The detection of diminished ovarian reserve in infertile women,☆☆,

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Abstract

Women in their mid to late 30s and early 40s with infertility constitute the largest portion of the total infertility population. These women frequently undergo multiple testing, and most will require expensive and invasive therapies, including assisted reproductive technologies, with markedly reduced pregnancy rates in those older than 40. These women also have a higher incidence of pregnancy loss even after documentation of fetal cardiac activity by ultrasonography. Identifying those women who have a very low chance of pregnancy (and a high chance of pregnancy loss) with their own gametes presents a daily challenge to the practicing clinician, especially before embarking on expensive treatments. This article reviews the contemporary investigation of reproductive aging with basal and provocative tests. Women with markedly diminished ovarian reserve should be counseled on their low chances of conception with their own gametes, even with assisted reproductive technologies. (Am J Obstet Gynecol 1998;179:804-12.)

Section snippets

Age-related changes in follicle-stimulating hormone levels

A series of studies in the 1970s and 1980s characterized the endocrinologic aspects of the transition through the climacteric.8, 9, 10, 11, 12, 13 Sherman et al12 and Sherman and Korenman13 documented that women with normal ovulatory cycles may commonly begin having subtle elevations in their follicle-stimulating hormone (FSH) levels in their mid 30s. Further studies confirmed these findings and consistently demonstrated that the first elevations occur in the early follicular phase.9, 11

Basal FSH levels and pregnancy rates

The earliest description of pregnancy rates and basal FSH levels was in a study by Muasher et al19 evaluating the relationship between gonadotropin-releasing hormone stimulation test results and the ovarian response to gonadotropins. Evaluation of the pregnancy rates after the IVF cycles revealed high rates in 58 women whose FSH levels were relatively low, whereas no pregnancies occurred in 21 women whose basal FSH values were higher. In a larger study from the same group, Scott et al6 found in

Intercycle and intracycle variability in basal FSH levels

If basal FSH levels are going to be used to counsel patients regarding their chances for conception, a number of questions regarding the reproducibility of the test have to be addressed. One of these was defining the magnitude of the intercycle variation in basal FSH levels. Scott et al28 evaluated the intercycle variability in basal FSH levels in 81 women undergoing multiple IVF cycles. The mean deviation was 4.2 ± 0.4 IU/L, with a range that extended from <1 IU/L to 42 IU/L. However, the

Basal FSH screening in women with one ovary

Because basal FSH level screening is believed to reflect the status of the developing cohort of follicles as a whole, considerable concern existed as to whether the predictive value of basal FSH would be maintained in women with 1 ovary. Khalifa et al31 compared the basal FSH levels in women with 1 or 2 ovaries and evaluated the predictive values of the test in each group. The 162 women with 1 ovary had higher mean basal FSH levels, and correspondingly had a poorer response to gonadotropin

E2 levels and basal day 3 FSH levels

The validity of FSH screening depends on the time in the cycle the sample is collected. Timing is considered optimal when circulating E2 levels are at their nadir, which is typically around cycle day 3. Some patients will have inappropriately high E2 levels on day 3, which suggests that they may be farther into their follicular phase than is clinically apparent. In these circumstances it is possible that the higher circulating E2 level might be able to suppress FSH levels back into the normal

Basal FSH/LH ratios

Although extensive data are available regarding the high level of specificity of basal FSH levels, the fact remains that the test may have limited sensitivity. Stated otherwise, patients with high ratios are typically low responders with very poor pregnancy rates (highly specific), but a substantial group of patients will have normal levels and yet still respond poorly to stimulation with associated poor pregnancy rates. This led some investigators to seek more sensitive tests (ie, FSH/LH

Current status of basal FSH screening

Elevated basal day 3 FSH concentrations are highly predictive of diminished ovarian reserve as defined by poor gonadotropin responsiveness and pregnancy rates in patients undergoing complex ovulation induction or one of the assisted reproductive technologies.6, 7, 20, 21, 22, 23, 24, 25, 28, 30, 31, 32, 33, 34, 35 The test is simple, inexpensive, and routinely available. The studies performed to date are limited to clinical circumstances requiring complex ovulation induction. No data are

The clomiphene citrate challenge test

The clomiphene citrate challenge test was described in 1987 by Navot et al39 as a means of assessing ovarian reserve in women 35 years of age and older. This simple test consisted of measuring serum FSH concentrations on cycle day 3 (basal) and then again on cycle day 10 after the administration of 100 mg of clomiphene citrate on cycle days 5 through 9. In the original study, which was published before any of the studies addressing the value of basal FSH levels, an abnormal test was defined by

The clomiphene citrate challenge test and pregnancy rates

After Navot’s initial report, several groups evaluated the predictive value of clomiphene citrate challenge test screening in patients participating in assisted reproductive technology programs.41, 42, 43, 44 Tanbo et al41 studied 91 women older than age 35 and found abnormal clomiphene citrate challenge tests in 37. Twenty of the 37 patients also had an elevated basal FSH concentration on cycle day 3. Only 1 patient had an abnormal value on day 3 with a normal value on day 10. The predictive

Clomiphene citrate challenge test screening in the general infertility population

The data generated during the initial evaluation of the clomiphene citrate challenge test were similar in nature to those evaluating basal FSH levels alone. The clomiphene citrate challenge test was initially used in assisted reproduction programs or in patients undergoing complex ovulation induction. Although the test is clearly useful in identifying patients with a poor prognosis in that setting, the results may not be readily extrapolated to the general infertility population. Legitimate

Predictive value of age and the clomiphene citrate challenge test

The data from the studies described above clearly define that the clomiphene citrate challenge test has better predictive values for pregnancy rates than does age alone. However, in clinical practice both age and clomiphene citrate challenge test results are now available. Scott et al48 performed life-table analyses of pregnancy rates of 589 couples from the general infertility population who were followed for up to 45 months. Analysis of the patients with abnormal clomiphene citrate challenge

Smoking and the clomiphene citrate challenge test

Women who smoke cigarettes go through menopause 1 to 4 years earlier than nonsmokers, and a direct relationship between the amount of cigarettes smoked and earlier menopause has been noted.49, 50, 51 This suggests that smokers deplete their pool of follicles at an accelerated rate, suggesting that these women may have the onset of diminished ovarian reserve at an earlier age. A recent study by Sharara et al52 examined the relationship between cigarette smoking and the prevalence of diminished

Current status of clomiphene citrate challenge test screening

An abnormal clomiphene citrate challenge test has excellent predictive values for diminished ovarian reserve and poor long-term pregnancy rates in natural cycles, during ovulation induction, and in IVF.40, 41, 42, 43, 44, 45, 46, 47, 48, 52 Although the test is quite specific, it has limited sensitivity, with a significant age-related diminution in reproductive potential occurring even among women with normal test results.3 The test may be superior to basal FSH screening because it is 2 to 3

The gonadotropin agonist stimulation test

Extending on earlier work by Padilia et al,55 Winslow et al56 evaluated the change in E2 levels 24 hours after the administration of 1 mg of leuprolide acetate on cycle day 2. The magnitude of the increase in E2 correlated strongly with IVF success. A recent study evaluating basal and stimulated (2 hours after the use of 0.3 mg buserelin acetate) FSH levels on day 1 of gonadotropin stimulation found no improvement over basal FSH in predicting IVF success.57 This test has not been validated

Assay variability

Immunoassays of LH and FSH are intrinsically difficult and imprecise. This reflects the fact that LH and FSH are glycoprotein hormones composed of a protein dimer backbone with variable degrees of glycosylation. Differences in the antibodies used to measure gonadotropin levels also contribute to the imprecision of these assays. Most of the commercially available assay systems use polyclonal antibody systems that bind differently to separate haptens on the glycoprotein hormone. It is important

Recommendations for ovarian reserve screening

The physiologic basis of screening for ovarian reserve is made on the basis of a number of observations regarding the concept of an aging follicular apparatus composed of compromised germ (oocytes) and accompanied somatic cells (granulosa). This concept has evolved through a number of independent but related studies. It is well documented that a reduction in the number of follicles occurs most dramatically between the ages of 36 and 38.60 Others have shown that this decrease in number of

References (64)

  • DB Seifer et al.

    Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome

    Fertil Steril

    (1997)
  • RT Scott et al.

    Intercycle variability of day 3 follicle-stimulating hormone levels and its effect on stimulation quality in in vitro fertilization

    Fertil Steril

    (1990)
  • JSB Martin et al.

    Future in vitro fertilization pregnancy potential of women with variably elevated day 3 follicle-stimulating hormone levels

    Fertil Steril

    (1996)
  • E Khalifa et al.

    Significance of basal follicle-stimulating hormone levels in women with one ovary in a program of in vitro fertilization

    Fertil Steril

    (1992)
  • FL Licciardi et al.

    Day 3 estradiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization

    Fertil Steril

    (1995)
  • DB Smotrich et al.

    Prognostic value of day 3 estradiol on in vitro fertilization outcome

    Fertil Steril

    (1995)
  • RP Buyalos et al.

    Basal estradiol and follicle-stimulating hormone predict fecundity in women of advanced reproductive age undergoing ovulation induction therapy

    Fertil Steril

    (1997)
  • T Mukherjee et al.

    An elevated day three follicle-stimulating hormone: luteinizing hormone ratio (FSH:LH) in the presence of a normal day 3 FSH predicts a poor response to controlled ovarian hyperstimulation

    Fertil Steril

    (1996)
  • D Navot et al.

    Prognostic assessment of female fecundity

    Lancet

    (1987)
  • E Loumaye et al.

    Prediction of individual response to controlled ovarian hyperstimulation by means of a clomiphene citrate challenge test

    Fertil Steril

    (1990)
  • RT Scott et al.

    Evaluation of the significance of a poor estradiol response during the clomiphene citrate challenge test

    Fertil Steril

    (1993)
  • GE Hofmann et al.

    Efficacy of selection criteria for ovarian reserve screening using the clomiphene citrate challenge test in a tertiary fertility center population

    Fertil Steril

    (1996)
  • FI Sharara et al.

    Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test (CCCT)

    Fertil Steril

    (1994)
  • EG Hughes et al.

    Cigarette smoking and the outcomes of in vitro fertilization: measurement of effect size and levels of action

    Fertil Steril

    (1994)
  • SL Padilla et al.

    Prognostic value of the early serum estradiol response to leuprolide acetate in in vitro fertilization

    Fertil Steril

    (1990)
  • KL Winslow et al.

    The gonadotropin-releasing hormone agonist-stimulation test: a sensitive predictor of performance in the flare-up in vitro fertilization cycle

    Fertil Steril

    (1991)
  • A Hershlag et al.

    Interinstitutional variability of follicle-stimulating hormone and estradiol levels

    Fertil Steril

    (1992)
  • A Pellicer et al.

    Effects of aging on the human ovary: secretion of immunoreative a-inhibin and progesterone

    Fertil Steril

    (1994)
  • DB Seifer et al.

    Proliferative index of human luteinized granulosa cells varies as a function of ovarian reserve

    Am J Obstet Gynecol

    (1993)
  • S Spandorfer et al.

    Abstract PP-20495

  • IT Cameron et al.

    Occult ovarian failure: a syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations

    J Clin Endocrinol Metab

    (1988)
  • DA Adamopoulos et al.

    Endocrinological studies in women approaching the menopause

    J Obstet Gynaecol Br Commonw

    (1971)
  • Cited by (0)

    From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine,a The Institute for Reproductive Medicine and Science of Saint Barnabas Medical Center,b and the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey, UMDNJ-Robert Wood Johnson Medical School.

    ☆☆

    Reprint requests: Fady I. Sharara, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, 405 West Redwood St, Baltimore, MD 21201.

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