Human Reproduction, Vol. 15, No. 11, 2341-2346,
November 2000
© 2000 European Society of Human Reproduction and Embryology
Day 3 serum inhibin B and FSH and age as predictors of assisted reproduction treatment outcome
1 Institut Clínic of Gynecology, Obstetrics and Neonatology and 2 Hormonal Laboratory, Faculty of Medicine-University of Barcelona, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Recent reports investigating the value of basal inhibin B determination as a predictor of ovarian reserve and assisted reproduction treatment have led to discordant results. This study was undertaken to further assess the relative power of day 3 inhibin B and follicle stimulating hormone (FSH) (defined before treatment) and the woman's age both as single and combined predictors of ovarian response and pregnancy in an in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programme. A total of 120 women undergoing their first cycle of IVF or ICSI was included. Forty consecutive cycles cancelled because of poor follicular response were initially selected. As a control group, the nearest completed IVF/ICSI cycles before and after each cancelled cycle (i.e. the closest cycles in temporal relationship to the index cycle) were used. Mean age and basal FSH concentrations were significantly higher in the cancelled than in the control group (P < 0.01 and P < 0.001 respectively), whereas basal inhibin B was significantly higher in the latter (P < 0.05). The association of basal FSH (with an accuracy or predictive value of ovarian response of 79%) with cancellation rate was significant, independent of, and stronger than the effects of age and inhibin B (P < 0.05). Any two or all three of these variables studied did not improve the predictive value of FSH alone. Woman's age was the only variable independently associated with pregnancy rate. It is concluded that the stronger predictors of success in patients undergoing their first IVF/ICSI treatment cycle are age and basal FSH rather than inhibin B. Basal FSH concentration was a better predictor of cancellation rate than age, but age was a stronger predictor of pregnancy rate.
Key words: assisted reproduction treatment/FSH/inhibin B/low responders/ovarian reserve
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The age-related decline in reproductive potential is the principal factor contributing to the increase in the prevalence of infertility in Western society (Sharara and Scott, 1997
). Many infertile women will finally undergo assisted reproduction treatments for their infertility. Implicit in these techniques is the recruitment and development of multiple ovarian follicles in response to stimulation with exogenous gonadotrophins. Recent extensive data link the age-related change in reproductive potential to follicular depletion and also diminished oocyte quality, factors which in aggregate are referred to as diminished ovarian reserve (Scott and Hofmann, 1995; Sharara and Scott, 1997). Assisted reproduction treatments are expensive, time-consuming and stressful for patients. Therefore, a major challenge to the assisted reproduction treatment teams is to predict prospectively patients who will be low responders and to counsel appropriately women who are potential candidates for assisted reproduction treatment.
Although ovarian reserve declines with age, it is a biological and not just a chronological function. In fact, the most important aspect of diminished ovarian reserve is that the timing of its onset is highly variable (Scott and Hofmann, 1995). Thus, a useful biomarker of ovarian response to ovulation induction is needed. The ideal parameter to estimate ovarian reserve would be easily measurable, minimally invasive, inexpensive, and have good predictive value (Sharara and Scott, 1997). Basal FSH concentrations on cycle day 3 have been described by some investigators as meeting these criteria (Scott and Hofmann, 1995; Sharara and Scott, 1997).
Other authors, however, have recently stressed that FSH concentrations alone may be an unreliable indicator of reproductive potential in older women because FSH measurement represents an indirect assessment of ovarian reserve (Seifer et al., 1997, 1999). On the contrary, the inhibin B concentration would offer a more direct assessment because inhibin B is produced by granulosa cells (Seifer et al., 1997, 1999). In addition, the decrease in inhibin B would be the earliest marker of the decline in follicle number across reproductive ageing (Welt et al., 1999). Thus, Seifer et al. (1997, 1999) reported that women with declining ovarian responsiveness and clinical outcomes in assisted reproduction treatment consistent with declining ovarian reserve had decreased day 3 serum inhibin B concentrations despite having non-elevated day 3 serum FSH concentrations. However, other recent reports disagree (Corson et al., 1999; Hall et al., 1999). Because studies are discordant, the need for further investigation has been stressed (Corson et al., 1999).
The present study is an attempt to assess further the usefulness of day 3 inhibin B concentration as a predictor of response to ovarian stimulation and pregnancy in an assisted reproduction treatment programme.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Patients studied
A total of 120 women undergoing their first cycle of IVF/intracytoplasmic sperm injection (ICSI) treatment was studied, thus avoiding possible bias from experience with previous cycles regarding ovarian response to exogenous gonadotrophin stimulation. Forty consecutive cycles which were cancelled because of a poor follicular response were initially selected. As a control group, the nearest completed assisted reproduction treatment cycle before and after each cancelled cycle (i.e. the closest cycles in temporal relationship to the index cycle) was used. The mean age of the women was 34.8 ± 3.35 years (mean ± SD) (range 25–42). Patient indications for IVF/ICSI included the following main diagnoses: male factor infertility (52% of patients), endometriosis (22%), tubal infertility (16%), and unexplained infertility (10%). All patients had both ovaries with no previous ovarian surgery and normal ovulatory function with regular menses. For the specific purpose of this study all subjects had blood samples drawn on day 3 of their cycle within 3 months of the IVF/ICSI attempt for assay of basal inhibin B, FSH and oestradiol which were measured at the completion of the study.
Stimulation regimen
Ovarian stimulation was carried out with FSH under pituitary suppression with gonadotrophin-releasing hormone (GnRH) agonist according to a protocol previously reported (Balasch et al., 1996). In all women, pituitary desensitization was achieved by s.c. administration of leuprolide acetate (Procrin; Abbott Laboratories, Madrid, Spain) (1 mg daily, which was reduced to 0.5 mg after ovarian arrest was confirmed) started in the mid-luteal phase of the previous cycle. Gonadotrophin stimulation of the ovaries was started when serum oestradiol concentrations declined to <50 pg/ml and a vaginal ultrasonographic scan showed an absence of follicles >10 mm diameter. On days 1 and 2 of ovarian stimulation, six ampoules/day of highly purified FSH (75 IU per ampoule) (Neo-Fertinorm, Serono SA, Madrid, Spain) were administered s.c. On days 3-7 of ovarian stimulation, two ampoules per day of FSH were administered to each patient. From day 8 onward, FSH was administered on an individual basis according to the ovarian response. The criteria for human chorionic gonadotrophin (HCG) administration were the presence of two or more follicles >18 mm in diameter with 
5 follicles measuring 14 mm in association with a consistent rise in serum oestradiol concentration. Oocyte aspiration was performed with vaginal ultrasonography 35–36 h after HCG administration. Up to four embryos per patient were replaced and the luteal phase was supported with additional doses of HCG. The cycle was cancelled when there were <3 follicles with diameter 14 mm after 8–9 days of gonadotrophin therapy or when requirements for HCG injection were not accomplished following 4 or 5 additional treatment days.
Hormone analyses and ultrasonography
Hormones were measured using commercially available kits. FSH serum concentrations were measured by an immunoenzymatic assay with two monoclonal antibodies (Immuno 1, Technicon; Bayer, Tarrytown, NY, USA) and data are expressed in terms of International Reference Preparation (IRP) 78/549. The sensitivity of the assay was 0.1 IU/l and the inter-assay coefficient of variation (CV) was 2.7%. oestradiol concentrations in serum were estimated by a competitive immunoenzymatic assay (Immuno 1). The sensitivity was 10 pg/ml and the interassay CV was 5%. Dimeric inhibin B was measured by a solid-phase sandwich enzyme-linked immunosorbent assay which uses two monoclonal antibodies (Serotec, Oxford, UK). The first monoclonal antibody is specific for the ßB-subunit of inhibin; the second one is directed to the 
-subunit and coupled to alkaline phosphatase. The assay utilizes an immunopurified mixture of inhibin forms from human follicular fluid calibrated against recombinant 32 kDa inhibin B. The sensitivity of the assay was 15 pg/ml and the intra-assay and inter-assay CV were <11 and 15% respectively. Ultrasonic scans were performed using a 5 mHz vaginal transducer attached to an Aloka sector scanner (Model SSD-620; Aloka Co. Ltd, Tokyo, Japan). Pregnancy was diagnosed by increasing serum concentrations of ß-HCG after embryo transfer, and the subsequent demonstration of an intrauterine sac by ultrasonography.
Statistics and probability testing
For statistical analysis Student's t-test and 
2-test were used as appropriate. Mean and SD were calculated for variables in each group of patients (cancelled and punctured cycles). A multivariate logistic regression model was performed to assess the joint effect of variables and to estimate the sensitivity and specificity values for all possible combinations of the study variables. The best joint model was obtained by a stepwise procedure considering P < 0.05 as the P-value associated with a variable to enter in the model. The discrimination attained between the study groups (cancelled versus punctured assisted reproduction treatment cycles, and pregnancy versus non-pregnancy cycles) was evaluated with receiver operating characteristic (ROC) analysis (Hanley and McNeil, 1982; Zweig and Campbell, 1993). Sensitivity, specificity, and the area under the ROC curve (AUCROC) which is a quantitative measure of accuracy, were obtained for each model. 95% confidence intervals (CI) were calculated for each of the estimates. The models' AUCROC were compared using the method of Hanley and McNeil (1982). Areas of 1.0 and 0.5 denote no overlapping and no discrimination, respectively, between groups. Data were analysed by Statistics Package for Social Sciences (SPSS, Chicago, IL USA) statistical software and MedCalc Software (Mariakarke, Belgium).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Table I
shows patient characteristics, basal inhibin B, FSH and oestradiol, dose of gonadotrophins used, and ovarian response observed in cancelled and control groups of patients. Indications for assisted reproduction treatment were similar in both groups of women. Mean age and basal FSH concentrations were significantly higher in the cancelled than in the control group, whereas basal inhibin B was significantly higher in the latter (P < 0.05). Mean body mass index and basal oestradiol concentrations were similar in both groups of patients. There were no differences regarding amount and duration of gonadotrophin stimulation between cancelled cycles and controls but, as expected, oestradiol peak concentrations and the number of follicles recruited were significantly higher in the control group (P < 0.001 for both). The number of oocytes retrieved and the clinical pregnancy rate per puncture in the control group were 8.0 ± 2.5 and 26% respectively. All control patients underwent embryo transfer and the mean number of embryos per replacement was similar for pregnant (3.1 ± 0.9) and non-pregnant women (3.1 ± 0.8). When pregnancy (n = 21) and non-pregnancy (n = 99) groups were compared, woman's age was the only variable independently associated with pregnancy rate, pregnant women (33.9 ± 3.8 years) being younger than non-pregnant patients (35.1 ± 3.4 years) (P < 0.05) (data not shown).
|
Table II
shows logistic regression analysis and individual probability estimates for age and basal FSH and inhibin B concentrations and for all possible combinations of the three variables regarding outcome of ovarian stimulation. Logistic regression analysis showed that the association for basal FSH (with an accuracy, predictive value of ovarian response, of 79%) with cancellation rate was significant (P < 0.05), independent of, and stronger than the effects of age and inhibin B. The analysis of the impact of age and inhibin B within the groups defined by basal FSH values did not further delineate any group with significantly higher or lower chances of cancellation. Finally, analysis of the groups created by the simultaneous evaluation of age and basal FSH and inhibin B did not delineate groups beyond those provided by FSH alone.
|
To analyse further the diagnostic accuracy of age and basal hormone determinations to discriminate between cancelled versus punctured cycles and pregnancy versus non-pregnancy cycles, the AUCROC determined with ROC analysis for age and each basal hormone and the best combination of them are also shown (Tables III and IV
). The AUCROC for FSH in predicting the likelihood of cancellation in an assisted reproduction treatment programme was higher than those for age, inhibin B or any combination of them (Table III). When the likelihood of pregnancy was analysed, the AUCROC for age was higher than those for basal FSH and inhibin B or any combination of them (Table IV). The cut-off point for age that discriminated the best between pregnancy and non-pregnancy cycles was 35.1 years (sensitivity 65.8; specificity 73.6) according to the ROC curve.
|
|
The ROC curve analysis was used to determine the best cut-off value for basal FSH in predicting ovarian response (Figure 1
). The best criterion value discriminating between punctured and cancelled cycles was 9.45 (sensitivity 64.7%, specificity 80.5%). Thus, to analyse further the potential contribution of basal inhibin B to the prediction of assisted reproduction treatment outcome, patients were subdivided according to their FSH concentration on cycle day 3: normal FSH concentration (
9.45 IU/l) and high FSH concentration (>9.45 IU/l) (Table V). A higher, albeit not statistically different, mean inhibin B value was obtained for patients having normal basal FSH concentrations who underwent oocyte aspiration as compared with patients having their cycles cancelled. There was marked overlap in baseline inhibin B concentrations between responders and non-responders to ovarian stimulation. Similarly, basal inhibin B was not discriminatory for pregnancy and non-pregnancy cycles for any of the two groups of patients delineated by the FSH cut-off value (data not shown).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Assisted reproduction cycles have revolutionized the treatment of infertility and they are being increasingly used. Because assisted reproduction treatments are costly and not universally successful, attempts have been made to determine the factors which predict a successful outcome in a given patient. A woman's age is considered as a prognostic factor when assisted reproduction treatment is proposed to infertile couples as a marked decline in success rates is observed at 35–37 years (Piette et al., 1990
; Scott and Hofmann, 1995; Barnhart and Osheroff, 1998). Oocyte donation has demonstrated that the age-related decline in female fecundity is due predominantly to ovarian rather than uterine factors, presumably due to a decrease in ovarian reserve (Sharara and Scott, 1995; Barnhart and Osheroff, 1998). However, women may change from having normal to diminished ovarian reserve at any age. Thus, there is still considerable interest in determining a woman's fertility potential independent of age.
Because pituitary FSH secretion increases with declining ovarian reserve, day 3 serum FSH concentrations are being routinely used in most assisted reproduction treatment programmes and they have been found to be a better predictor of assisted reproduction treatment outcome than age (Scott and Hofmann, 1995; Barnhart and Osheroff, 1998). Both age and FSH concentrations, however, are indirect markers of ovarian function and this has been the reason to explain the low sensitivity of day 3 serum FSH concentrations as an indicator of reproductive potential in women undergoing assisted reproduction treatment (Barnhart and Osheroff, 1998). Theoretically, the direct products of granulosa cells might better reflect ovarian secretory capacity and follicle number. Inhibin is a heterodimeric glycoprotein produced by granulosa cells and consisting of - and ß-subunits. There are two distinct molecular forms of the ß-subunit that exist (ßA and ßB) and, when combined with an -subunit, form inhibin A and inhibin B, respectively. With increasing understanding of the control of synthesis and secretion of the inhibins and their potential endocrine role in the regulation of FSH in the human, attention has focused to the possibility that this family of peptides may provide a more direct index of ovarian reserve and improved predictors of assisted reproduction treatment outcome.
Earlier studies using immunoreactive -inhibin measurements found that ovarian inhibin secretion decreases with declining ovarian function with advancing age (Hughes et al., 1990; Buckler et al., 1991; Pellicer et al., 1994) as a result of a reduced cellular function rather than a decrease in the follicular population (Pellicer et al., 1994). Accordingly, in a previous report where the same study design as in the present investigation was used, it was shown that basal FSH and immunoreactive -inhibin had similar predictive properties in IVF cycles stimulated with gonadotrophins under pituitary suppression (Balasch et al., 1996). The cross-reactivity of inhibin assays, however, has been a source of confusion for many years (Hayes et al., 1998). Recently two-site directed assays have been developed capable of reliably and specifically measuring the inhibin dimers, inhibin A and inhibin B (Groome et al., 1994, 1996). Thus, it has been claimed that these new assays will become widespread in their use, enabling the identification of situations in which measurements of inhibin A and B are of clinical value (Hayes et al., 1998).
In the female, the pattern of secretion of the inhibins suggests that early follicular phase inhibin B may reflect the number of follicles present at baseline, whereas inhibin A may indicate follicle maturity (Groome et al., 1994, 1996; Hayes et al., 1998). On this basis, recent reports have focused on the potential usefulness of basal serum inhibin B measurement in predicting successful outcome in assisted reproduction treatment. Thus, Seifer et al. (1997) reported significantly higher cancellation rates and lower pregnancy rates in women with `low' (<45 pg/ml) day 3 serum inhibin concentrations. Recent studies, however, have shown that neither 45 pg/ml (Corson et al., 1999) nor any other inhibin B threshold value (Hall et al., 1999) were good predictors of assisted reproduction treatment outcome. In fact, as much as 118 of 156 patients (76%) studied by Seifer et al. (1997) had `normal' basal serum inhibin B concentrations despite a mean age of 35 years. As recently stressed (Hall et al., 1999), considering that the lowest measurable concentration of inhibin B by enzyme-linked immunosorbent assay (Serotec) is 15 pg/ml and inter-assay CV 15%, a considerable overlap can be expected when measuring concentrations of ~50 pg/ml. Also, in the study by Seifer et al. (1997), basal FSH concentrations were significantly higher in the group of patients having `low' inhibin B but both hormones were not compared with respect to their predictive value. Finally, in that study, 95% of patients investigated had basal FSH concentrations 9.5 IU/l, a value considered by those authors as the upper limit associated with a normal ovarian reserve. In contrast, basal FSH concentrations in patients included in the present study ranged between 3.92 and 19.45 IU/l (35% of women having FSH >9.45 IU/l).
The hypothesis that women with declining ovarian reserve may have decreased day 3 serum inhibin B concentrations despite having non-elevated day 3 serum FSH concentrations was further tested and expanded in a later study by the same team of authors (Seifer et al., 1999). In this latter study, however, 47 women who had previously proven declining ovarian reserve on the basis of a poor response to exogenous gonadotrophin stimulation in a previous assisted reproduction treatment cycle were compared with 109 women having tubal factor or male factor. The mean age of patients in the study group (40 years) was significantly higher than that of control patients (34 years) and study patients received a different stimulation protocol with leuprolide acetate and gonadotrophins than controls in order to improve their poor response to stimulation. Thus, inclusion criteria and study design in that report (Seifer et al., 1999) were different from those used in the present investigation where only women undergoing the first cycle of assisted reproduction treatment were included. The results of the current study, as well as those reported by others (Corson et al., 1999; Hall et al., 1999), do not support the use of day 3 inhibin B as a predictive marker of ovarian response and pregnancy in an assisted reproduction treatment general programme. The current study has demonstrated that: (i) basal FSH is a better marker of ovarian response than inhibin B and age; (ii) age, but not basal FSH or inhibin B, was independently associated with pregnancy rate. The combination of any two or all three of these variables studied did not improve the predictive value of FSH or age alone.
The current results indicate that as a single predictor of ovarian response to gonadotrophin stimulation basal FSH is not surpassed by inhibin B. This seems in contrast with studies indicating that inhibin B determination as a direct measure of ovarian function may be a more sensitive indicator of ovarian reserve than indirect indicators such as pituitary FSH secretion (Danforth et al., 1998). However, to presume that a singular deficiency in inhibin activity could account for age-related elevations in FSH fails to consider the extensive structural and functional overlap that exists among the other component FSH regulatory proteins known to mediate FSH regulation. On the contrary, the monotropic rise in FSH is more likely to be dictated by the sum effect of inhibitory inputs stemming from inhibins, follistatins, as well as oestradiol, and the stimulatory inputs from GnRH and activin (Reame et al., 1998).
A remarkable feature of the present study is that it provides evidence indicating that, unexpectedly, the predictive ability of basal inhibin B is not better than that afforded by immunoreactive -inhibin measurement in previous studies (Balasch et al., 1996). In our previous report an immunoenzymatic method was used which utilized antibodies directed at the -subunit of inhibin, thus measuring inhibin A, inhibin B and the non-biologically active -subunit (Balasch et al., 1996). Recent studies (Burger et al., 1998; Hayes et al., 1998), however, have shown that only -inhibin and inhibin B are measured in significant quantities in the early follicular phase of the menstrual cycle, and thus they were probably the only inhibin species measured at this time in the menstrual cycle in those earlier studies. In fact, when immunoreactive inhibin concentrations across the menstrual cycle have been compared with those obtained using the two-site directed assays, the overall pattern of inhibin secretion was similar except that the magnitude of the changes observed was greater with the new assays (Hayes et al., 1998).
In conclusion, in patients undergoing their first treatment cycle in an assisted reproduction treatment general programme, the stronger predictors of success were age and basal FSH rather than inhibin B. Basal FSH concentration was a better predictor of cancellation rate than age, but age was a stronger predictor of pregnancy rate. However, several facts should be considered before the results of the present study are applied in clinical practice. First, the predictive value of FSH in predicting the ovarian response of 79% may be flattered because of the study design which ensured a high prevalence of cancellation (33%). In a non-selected IVF/ICSI population the prevalence of cancellation is generally much lower. Since the predictive value of a diagnostic test is dependent on the prevalence of outcome, one can assume that the accuracy of basal FSH in predicting ovarian response in clinical practice will be lower. Thus, the predictive performance of FSH for cancellation and of age in discriminating between pregnant and not pregnant using the best discriminating cut-off value should be determined in an unselected assisted reproduction treatment general population. On the other hand, it is possible that a greater number of women with decreased ovarian reserve could have been identified using the clomiphene citrate challenge test which may uncover an abnormality that would be missed by obtaining a basal day 3 FSH value alone (Barnhart and Osheroff, 1998). Finally, further work is warranted before widespread usage of the inhibin B assay which is technically challenging and not readily available. Thus, there is no international assay standard for inhibin B yet and both follicular fluid and recombinant standards are being used. This makes comparison of results between laboratories difficult and may explain discrepancy between different studies.
|
Notes |
|---|
3 To whom correspondence should be addressed at: Institut Clínic of Gynecology, Obstetrics and Neonatology, Hospital Clínic,C/Casanova 143, 08036-Barcelona, Spain.E-mail: jbalasch{at}medicina.ub.es
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Balasch, J., Creus, M., Fábregues, F. et al. (1996) Inhibin, follicle-stimulating hormone, and age as predictors of ovarian response in in vitro fertilization cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment. Am. J. Obstet. Gynecol., 175, 1226–1230.[Web of Science][Medline]
Barnhart, K. and Osheroff, J. (1998) Follicle stimulating hormone as a predictor of fertility. Curr. Opin. Obstet. Gynecol., 10, 227–232.[Web of Science][Medline]
Buckler, H.M., Evans, C.A., Hamtora, H. et al. (1991) Gonadotropin, steroid, and inhibin levels in women with incipient ovarian failure during anovulatory and ovulatory rebound cycles. J. Clin. Endocrinol. Metab., 72, 116–124.
Burger, H.G., Groome, N.P. and Robertson, D.M. (1998) Both inhibin A and B respond to exogenous follicle-stimulating hormone in the follicular phase of the human menstrual cycle. J. Clin. Endocrinol. Metab., 83, 4167–4169.
Corson, S.L., Gutmann, J., Batzer, F.R. et al. (1999) Inhibin-B as a test of ovarian reserve for infertile women. Hum. Reprod., 14, 2818–2821.
Danforth, D.R., Arbogast, L.K., Mroueh, J. et al. (1998) Dimeric inhibin: a direct marker of ovarian aging. Fertil. Steril., 70, 119–123.[Web of Science][Medline]
Groome, N.P., Illingworth, P.J., O'Brien, M. et al. (1994) Detection of dimeric inhibin throughout the human menstrual cycle by two-site enzyme immunoassay. Clin. Endocrinol. (Oxf.), 40, 717–723.[Medline]
Groome, N.P., Illingworth, P.J., O'Brienm M, et al. (1996) Measurement of dimeric inhibin-B throughout the human menstrual cycle. J. Clin. Endocrinol. Metab., 81, 1401–1405.[Abstract]
Hall, E., Welt, C.K. and Cramer, D.W. (1999) Inhibin A and inhibin B reflect ovarian function in assisted reproduction but are less useful at predicting outcome. Hum. Reprod., 14, 409–415.
Hanley, J.A. and McNeil, B.J. (1982) The meaning and use of the area under receiving operating characteristic (ROC) curve. Radiology, 143, 29–36.
Hayes, F.J., Hall, J.E., Boepple, P.A. et al. (1998) Differential control of gonadotropin secretion in the human: endocrine role of inhibin. J. Clin. Endocrinol. Metab., 83, 1835–1841.
Hughes, E.G., Robertson, D.M., Handelsman, D.J. et al. (1990) Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome. J. Clin. Endocrinol. Metab., 70, 358–364.
Pellicer, A., Mari, M., de los Santos, M.J. et al. (1994) Effects of aging on the human ovary: the secretion of immunoreactive -inhibin and progesterone. Fertil. Steril., 61, 663–668.[Web of Science][Medline]
Piette, C., de Mouzon, J., Bachelot, A. et al. (1990) In-vitro fertilization: influence of women's age on pregnancy rates. Hum. Reprod., 5, 56–59.
Reame, N.E., Wyman, T.L., Phillips, D.J. et al. (1998) Net increase in stimulatory input resulting from a decrease in inhibin B and an increase in activin A may contribute in part to the rise in follicular phase follicle-stimulating hormone of aging cycling women. J. Clin. Endocrinol. Metab., 83, 3302–3307.
Scott, R.T. Jr and Hofmann, G.E. (1995) Prognostic assessment of ovarian reserve. Fertil. Steril., 63, 1–11.[Web of Science][Medline]
Seifer, D.B., Lambert-Messerlian, G., Hogan, J.W. et al. (1997) Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome. Fertil. Steril., 67, 110–114.[Web of Science][Medline]
Seifer, D.B., Scott, R.T. Jr, Bergh, P.A. et al. (1999) Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 follicle-stimulating hormone. Fertil. Steril., 72, 63–65.[Web of Science][Medline]
Sharara, F.I. and Scott, R.T. Jr (1997) Assessment of ovarian reserve and treatment of low responders. Infertil. Reprod. Med. Clin. North Amer., 8, 501–522.
Welt, C.K., McNicholl, D.J., Taylor, A.E. et al (1999) Female reproductive aging is marked by decreased secretion of dimeric inhibin. J. Clin. Endocrinol. Metab., 84, 105–111.
Zweig, M.H. and Campbell, G. (1993) Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin. Chem., 39, 561–577.
Submitted on April 6, 2000; accepted on July 27, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Fabregues, J. Penarrubia, M. Creus, D. Manau, G. Casals, F. Carmona, and J. Balasch Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial Hum. Reprod., February 1, 2009; 24(2): 349 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.E.M. Verhagen, D.J. Hendriks, L.F.J.M.M. Bancsi, B.W.J. Mol, and F.J.M. Broekmans The accuracy of multivariate models predicting ovarian reserve and pregnancy after in vitro fertilization: a meta-analysis Hum. Reprod. Update, March 1, 2008; 14(2): 95 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. B. Baart, E. Martini, M. J. Eijkemans, D. Van Opstal, N. G.M. Beckers, A. Verhoeff, N. S. Macklon, and B. C.J.M. Fauser Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial Hum. Reprod., April 1, 2007; 22(4): 980 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. McIlveen, J.D. Skull, and W.L. Ledger Evaluation of the utility of multiple endocrine and ultrasound measures of ovarian reserve in the prediction of cycle cancellation in a high-risk IVF population Hum. Reprod., March 1, 2007; 22(3): 778 - 785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F.J. Broekmans, J. Kwee, D.J. Hendriks, B.W. Mol, and C.B. Lambalk A systematic review of tests predicting ovarian reserve and IVF outcome Hum. Reprod. Update, November 1, 2006; 12(6): 685 - 718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Maheshwari, P. Fowler, and S. Bhattacharya Assessment of ovarian reserve--should we perform tests of ovarian reserve routinely? Hum. Reprod., November 1, 2006; 21(11): 2729 - 2735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.A. Anderson, A.P.N. Themmen, A.A. -Qahtani, N.P. Groome, and D.A. Cameron The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer Hum. Reprod., October 1, 2006; 21(10): 2583 - 2592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Balasch, F. Fabregues, J. Penarrubia, F. Carmona, R. Casamitjana, M. Creus, D. Manau, G. Casals, and J. A. Vanrell Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH Hum. Reprod., July 1, 2006; 21(7): 1884 - 1893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. S. Macklon, R. L. Stouffer, L. C. Giudice, and B. C. J. M. Fauser The Science behind 25 Years of Ovarian Stimulation for in Vitro Fertilization Endocr. Rev., April 1, 2006; 27(2): 170 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Abdalla and M.Y. Thum Repeated testing of basal FSH levels has no predictive value for IVF outcome in women with elevated basal FSH Hum. Reprod., January 1, 2006; 21(1): 171 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Eldar-Geva, A. Ben-Chetrit, I. M. Spitz, R. Rabinowitz, E. Markowitz, T. Mimoni, M. Gal, E. Zylber-Haran, and E. J. Margalioth Dynamic assays of inhibin B, anti-Mullerian hormone and estradiol following FSH stimulation and ovarian ultrasonography as predictors of IVF outcome Hum. Reprod., November 1, 2005; 20(11): 3178 - 3183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Weghofer, M. Margreiter, Y. Fauster, T. Schaetz, A. Brandstetter, D. Boehm, and W. Feichtinger Age-specific FSH levels as a tool for appropriate patient counselling in assisted reproduction Hum. Reprod., September 1, 2005; 20(9): 2448 - 2452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vujisic, F. Stipoljev, R. Bauman, R. Dmitrovic, and D. Jezek Pericentric inversion of chromosome 2 in a patient with the empty follicle syndrome: Case report Hum. Reprod., September 1, 2005; 20(9): 2552 - 2555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. H. Y. Ng, C. C. W. Chan, O. S. Tang, and P. C. Ho Antral follicle count and FSH concentration after clomiphene citrate challenge test in the prediction of ovarian response during IVF treatment Hum. Reprod., June 1, 2005; 20(6): 1647 - 1654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Penarrubia, F. Fabregues, D. Manau, M. Creus, G. Casals, R. Casamitjana, F. Carmona, J. A. Vanrell, and J. Balasch Basal and stimulation day 5 anti-Mullerian hormone serum concentrations as predictors of ovarian response and pregnancy in assisted reproductive technology cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment Hum. Reprod., April 1, 2005; 20(4): 915 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. P Hohmann, J. S E Laven, F. H de Jong, and B. C J M Fauser Relationship between inhibin A and B, estradiol and follicle growth dynamics during ovarian stimulation in normo-ovulatory women Eur. J. Endocrinol., March 1, 2005; 152(3): 395 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Lutchman Singh, M. Davies, and R. Chatterjee Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing Hum. Reprod. Update, January 1, 2005; 11(1): 69 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.E. Bath, G. Tydeman, H.O.D. Critchley, R.A. Anderson, D.T. Baird, and W.H.B. Wallace Spontaneous conception in a young woman who had ovarian cortical tissue cryopreserved before chemotherapy and radiotherapy for a Ewing's sarcoma of the pelvis: Case report Hum. Reprod., November 1, 2004; 19(11): 2569 - 2572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.E. Bath, W.H.B. Wallace, M.P. Shaw, C. Fitzpatrick, and R.A. Anderson Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Mullerian hormone, inhibin B and ovarian ultrasound Hum. Reprod., November 1, 2003; 18(11): 2368 - 2374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. H. Y. Ng, W. S. B. Yeung, D. Y. T. Fong, and P. C. Ho Effects of age on hormonal and ultrasound markers of ovarian reserve in Chinese women with proven fertility Hum. Reprod., October 1, 2003; 18(10): 2169 - 2174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Chu, K. M. Rath, J. Huie, and H. S. Taylor Elevated basal FSH in normal cycling women is associated with unfavourable lipid levels and increased cardiovascular risk Hum. Reprod., August 1, 2003; 18(8): 1570 - 1573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.J. Scheffer, F.J.M. Broekmans, C.W.N. Looman, M. Blankenstein, B.C.J.M. Fauser, F.H. de Jong, and E.R. te Velde The number of antral follicles in normal women with proven fertility is the best reflection of reproductive age Hum. Reprod., April 1, 2003; 18(4): 700 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Y.K. Yong, D. T. Baird, K.J. Thong, A. S. McNeilly, and R. A. Anderson Prospective analysis of the relationships between the ovarian follicle cohort and basal FSH concentration, the inhibin response to exogenous FSH and ovarian follicle number at different stages of the normal menstrual cycle and after pituitary down-regulation Hum. Reprod., January 1, 2003; 18(1): 35 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Platteau, K. Sermon, S. Seneca, A. Van Steirteghem, P. Devroey, and I. Liebaers Preimplantation genetic diagnosis for fragile Xa syndrome: difficult but not impossible Hum. Reprod., November 1, 2002; 17(11): 2807 - 2812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Eldar-Geva, E.J. Margalioth, A. Ben-Chetrit, M. Gal, D.M. Robertson, D.L. Healy, Y.Z. Diamant, and I.M. Spitz Serum inhibin B levels measured early during FSH administration for IVF may be of value in predicting the number of oocytes to be retrieved in normal and low responders Hum. Reprod., September 1, 2002; 17(9): 2331 - 2337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-L. Chang, T.-H. Wang, S.-G. Horng, H.-M. Wu, H.-S. Wang, and Y.-K. Soong The concentration of inhibin B in follicular fluid: relation to oocyte maturation and embryo development Hum. Reprod., July 1, 2002; 17(7): 1724 - 1728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fawzy, A. Lambert, R.F. Harrison, P.G. Knight, N. Groome, B. Hennelly, and W.R. Robertson Day 5 inhibin B levels in a treatment cycle are predictive of IVF outcome Hum. Reprod., June 1, 2002; 17(6): 1535 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D.L. Hundscheid, D. D.M. Braat, L. A.L.M. Kiemeney, A. P.T. Smits, and C. M.G. Thomas Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives Hum. Reprod., March 1, 2001; 16(3): 457 - 462. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||