predicting poor response.22   However, basal estradiol level on cycle day 3 is a useful determinant of response to stimulation in IVF patients who have normal basal FSH levels.23

Clomiphene citrate challenge test

The CCCT requires administration of 100 mg clomiphene citrate on cycle days 5-9, while the FSH concentration is assessed on days 3 (before treatment with clomiphene citrate) and 10 (after treatment).2,24   An abnormally high value on day 10 (cut off point 10-26 mIU/ml) indicates diminished ovarian reserve. Rising inhibin B and estradiol levels derived from ovarian follicles suppress FSH in women with normally responsive ovaries. On the contrary, women with DOR will produce less inhibin B and estradiol that will eventually lead to subdued suppression of FSH secretion and higher stimulated FSH concentrations. An elevated FSH concentration after clomiphene stimulation is therefore predictive of DOR. In other words, clomiphene citrate-dependent rise in FSH is suppressed by estradiol and inhibin B produced by the follicles in normally responsive ovaries. Therefore, an abnormal test will be characterized by an abnormally high FSH on day 3 or day 10.2,24

A systematic review identified and analyzed 12 studies on the CCCT and evaluated the significance of the test in predicting poor ovarian response and pregnancy in IVF. In predicting poor response, the sensitivity and specificity of the CCCT ranged between 35% and 93% and 47% and 98%, respectively. In predicting nonpregnancy, the sensitivity varied from 13% to 66% and specificity varied from 73% to 97%. Owing to heterogeneity among studies, it becomes difficult to obtain a summary ROC curve.25

Hendriks et al26   have reported that a CCCT, either single or repeated, is effective in predicting poor response in IVF. However, the predictive accuracy may not be better than that of basal FSH in combination with an AFC. It was thus suggested that the use of CCCT as a predictor of outcome in IVF should be avoided. The test may be a useful tool when performed before initiating treatment for infertility.27   The test may be of great help in determining a woman’s ovarian capacity before the infertility treatment is started.27   An abnormal test successfully predicts DOR and may also be superior to a basal FSH concentration on day 3.28

Antimullerian hormone

Antimullerian hormone (AMH) is a glycoprotein that is secreted by the granulosa cells of (pre)antral follicles. It serves as a quantitative marker of the ovarian reserve. AMH is useful in detecting patients most likely to display poor response to stimulation. Of note, AMH is not a predictor of live birth rate following IVF.29   Lower baseline serum AMH concentrations are associated with poor response to IVF, thereby suggesting a DOR.8   Additionally, the predictive value of AMH for poor ovarian response is comparable with that of AFC and can therefore replace AFC in predicting ovarian response to controlled ovarian hyperstimulation in IVF.8

Celik et al30   recently conducted a study to determine the significance of serum and follicular AMH concentrations for ovarian reserve and clinical pregnancy. A statistically significant correlation was evident between serum AMH and number of retrieved oocytes; the number of retrieved oocytes and baseline AFC; ovarian reserve and baseline FSH; and ovarian reserve and serum AMH. The cut-off value of serum AMH for normal ovarian reserve was calculated as 0.37 ng/ml with a sensitivity of 71.43%, specificity of 66.67%, PPV of 83.33% and NPV of 50%. Interestingly, evaluation of serum AMH concentration in older patients (>40 years) appears promising for the prediction of oocyte numbers which may be obtained in IVF. A cut-off level of 1.0 ng/ml AMH may help predict poor ovarian response.31   AMH may be the single best predictor of ovarian response to gonadotrophin stimulation among those considered to be poor responders and undergoing IVF.32   In another study conducted to evaluate the relevance of AMH in a routine IVF program, levels ≤  1.26 ng/ml significantly predicted reduced ovarian reserve.33   AMH is comparable with other commonly used ovarian reserve tests, however, it is probably the most applicable one in general practice.34

It must be noted that the AMH concentration varies during menstrual cycle among women with adequate ovarian reserve, and the clinical classification of the ovarian response may therefore be altered.35   However, it has the advantage of reduced variability of its serum concentrations along the menstrual cycle when compared with FSH  , inhibin B and estradiol.36

EFORT test

EFORT test serves as a screening test for good and poor responders in IVF. Day 3 FSH and estradiol serum concentrations as well as the estradiol response following a 300 IU FSH injection on day 3 are determined.24

Fanchin et al37   subjected 52 IVF candidates, 27-42 years old, to 52 consecutive IVF cycles. Candidates received 300 IU of purified FSH on cycle day 3. Plasma FSH and estradiol were assessed before injection while 24 h later, plasma estradiol concentration was determined. Two menstrual cycles later, ovarian stimulation was performed for IVF using a time-release GnRHa and human menopausal gonadotrophin (HMG). The post-FSH plasma estradiol increment (delta E2) and the baseline plasma FSH values (bFSH) were employed to interpret the EFORT results. There appeared to be a statistically significant improvement of the predictive value of the bFSH on the ovarian stimulation outcome with synergistic analysis of the EFORT parameters (bFSH and delta E2). Dzik et al38   reported in their study that Δ   inhibin B after EFORT might be helpful in predicting ovarian response to hyperstimulation in a subsequent IVF cycle. The EFORT is superior to CCCT for prediction of hyper-response in IVF, but at the cost of a high rate of false positives.39

Inhibin B

Basal measurements of inhibin B signify the number of follicles that will ultimately reach maturity. Additionally, inhibin B and AMH concentrations decline before an increase in basal FSH levels and serve as earlier markers of a reduction in ovarian reserve.40   However, inhibin B displays significant inter-cycle variability. Therefore, basal inhibin B measurement cannot be used alone as a predictor of ovarian reserve.40

In patients undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI), both basal and stimulated serum inhibin B levels are lower in poor responders. Also, stimulated inhibin B is a more accurate predictor of ovarian response in these patients as compared to AMH.41   Day-5 inhibin B has been shown to be a superior predictor of live birth than AFC.42   Using 283 pg/ml of inhibin B as the cut-off point, day 5 inhibin B has 77% sensitivity, 30% specificity, 31.2% PPV and 76.7% NPV for poor ovarian response. This test, therefore, cannot be used as a strong predictor of cancellation, pregnancy and poor resp  onse.43

Antral follicle count

Antral follicle count (AFC) has been noted to have favorable inter-cycle and inter-observer reliability.2   A count of 8-10 follicles serves as a predictor of a normal response.6   Both AMH and AFC are good predictors of ovarian response; however, AFC may be a better predictor.44   AFC has a significant correlation with the number of eggs collected and predicts clinical pregnancy.45   In a recent study, poor responders in IVF had lower AFC and AMH but higher basal FSH levels. AFC was the best and only independent parameter to predict poor response to ovarian stimulation. The cut-off point for AFC in discriminating the best between poor and normal ovarian response cycles was 5.5, with a sensitivity of 91% and a specificity of 91%, respectively.46   Of note, AFC can be measured irrespective of the phase of the menstrual cycle without any marked impact on its predictive value for poor ovarian response.47

Ovarian volume

A cohort study reported that pretreatment small AFC and ovarian volume could identify women with a higher probability to achieve pregnancy in IVF.48   Ovarian volume measurement, at a cut-off value of 3 cm3  , has a specificity of 92% for prediction of cycle cancellation and 93% for non-pregnancy.49   Another study reported that predictive performance of ovarian volume for poor response is inferior compared to AFC.50   AFC and ovarian volume are significantly depleted in women exhibiting poor response (9 ± 3.3 and 6.3 ± 3.5 cm3  , respectively) as compared to normal responders (19.2 ± 9.9 and 8.9 ± 4.8 cm3  , respectively). Yet, AFC is a better predictor of poor ovarian response.51

Combined ovarian reserve tests

As evident from the aforementioned data, no single test for determining ovarian reserve is reliable enough or has a 100% sensitivity or specificity to be regarded as the single best predictor of ovarian reserve. Thus, a need to combine several measures to improve outcome was felt.

In an attempt to quantify predictors of poor ovarian response in IVF, 120 women undergoing their first IVF cycle were subjected to measurements of the number of antral follicles and the total ovarian volume, and of basal levels of FSH, estradiol and inhibin B on cycle day 3.22   Addition of basal FSH and inhibin B levels to the AFC helped improve the prediction of poor response; however, adding basal estradiol levels and total ovarian volume did not improve the prediction. Licciardi and his team noted that a combined application of day 3 FSH and estradiol improved the prognostic ability of either of these hormones used alone for ovarian stimulation response.52

Balasch and colleagues53   had noted in their study that age was a poor predictor than pretreatment basal FSH and inhibin levels for ovarian response in IVF cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment. They also noted that any two or all three of the variables studied had no impact on the predictive value of FSH or inhibin alone. It has also been noted that AMH and AFC, either applied individually or combined, exhibit a similar predictive power for poor response to ovarian stimulation but have no role in the prediction of nonconception.54

To summarize….

  • An ovarian reserve test, to be termed as the ideal one, should have low inter- and intra-cycle variability
  • An ideal test should yield high specificity, i.e. ability to identify individuals without DOR
  • Routine testing of basal FSH is not recommended in subfertile couples
  • FSH cutpoints that have high specificity (80%-100%) end up having low sensitivities (10%-30%)
  • Basal estradiol may not have any significant role in predicting poor response
  • Basal estradiol on cycle day 3 is a useful determinant of response to stimulation in IVF patients with normal basal FSH levels
  • CCCT may be useful in determining a woman’s ovarian capacity before the infertility treatment is started
  • The predictive accuracy of CCCT for poor response in IVF may not be better than that of basal FSH in combination with an AFC
  • AMH is a potential screening test in the general IVF population and in women at high risk for DOR, but not in women at low risk for DOR
  • AMH may be the single best predictor of ovarian response to gonadotrophin stimulation among poor responders undergoing IVF
  • EFORT is superior to CCCT for prediction of hyper-response in IVF, but at the cost of a high rate of false positives
  • Inhibin B cannot be used as a strong predictor of cancellation, pregnancy and poor response
  • AFC can be measured irrespective of the phase of the menstrual cycle without any marked impact on its predictive value for poor ovarian response
  • AFC is a better predictor of poor ovarian response than ovarian volume.  

Conclusion

A wide array of tests are available to measure ovarian reserve; however, no single test can be termed as the best to predict pregnancy. Although there is good amount of evidence to establish the utility of several of the tests, either alone or in combination, in predicting ovarian reserve and response to stimulation; the data regarding their predictive ability for occurrence of pregnancy is limited. A recent individual patient data meta-analysis reported that none of the ovarian reserve tests added any information to the limited capability of female age to predict ongoing pregnancy after IVF. The potential of the tests, prior to IVF, is limited to the prediction of ovarian response.55   The potential implication of these tests is limited by heterogeneity with regard to the population sampled and the index and reference tests. Further research is therefore required in this field in order to improve results.

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