Middle East Fertility Society Journal Middle East Fertility Society ISSN: 1110-5690 Vol. 9, Num. 1, 2004, pp. 47-57

Middle East Fertility Society Journal, Vol. 9, No. 1, 2004, pp. 47-57

Ovulation prediction in spontaneous and induced cycles: the role of ovarian reserve markers

Amgad O. Gohar, M.D., A.R. El-Edwi, M.D., Hossam ELDin S.H. Abdallah, M.D.

Department of Obstetrics and Gynaecology, Faculty of Medicine, El Minia University, El Minia , Egypt .

Correspondence and reprint request: Dr. AmgadOsmanGohar, Dept. of Ob Gyn. El Minia University Hospital, El Minia , Egypt , E-Mail: Amgad_gohar2003@yahoo.com

Received on September 17, 2003;
revised and accepted on December 4, 2003

Code Number: mf04008

ABSTRACT

Objective (s): To evaluate the role of day 3 serum; FSH, inhibin-B and estradiol, (biochemical markers), ultrasound measured antral follicle count AFC and ovarian volume OV (biophysical markers) in ovulation prediction in induced cycles in infertile patients with different induction protocols. Also, the secondary aim was to analyze the correlations between these markers and prediction of ovulation success in induced cycles with different induction protocols.
Design: Prospective comparative controlled study
Settings: Infertility Clinic, University Hospital , El Minia & IVF center, Egypt .
Patients: Eighty infertile patients (study group) classified into four subgroups, twenty patients each according to the method of ovulation induction and twenty matched fertile subjects (control group).
Interventions: Day 3 serum; inhibin-B, FSH and estradiol were measured together with transvaginal ultrasound measurements of the antral follicle count and ovarian volume in the study and the control groups. The study group was subdivided into four subgroups according the method of ovulation induction; whether clomiphene citrate (group I), or urinary follicle stimulating hormone (group II), or low dose recombinant follicle stimulating hormone (group III) or long protocol (group IV).
Main outcome measures: The predictive values of different screening markers in relation to ovulation. Other outcome measures were the analysis of the correlations between various biochemical and biophysical markers and prediction of ovulation success in induced cycles with different induction protocols.
Results: The predictive values of FSH (<10 IU/L), inhibin-B (> 45 pg/ml), estradiol (<75 pg/ml), AFC (> 6), and OV (>3 cm³) in relation to ovulation prediction were statistically comparable (P>0.05). Multivariate analysis of the variables that predict ovulation in induced cycles demonstrated that of the biochemical variables FSH was the most significant contributor to ovulation (R2 = 0.93, P ≤ 0.01), while of the biophysical variables AFC is the most significant one (R 2= 0.46, P ≤ 0.01).
Conclusions: Day 3 serum; FSH, inhibin-B and estradiol, ultrasound measured AFC and ovarian volume are comparable screening markers of the ovarian reserve in the general infertility patients. Of the biochemical factors the main predictor for ovulation in induced cycles is FSH while AFC is the main biophysical one.

Key words: Ovulation prediction, FSH, Inhibin-B, estradiol, transvaginal ultrasound, antral follicle count AFC, ovarian volume OV, Infertility

 “Ovarian reserve” describes the native oocyte endowment and is closely associated with reproductive potential. As a diagnostic entity, ovarian reserve screening developed  from  clinical experience with the advanced reproductive technologies. Diminished ovarian reserve generally presages a poor response to any fertility treatment, and sharply limits the possibility of successful pregnancy. Screening for the ovarian reserve is a fundamental component of the initial infertility evaluation, since it is a key determinant of what, if any, treatment should be offered. A number of tests have been described that attempt to best assess ovarian reserve (1).

The concentration of circulating FSH on the third day has been recognized as a marker of ovarian reserve and important predictor of the ovarian response to hormonal stimulation and IVF outcome than age (2). However, some clinicians have questioned the usefulness of widespread FSH screening because of the difficulty in establishing absolute FSH breakpoints compatible with achieving pregnancy (3).

It has been suggested that the serum measurement of Inhibin B concentration in the early follicular phase may be of value in the assessment of "poor responders" to IVF treatment (4).However, it has been concluded that, so far as for clinical usefulness, it remains a horizon topic because of the lack of a satisfactory assay to quantify it (4-9).

Early follicular estradiol levels may reflect cycle dynamics and the likelihood of conception (2).A number of studies have examined the estradiol levels on day 3 of the cycle as an independent risk factor in IVF cycles, with the general findings that cycles are more likely to be cancelled because of poor stimulation, oocytes retrieved are fewer, and pregnancy rate are lower when estradiol values exceed 60 pg/ml, in one study and 80 pg/ml in the other two (10-12).

Since the loss of ovarian reserve is functionally related to fewer primordial follicles available for gonadotropine recruitment, ovarian imaging via transvaginal ultrasound has been used to gain a direct assessment of gonadal status and activity both before and during fertility treatment (1). There is currently much interest in determing the size of the growing follicular pool (13).Antral follicle count AFC assessment as a tool for predicting outcome in IVF has been suggested. Day 3 FSH, maternal age and antral follicle assessment were found to be strongly related to IVF outcome. Pregnancy rate was significantly higher in the group with antral follicle >6 compared to that in the group with the antral follicle < 6. It has been concluded that antral follicle assessment was a better predictor of IVF outcome than age or FSH. Antral follicle assessment may provide a marker for the ovarian age that is distinct from chronological age or hormonal markers (14).

Also, ultrasonic measurement of the ovarian volume OV as an indictor of reproductive success had been suggested (15, 16).A significant correlation between pretreatment ovarian volume and gonadotropin dosage required to detect ovulation induction, follicular yield, and oocyte recovery has been found (17).Yet, it has been concluded that, a confirmation is needed in order to determine if this is a reliable index of ovarian function (18).

The aim of the work was to evaluate the role of day 3 serum; FSH, inhibin-B and estradiol (biochemical markers), ultrasound measured antral follicle count AFC and ovarian volume (biophysical markers) in ovulation prediction in induced cycles in infertile patients with different induction protocols. Also, the secondary aim was to analyze the correlations between these markers and prediction of ovulation success in induced cycles with different induction protocols

MATERIALS AND METHODS

Eighty patients attending the Infertility clinic of El Minia University Hospital with primary or secondary infertility and with otherwise normal complete infertility work-up (study group) together with 20 fertile subjects matched for age, weight and body mass index (BMI) and using local methods of non-hormonal contraception recruited from The Family Planning Clinic (control group) were included in the study which was done from September 2002 to August 2003.

The ages of the subjects were between 35-38 years with a duration of infertility of at least two years and normal menstrual cycle (range 24-35 days).Exclusion criteria were, smoking, endometriosis, the presence of only one ovary or previous ovarian surgery, polycystic ovary syndrome, positive Chlamydia infection, or other endocrine or medical disorders, exposure to study drugs or other ovulation induction drugs within 3 months of participation in the study. Those women with male partners having a total sperm concentration < 20 million/ml, with sperm motility and normal morphology < 40 % (19), were excluded from the study.

The study group was further subdivided into four groups according to the method of ovulation induction.

Group I: (Clomiphene Citrate; CC group) including 20 patients receiving clomiphene citrate (Clomid, Epico, Egypt) oral tablets (50- 200 mg /day for 5 days) starting on the third day of the menstrual cycle.

Group II: (Human urinary FSH, u-FSH group): including 20 patients receiving human urinary FSH (Meterodin HP, Serono BV, Netherlands ) (75- 150 I.U. I.M daily or every other day) starting on the third day of the menstrual cycle.

Group III: (Low dose recombinant Follicle stimulating hormone; rFSH group): including 20 patients receiving recombinant FSH (Puregon, Organon NV , Netherlands ) in a daily dose of 50 IU starting on the third day of the menstrual cycle.

Group IV: (IVF group) including 20 patients receiving the long protocol of IVF. IVF protocol was performed as described by Harrison et al., (20, 21) and Gordon et al., (22) in IVF center.

An informed consent was taken from each participant after careful explanation of the purpose and the procedures of the study.

Methods

Complete history and examination were done to all participants.In day 3 of the normal menstrual cycle, all participants were subjected to blood sampling for measurements of serum inhibin-B, FSH, estradiol and ultrasound measurement of the antral follicle count AFC and ovarian volume OV.

Blood sampling and Hormonal assays

Blood samples for screening markers (FSH, Inhibin- B and Estradiol) were withdrawn from the ante-cubital vein at 7: 10 Am on Day 3 of the menstrual cycle in treatment cycles in all groups except group IV. Blood samples for group IV (IVF group) were collected in day 3 of the pre-treatment cycle. Other blood samples for ovulation monitoring (LH, E2) and detection (progesterone) were withdrawn according the schedule of monitoring. Another blood sample was collected in the 10th day of the menstrual cycle in group I (CC group) for measurement of FSH & E2.

Blood samples were allowed to clot; serum was separated, labeled and stored in -40 C° for subsequent assays.

B- Inhibin was measured in duplicate using two-site enzyme linked immunosorbents assays ELISA (Serotech Limited, Kindlington, Oxford, UK) using plates coated with specific monoclonal antibodies.Theinhibin-B assay cross-reacts approximately 1% with inhibin-A. Assay sensitivity for inhibin-B was 16 pg/ml. Inter- and intraplate coefficient of variations were both <7 %.

Estradiol and progesterone were analyzed using solid phase radio-immunoassay technique RIA technique (Diagnostic Products, Los Angeles , CA , USA ) with an interaassay and interassay coefficient of variation of 4.7 % and 6.4 %, respectively for E2 and 4.7% and 7.9%, respectively for progesterone in the 1ng/ml range.

Serum concentrations of FSH and LH were measured using Immulite chemiluminescent assay kits ( DPC, Glyn Rhonwy, Llanberis, Gwynedd, UK).The detection ranges of FSH and LH were 0.1 -170 and 0.7-400 mIU /ml, respectively.

All hormone analyses were done under the supervision of an investigator unaware of the diagnosis.

The cut off limit for FSH was 10 m IU/ml (normal <10 m IU/ml; abnormal ≥10 m IU/ml) (cycle day # 3 criteria of Georgia Reproductive Specialists, U.S.A. )(1). The cut off limits for serum inhibin-B was 45 pg/ml (normal >45 pg/ml; abnormal ≤ 45 pg/ml) (cycle day # 3 criteria of Radeliffe Hospital/Oxford University,U.K)(1) and the cut off limit for estradiol ( normal < 75 pg/ml ; abnormal ≥75 pg/ml)(11).

Ultrasound

Transvaginal ultrasound was done by 6.5 MHz sector transducer, (model 415 EUB, Hitachi Med. Corp, Tokyo , Japan ). The antral follicle count and ovarian volume were measured together with routine ultrasound examination. The cut off limit for AFC was 6 follicles 2-6 mm in all diameters, in both ovaries [(normal > 6; abnormal ≤6) (ultrasound criteria of Nahum et al., (14)]. The limit of the sensitivity was 2 mm.  The cut off limit for ovarian volume was 3 cm³ (normal ≥ 3 cm³; abnormal < 3 cm) (transvaginal ultrasound volumetric criteria of University of Oslo , Norway ) (1). Ovarian volume was calculated using the formula for the volume of ellipsoid (π/6 x length x width x height), and the mean volume was determined. Ovaries with cystic enlargements ≥ 15 mm were excluded from the analysis of the ovarian volume.

Follow up

Luteal phase was supported in documented ovulatory patients in the study group by progesterone suppository 50 mg daily or minimally three injections of 1500 IU hCG for at least two weeks. Biochemical pregnancy was defined as a positive urinary pregnancy test (Clearview, hCG II, Unipath Ltd, Bedford, U.K. ) more than 3 days after the expected menses.

Statistical Analysis

Results were expressed as means ± SD for quantitative characteristics and number and percentages for qualitative characteristics. Statistical comparisons were made using Chi-square χ² test or Fisher exact test for qualitative characteristics when appropriate. Unpaired data were compared using the non-parametric Mann-Whitney U test. One way analysis of variance ANOVA was used to compare the numerical results among different groups. Pearson's correlation analysis was carried out to study the relationship between biochemical markers (FSH, inhibin-B and E₂) and biophysical markers (Antral follicle count AFC and ovarian volume OV). Multivariate regression analysis was used in a stepwise fashion to test the relative significance of different biochemical markers (FSH, inhibin-B and estradiol) or biophysical markers (AFC and OV) in relation to ovulation.

Statistical analysis was performed on an IBM personal computer using SPSS statistical package for windows (SPSS, Inc, USA ).  P values of ≤ 0.05 or 0.01 were considered as the level of significance.

RESULTS

Patients' characteristics on admission in the study and control groups are summarized in Table 1. There was no statistically significant difference between the study group and control group regarding age or weight or height or BMI. Biochemical (FSH, inhibin-B and estradiol) and biophysical markers (AFC and OV) were comparable in both groups (8.11± 3.66, 92.77 ± 20.53 and 55.00 ± 12.31) & (10.77 ± 2.70 and 5.38 ±1.19) Vs (7.35 ± 1.30, 93.70 ± 17.53 and 51.90 ± 9.40) & (10.75 ± 1.99 and 5.60 ± 0.99), respectively (P > 0.05) (for each).

Table 2 shows comparison between patients with normal and abnormal screening tests results in

relation to admission characteristics. Age was significantly higher in patients with abnormal test results (poor ovarian reserve) compared with those with normal test results (good ovarian reserve) (37.77± 0.55, # 36.59 ± 0.85, P ≤ 0.05). Weight, BMI, FSH and estradiol were significantly lower in patients with normal test results compared with patients with normal test results (P≤ 0.01) (for each). Inhibin-B, AFC and OV were statistically higher in patients with normal test results compared with those with abnormal test results (P ≤ 0.01) (for each).

The predictive values (sensitivity, specificity, positive predictive value, negative predictive value and accuracy ) in relation to ovulation prediction of FSH (<10 IU/L), serum inhibin-B ( > 45 pg/ml), estradiol (< 75 pg/ml) antral follicle count (> 6) and ovarian volume (> 3 cm≥ ) were statistically comparable (P > 0.05) (Table 3)

Ovulation rate, number of follicles (> 3) greater or 15 mm in diameter on the day of hCG administration, peak estradiol level of > 200 ng/ml in response to different induction drugs were comparable among different study subgroups and compared with the control group (P > 0.05) (for each)(Table 4).

Ovulation rate, number of follicles (> 3) greater or 15 mm in diameter on the day of hCG administration, peak estradiol level of > 200 ng/ml were significantly higher in patients with normal test results (good ovarian reserve) compared to those with abnormal tests (diminished ovarian reserve) (P ≤ 0.01) (for each, respectively, n=100) (Table 5).

Eight poor responders (10%) were found in the study group (n=80) (Three in group I, two in group II, two in group III and one in group IV).All of them were with abnormal screening test results. In each study subgroup, all responders received the same average drug dosage. The dosage was found to be increased only in poor responders. Cancellation rate was significantly higher in patients with abnormal test results compared to those with normal test results in the study group (P ≤ 0.01, n=80). Biochemical pregnancy rate was significantly higher in patients with normal test results compared to those with abnormal test results in the study group (n=80) (P≤0.01) (Table 6).

Ovulation was significantly correlated to the levels of FSH (r =-, 813, P ≤ 0.01) inhibin-B (r =.719, P ≤ 0.01) estradiol ( r = -,684, P ≤ 0.01), AFC (r =.654,P ≤ 0.01) and ovarian volume ( r =.600, P ≤ 0.01) in the study group (n= 80) (Table 7).

Multivariate analysis of the variables that predict ovulation in induced cycles demonstrated that ;of the biochemical variables FSH was the most significant contributor to ovulation ( R2 = 0.93 P ≤ 0.01),while of the biophysical variables AFC is the most significant one ( R 2= 0.46, P ≤ 0.01). (Table 8)

DISCUSSION

Screening for the ovarian reserve is needed. Resisting the temptation to obtain all possible tests for the ovarian reserve should be done by clinicians for better interpretation of their results (18).

In this study the predictive values ( sensitivity, specificity, positive predictive value, negative predictive value and accuracy) of day 3 serum inhibin-B ( > 45 pg/ml) were in agreement with Seifer et al., (4), who observed that when the day 3 serum inhibin-B titer was < 45 pg/ml, the response to gonadotropine stimulation was blunted, the cancellation rate was higher, the number of retrieved oocyte was lower, and the pregnancy rate was significantly reduced in a comparison with subjects whose day 3 inhibin-B values were ≥ 45 pg/ml. Also, this is in agreement with Smith et al., (24) who found that day 3 serum inhibin-B and estradiol are the best predictors of success in assisted reproductive technologies. It was noticed that the rise in early follicular FSH with reproductive aging correlates with the fall in inhibin-B levels (25). Hofmann et al., (7) confirmed that women with diminished ovarian reserve had lower inhibin-B levels and they postulated that this may be due to reduced granulose cell inhibin-B production. Furthermore, it was postulated that the earliest demonstration of diminished ovarian reserve may be reflected by a decrease in day 3 inhibin-B levels before a significant rise in day 3 serum FSH (26). Unfortunately, determination of inhibin-B had been criticized by the lack of a satisfactory assay to quantify it (4-9). Also, several recent studies failed to find clinical value in measuring basal inhibin-B levels with regard to IVF outcome (8, 27, 28).Perloe et al., (1), in their review of the current inhibin-B status in evaluation of the ovarian reserve concluded that although these early reports confirm that inhibin-B can extend the sensitivity of ovarian reserve screening, more data are needed before meaningful normal ranges of inhibin -B can be applied routinely in clinical practice (27-30).

The predictive values of FSH in this study (<10 IU/L) were in agreement with the findings of Scott et al., (31), who found that that women undergoing IVF with a day 3 FSH < 15 m IU/ml were twice as likely to conceive as women with FSH between 15 and 24.9 m IU/ml. Also, Toner et al., (32) found that the predictive value of FSH for reproductive outcome in IVF as superior to female age alone. Another study found that when day 3 FSH level exceeded 20 IU/L conception rates fell precipitously (33). On the other hand, a single measurement of day 3 FSH may not be representative of actual ovarian reserve and confirmation of a very high result should be sought in a subsequent cycle (1). Also, clinical interpretation of such inter-cycle day 3 FSH fluctuations is controversial (34,35).There is a debate whether elevated FSH levels seen with reproductive aging may represent a primary neuroendocrine change rather than ovarian one (36). Finally, some clinicians, because of the possibility of confusing results in women with low risk for poor ovarian response, have questioned the value of widespread FSH screening (3).

The predictive values of serum estradiol in this study (< 75 pg/ml) were in agreement with the findings of Licciardi et al., (11) who studied the correlation of reproductive outcome with systematic measurement of both serum E2 and FSH on cycle day 3. They observed that even when FSH values were <20 mIU/ml, no pregnancy occurred when day 3 serum E2 was > 75 pg/ml. This was supported by Buyalos et al.,(37) who found that day 3 serum E2 < 80 pg/ml with normal FSH was associated with better outcome in women who are undergoing fertility treatment. Smotrich et al., (12) and Evers et al., (10) also found that low day 3 E2 levels were associated with improved stimulation response and pregnancy rates, as well as lower cancellation rates (10,12).

The predictive values of the antral follicle count (> 6) were in concordance with the findings of other studies. Bansci et al.,(38) studied the predictors of poor ovarian response in IVF and found that AFC provides better prognostic information on the occurrence of poor response during hormonal stimulation for IVF than does chronological age and the currently used endocrine markers. However, they concluded that endocrine tests remain informative. Also, Sylvestre et al., (39) studied the role of baseline ultrasound and serum hormonal levels in prediction of follicular response to gonadotropine stimulation during IVF. They found that antral follicle count is the best pre-treatment predictor of the follicular response to gonadotropine stimulation during IVF. Furthermore, Morris et al., (40) studied the role of TVS in determination of the number of primordial follicles as a measure of the ovarian reserve. They concluded that the number of antral follicles detected by TVS has been shown to be a predictor of fertility treatment outcome.

The predictive values of the ovarian volume (> 3 cm³) were similar to the findings of Lass et al.,(20) and Syrop et al., (15,16). They found that measurement of the ovarian volume by transvaginal ultrasound before treatment with gonadotropins can predict the ovarian responsiveness in IVF. Also, the role of ovarian volume in evaluation of the ovarian reserve in assisted reproduction has been emphasized by Frattarelli et al., (41) who suggested a prospective novel method of determination of the ovarian size during IVF cycles. In contrary, Tomas et al., (42) and Dumesic et al., (30), fail to find a significant relationship between ovarian volume and ovarian response.

The findings in this study are supported by the findings of several studies which investigated the incidence, clinical characteristics, biochemical (FSH, inhibin-B and estradiol), and biophysical markers (AFC and OV) and reproductive performance in the general infertility patients including those receiving different ovulation induction drugs and particularly those with poor or diminished ovarian reserve (4-6,10-17,24,31, 32,37-40,43).

Scott et al., (44) found that approximately 10% of the patients in the general infertility population had an abnormal test and the incidence increases with age. Failure of ovulation with different ovulation induction drugs is known to occur in the general infertility patients particularly with those with poor or diminished ovarian reserve i.e. "poor responders". (43,45, 46).

Using Univariate analysis, in this study, ovulation was significantly correlated to the levels of FSH, inhibin-B, estradiol, AFC and ovarian volume in the study group (n= 80). These findings are in accordance with the findings of other studies which evaluated the role of different screening parameters in prediction of the ovulation induction success with different end points of evaluation i.e. no of mature oocytes, ovulation rate, estradiol level, no of oocytes retrieved, fertilization rate, biochemical or ultrasound confirmed pregnancy rate...etc. For example, Chuang et al., (47) found that serum concentration of FSH in early follicular phase show an inverse relationship to the size of follicular cohort. Inhibin-B can serve as the earliest index of FSH dependent growth of the antral follicles (13). Also, the serum concentration of FSH during the cycle was found to be regulated by the negative feedback of ovarian hormones i.e. estradiol and inhibin-B (48,49). Muttukrishna et al.,(50) observed a negative correlation between FSH, inhibin-A and inhibin-B in women undergoing surgical menopause. They concluded that this relation may contribute to the observed early rise of FSH after surgical menopause.

On Multivariate analysis of the variables that predict ovulation in induced cycles -in this study- it was demonstrated that of the biochemical variables FSH was the most significant contributor to ovulation, while of the biophysical variables AFC is the most significant one. These findings are in agreement with different studies which investigated the role of different markers in prediction of IVF success. Fawzy et al., (51) stated that day 3 basal FSH levels has proved the most useful, in that a poor IVF outcome was associated with higher levels of the hormone even within the normal range(52), and these results are in broad agreement with those reported by previous investigators (4,53,54). Yong et al.,(13) found that early follicular phase FSH supplemented by AFC remain of greater value in determination of the number of growing oocytes. AFC was found to provide better prognostic information on the occurrence of poor response during hormonal stimulation for IVF than does chronological age and the currently used endocrine markers (38). Nahum et al.,(11) found that antral follicle count was a better predictor of IVF outcome than were age or FSH. They concluded that AFC assessment may provide a marker for the ovarian age that is distinct from chronological age or hormonal markers. Child et al., (55) using multiple linear regression, found that the AFC was shown to be the most important independent predictor of the numbers of oocytes retrieved. AFC, OV and maximum ovarian stromal blood flow velocity can predict the number of oocytes retrieved in unstimulated cycles. However, there is a great debate among different studies about the best predictor of IVF success. Some studies suggested that age is a strong predictor of pregnancy rate (27,56-58), although other studies contradict this finding (59,60). Chuang et al., (47) found that both age and basal FSH levels contributed to the prediction of the quantitative ovarian reserve as reflected by the number of oocyte collected. However, they concluded that age is better predictor of pregnancy potential than FSH levels in women undergoing IVF.

In conclusion, Day 3; serum FSH, inhibin-B, estradiol, AFC and ovarian volume are comparable screening markers of the ovarian reserve in the general infertility patients. Of the biochemical factors the main predictor for ovulation in induced cycles is FSH while AFC is the main biophysical one.

REFERENCES

1. Perloe M, Levy DP, Sills SE. Strategies for ascertaining ovarian reserve among women suspected of subfertility. Int J Fertil 2000; 45:215-24.
2. Helsa JS. Current concepts in assisted reproductive technology. In Rock, J. A., (ed.,): Advances in Obstetrics and Gynaecology. Mosby Year Book.Chicago. 1994. P,231.
3. Barnhart K, and Osheroff J. We are over interpreting the predictive value of serum follicle stimulating hormone levels. Fertil Steril 1999; 72:8-9.
4. Seifer DB, Lambert-Messerlian G, Hogan JW, Gardiner AC, Blazar AS Berk CA. Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome. Fertil Steril 1997; 67:110-14.5.     
5. Lockwood GA , Muttukrishna S, Groome NP, and Ledger WL. Predicting the unpredictable.: inhibin-B is prognostic of the unexpected under and over response to gonadotropine stimulation in IVF. Fertil Steril 1997; 67:ASRM Programe Suppl., S 90-1.   
6. Lockwood GA , Muttukrishna S, Groome NP, and Ledger WL. Inhibin-B ; a better marker of response to gonadotropine stimulation. The 17th Joint Meeting of British Endocrine Societies. J Endocrinol 1998; 153:Suppl., 262.
7. Hofmann GE, Danforth DR, Seifer DB. Inhibin-B: the physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening. Fertil Steril 1998;69:474-7.
8. Corson SL, Gutmann J, Batzer FR, Wallace H, Klein N, Soules MR. Inhibin-B as a test of the ovarian reserve for infertile women. Hum Reprod 1999; 14:2818-21.
9. Creus M, Penarraubia J, Fabregues F, Vidal E, Carmona F, Casamitjana R, Vandrell JA, Balasch J. Day 3 serum inhibin B, FSH and age as predictors of assisted reproduction treatment outcome. Hum Reprod 2000;15: 2341 -46.
10. Evers JL, Slaats P, Land JA, Dumoulin JC, Dunselman GA. Elevated levels of basal estradiol 17-B predict poor response in patients with normal basal levels of follicle stimulating hormone undergoing in vitro fertilization. Fertil Steril 1998; 69:1010-14.
11. Licciardi FL, Liu HC, Rosenwaks Z. Day 3 esrtadiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization. Fertil Steril 1995; 64:991-4.
12. Smotrich DB, Widra EA, Grindoff PR, Levy MJ, Hall JL, Stillman RJ. Prognostic value of day 3 estradiol on in vitro fertilization outcome. Fertil Steril 1995; 64: 1136 -40.
13. Yong PYK, Baird DT, JooThong K, McNeilly AS, Anderson RA. 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 2003; 18:35-44.
14. Nahum R, Shifren JL, Chang Y, Leykin L, Isaacson K, Toth TL. Antral follicle assessment as a tool for predicting outcome in IVF- Is it better predictor than age and FSH ?. J Assist Reprod Genet 2001; 18:151-5.
15. Syrop CH, Willhoite A, Van Voohris BJ. Ovarian volume : a novel outcome predictor for the assisted reproduction. Fertil Steril 1995; 64:1167-71
16. Syrop CH, Dawson JD, Husman KJ, Sparks AE, Van Voorhis BJ. Ovarian volume may predict assisted reproductive outcome better than follicle stimulating hormone in day 3. Hum Reprod 1999; 14:1752-56.
17. Lass A, Skull J, McVeight E, Margara R, Winston RM. Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotropine for in vitro fertilization can predict poor response.Hum Reprod 1997;12:194-7.
18. Gutmann JN, and Corson SL. Female reproductive endocrinology at the turn of the millennium. Int J Fertil 2001; 46;101-115.
19. World Health Organization. Laboratory Manual For the Examination of Human semen and Sperm -Cervical Mucus Interaction. 4th edition. Cambridge University Press. 1999. Cambridge
20. Harrison RF, Barry-Kinsella C, Drudy L, Gordon A, Hannon K, et al. An Irish out-patient based in vitro fertilization service. Ir Med J 1992;85:63-5.
21. Harrison RF, Jacob S, Spilllane E, Mallon E, Hennlley B. A prospective randomized clinical trial of differing starter doses of recombinant stimulating hormone (follitropin-B) for the first time in vitro fertilization and intracytoplasmic sperm injection treatment cycles. Fertil Steril 2001; 75:23-31.
22. Gordon UD, Harrison RF, Fawzy M, Hennelly B, Gordon AC. A randomized prospective assessor-blind evaluation of lutinizing hormone dosage and in vitro fertilization outcome. Fertil Steril 2001; 75:324-31.
23. Gonen Y, and Casper RF. Sonographic determination of an adverse effect of clomiphene citrate on endometrial growth. Hum Reprod 1990; 5:670-74.
24. Smith D, Carr B, O'Neil, Ackerman G, Byrd W. Levels of inhibin A and B in GnRH agonist down regulated women prior to gonadotropine stimulation for in vitro fertilization are highly predictive of pregnancy outcome. Fertil Steril 1999; 72 (Suppl.1):S9-10.
25. Klein NA, Illingworth PJ, Groome NP, McNeilly AS, Battaglia DE, Sovles MR. Decreased inhibin-B secretion is associated with the menotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimericinhibin A and B in spontaneous menstrual cycles. J ClinEndocrinolMetab 1996; 81:2742-5.
26. Seifer DB, Scott RT Jr, Bergh PA, Abrogast LK, Friedman CI, Mack CK, Danforth DR. Women with decline ovarian reserve may demonstrate decrease in day 3 serum inhibin-B before a rise in day 3 follicle stimulating hormone. Fertil Steril 1999; 72:63-5.
27. Hall JE, Weltand CK, Cramer DW. Inhibin A and inhibin B reflect ovarian function in assisted reproduction but are less useful at predicting the outcome. Hum Reprod 1999; 14:409-15.
28. Ravhon A, Lavery S, Micheal S, Donaldson M, Margara R, Trew G, Winston R. Dynamic assays of inhibin-B and estradiol following buserelin acetate administration as predictors of ovarian response in IVF. Hum Reprod 2000; 15:2297-301.
29. Renier MA, Vereecken A, Buytaret P. Inhibins,activins and follistatins : a review of complex regulators of the reproductive system. Eur J Contracept Reprod Health 1998; 3:129-35.
30. Dumesic DA, Damario MA, Session DR, Famuyide A, Lesnick TG, Thrnhill AR, McNeilly AS. Ovarian morphology and serum hormones markers as predictors of ovarian follicle recruitment by gonadotropins for in vitro fertilization. J ClinEndocrinolMetab 2001; 86:2538-43.
31. Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z. Follicle stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989; 51:651-4.
32. Toner JP, Philput CB, Jones GS, Muasher SJ. Basal follicle stimulating hormone level is a better predictor of in vitro fertilization performance than age. Fertil Steril 1991; 55: 784-91.
33. Martin JSB, Nisker JA, Tummon IS, Daniel SAJ, Auckland JL, Felyes W. Failure of in vitro fertilization pregnancy potential of women with variably elevated day 3 follicle stimulation hormone levels. Fertil Steril 1996; 65:1238-40.
34. Sharara FI, Scott RT Jr, Seifer DB. The detection of diminished ovarian reserve in the infertile women., Am J Obstet Gynaecol 1998; 179:804-12.
35. Jain T, Lee DM, Klein NA, Soules MR. Inter-cycle variability of day 3 serum FSH levels in normal eumenorrheic young and older women. Fertil Steril 1999; Supp 72 :S186.
36. Klein NA,Battaglia DE, Clifton DK, Bremmer WJ, Soules MR. The gonadotropine secretion pattern in normal women of advanced reproductive age in relation to the monotropic FSH rise. J Soc Gynaecol  Invest 1996; 3:27-31.37.    
37. Buyalos RP, Daneshmand S, Brzechffa PR. Basal estradiol and follicle stimulating hormone predict fecundity in women of advanced reproductive age undergoing ovulation induction therapy. Fertil Steril 1997; 68:272-7.
38. Bansci LF, Broekmans FJ, Eijkemans MJC, de Jong FH, Habbema JDK, Valder ER. Predictors of poor ovarian response in vitro fertilization: a prospective study comparing basal markers of ovarian reserve. Fertil Steril 2002; 77:328-36.
39. Sylvestre CV, Child T, Pirwany S, Tan SL. Baseline ultrasound and serum hormonal prediction of follicular response to gonadotropine stimulation during IVF. Fertil Steril 2002; Supp 87: S 6-7.
40. Morris JL, Thyer AC, Michael R, Soules MR, Klein NA. Antral follicle count by transvaginal ultrasound is reflective of the actual primordial follicle pool. Fertil Steril 2002; Supp,78, S 3-4.
41. Frattarelli JL, Levi AJ, Miller BT. A prospective novel method of deter-mining ovarian size during in vitro fertilization cycles. J Assist Reprod Genet 2002; 9:39- 41
42. Tomas C, Nuojua-Huttunen S, and Martikainen H. Pretrement transvaginal ultrasound examination predicts ovarian responsiveness to gonadotrphins in in vitro fertilization. Hum Reprod 1997; 12:220:23.
43. Navot  D, Rosenwacks Z, Margohoth EJ. Prognostic assessment of the female fecundity. Lancet 1987; 2:645.
44. Scott RT Jr, Leonardi MR, Hofmann GE, Illios EH, Neal GS, Navot D. A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population. Obstet Gynaecol 1993; 82:539-44.
45. Kligman I, and Rosenwaks Z. Differentiating clinical profiles: Predicting good responders, poor responders., and hyperresponders. Fertil Steril 2001; 76: 1185-90.
46. Sharara FI, and Scott RT Jr. Assessment of the ovarian reserve and treatment of low responders. In Diamond MP, DeCherney AH, (eds): Unexplained infertility: Infertility and Reproductive Medicine Clinics of North America 1997; 8:501-22.
47. Chuang CC, Chen CD, Chao KH, Chen SU, Ho NH, Yang YS. Age is a better predictor of pregnancy potential than basal follicle stimulating hormone levels in women undergoing in vitro fertilization. Fertil Steril 2003; 79:63-8.
48. Hayes FJ, Hall JE, Boepple PA, Crowley WFJ. Differential control of gonadotrophin secretion in human: endocrine role of inhibin. J CliniEndocrinolMetabol 1998; 83:1835-41.
49. Baird DT. Folliculogenesis and gonadotrophins. In Adahi,E.Y., Baird,D.T., Grosignani,P.G., (eds): Gonadotrophins and fertility in the woman. Serono Fertility Series 1999; Rome, Vol., 3.:P, 1-10.
50. Muttukrishna S, Sharma S, Barlow DH, Ledger W, Groome N, Sathanandan M. Serum inhibins, estradiol, progesterone, and FSH in surgical menopause : a demonstration of ovarian pituitary feedback in women. Hum Reprod 2002; 17:2535-9.
51. Fawzy M, Lambert A, Harrison RF, Knight PG, Groome N, Hennelly B, Robertson WR. Day 5 inhibin-B levels in the treatment cycle are predictive of IVF outcome. Hum Reprod 2002; 17; 1535-43.
52. Fawzy M, Harrison RF, Barrett T, Mallon E. Stratification improves the prognostic capability of normal range day 3 FSH for IVF. Adv Contracept Delivery Systems 1997; 13:278-89.,
53. Cahill DJ, Prosser CJ, Wardle PG, Ford WC, Hull MG. Relative influence of serum follicle stimulating hormone, age, and other factors of the ovarian reserve to gonadotrophins stimulation. Br J Obstet Gynaecol 1994;101:999-1002.
54. Penarrubia J, Balasch J, Fabregues F, Carmona F, Casamitjana R, Moreno V, Calafell JM, Vanrell JA. Day 5 inhibin-B serum concentrations as predictors of assisted reproductive technology outcome in cycles stimulated with gonadotrophin -releasing hormone agonist-gonadotrophin treatment. Hum Reprod 2000; 11:109-13.
55. Child TJ, Sylvestre C, Pirwany I, Tan ST. Basal serum levels of FSH and estradiol in ovulatory and anovulatory women undergoing treatment by in vitro maturation of immature oocytes. Hum Reprod 2002; 17:1997-2002.
56. Commenges-Ducos M, Tricaud S, Papaxanthos-Roche A, Dally D, Horovitz J, Commenges D. Modeling of the probability of success of the stages of in vitro fertilization and embryo transfer: stimulation, fertilization and implantation. Hum Reprod 1998; 13:78-83.
57. Sharif K, El Gendy M, Lashen H, Afnan M. Age and basal follicle stimulating hormone as predictors of in vitro fertilization outcome. BJOG 1998; 105:107-112.
58. Fabregues F, Balasch J, Creus M, Carmona F, Puerto B, Quinto L, Casamitjana R, Vanrell JA. Ovarian reserve test with human menopausal gonadotropin as a predictor of in vitro fertilization outcome. J Assist Reprod Genet 2000; 17:13-19.
59. Toner JP. The significance of elevated FSH. BailliereClin Obstet Gynaecol1993; 7:183-95.
60. Check JH, Lurie D, Callan C, Baker A, Benfer K. Comparison of the cumulative probability of pregnancy after in vitro fertilization -embryo transfer by infertility factor and age. Fertil Steril 1994;61:257-61.

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