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Use of Follicle-Stimulating Hormone Test to Predict Poor Response in In Vitro Fertilization

Akira Iwase, MD, PhD^*, Hisao Ando, MD, PhD^*, Keiko Kuno, MD^* and Shigehiko Mizutani, MD, PhD^*

From the *Department of Obstetrics and Gynecology and Department of Maternal and Perinatal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
OBJECTIVE: Optimized ovarian stimulation protocols are required for the success of in vitro fertilization (IVF). The purpose of this study was to estimate whether the ovarian reserve test using exogenous follicle-stimulating hormone (FSH) could predict ovarian response in IVF.

METHODS: This was a prospective observational study of 110 patients who underwent their first IVF cycle. The FSH test was administered as 150 IU of urinary FSH daily from day 3 to day 6 of the menstrual cycle preceding the IVF cycle for evaluation of the plasma estradiol level. Outcomes of IVF, including ovarian response, were analyzed.

RESULTS: A negative correlation was observed between the duration of stimulation and the result of the FSH test (r = –.238, P = .014) and between the dose of FSH per retrieved mature oocyte (metaphase II oocyte) and the result of the FSH test (r = –.308, P < .001). In addition, our results showed that the result of the FSH test was significantly lower in poor responders defined by FSH of 400 IU/metaphase II oocyte or greater (207 ± 149 compared with 293 ± 174 pg/mL, P = .007).

CONCLUSION: The FSH test can be a useful tool for determining the conditions of individualized clinical management plans and optimizing stimulation protocols in IVF.

LEVEL OF EVIDENCE: II-2

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
From January 1995 to December 2001, 110 women (including 3 patients with cycle cancellation) who underwent the FSH test before their first controlled ovarian hyperstimulation for IVF (n = 41) or intracytoplasmic sperm injection (ICSI, n = 66) were analyzed. Our inclusion criteria were infertile women of all ages with 1) both ovaries, 2) normal thyroid function tests, and 3) normal serum prolactin levels. All eligible patients were included. Women with an incomplete record regarding hormone screening, FSH test, and/or IVF outcome were excluded. All of the patients were assigned to 1 of 3 groups based on the main cause of infertility: tubal factor, male factor, or unexplained infertility. The patients with unexplained infertility underwent intrauterine insemination with clomiphene citrate and/or FSH/human menopausal gonadotropin (hMG) 3 to 6 times before their first IVF/ICSI. Informed consent from each patient was obtained before the study as well as institutional review board approval.

FSH and luteinizing hormone (LH) on day 3 of a spontaneous cycle were measured using immunoradiometric assay kits (SPAC-S FSH Kit, SPAC-S LH Kit; Daiichi Radioisotope Labs. Ltd., Tokyo, Japan). The intra-assay and interassay coefficients of variation for the FSH assay were 4.6% and 2.4%, respectively (for 1.31 mIU/mL), and 1.5% and 2.4%, respectively (for 8.25 mIU/mL). The intra-assay and interassay coefficients of variation for the LH assay were 5.3% and 6.9%, respectively (for 2.07 mIU/mL), and 2.8% and 3.7%, respectively (for 8.34 mIU/mL).

The FSH test was performed during the menstrual cycle preceding the first ovarian stimulation for IVF or ICSI. All women received 150 IU of a purified preparation of urinary FSH (HMG "Nikken"; Nikken Chemicals, Tokyo, Japan) containing less than 5% LH intramuscularly for 4 consecutive days from the third day of their menstrual cycles. On day 7 of the cycle after the FSH test, venous blood samples were drawn for E2 measurements. The plasma E2 level was assayed using a radioimmunoassay kit (Coat-A count; DPC Diagnostics, Los Angeles, CA). The intra-assay and interassay coefficients of variation for the assay were 7% and 8.1%, respectively, at 48 pg/mL, and 6% and 6.8%, respectively, at 168 pg/mL.

The IVF/ICSI treatment followed within 3 months of the FSH test. Pituitary desensitization by nafarelin acetate (Nasanyl; Yamanouchi Pharmaceutical, Tokyo, Japan) administration was started in all women in the midluteal phase and ovarian stimulation was started after menstruation with confirmation of complete pituitary desensitization by the demonstration of low plasma E2. The initial FSH (HMG "Nikken") dose administered for the first 2 days was set at 300 IU per day. Further administration of FSH was adjusted individually based on the follicular response monitored by transvaginal ultrasonography and plasma E2 measurements. When at least 3 follicles had developed and at least 2 follicles reached 16 mm or more as mean diameter, human chorionic gonadotropin (Gonatropin; Teikoku Hormone MFG, Tokyo, Japan) was administered, and oocyte retrieval was performed 36 hours later under the guidance of transvaginal ultrasound. The procedures of sperm and oocyte preparation, IVF, and ICSI have been described previously.¹² We classified a metaphase II (M II) oocyte with the first polar body as a mature oocyte with microscopic observation after removal of granulosa cells. Oocytes with germinal vesicle and metaphase I oocytes without the first polar body were considered to be immature. A maximum of 3 embryos was transferred. The luteal phase was supported by either human chorionic gonadotropin (Gonatropin) or progesterone (Luteum; Teikoku Hormone MFG). Clinical pregnancies were defined as the presence of fetal cardiac activity. For this study, a multiple pregnancy was regarded as 1 pregnancy.

Data were analyzed with the SPSS and the SigmaStat (SPSS Inc., Chicago, IL) programs. Simple linear regression analyses and Pearson correlation were applied where appropriate. We used the Student t test, the ² test, and the Fisher exact test for comparing screening and treatment variables between poor responders and normal responders. The Mann–Whitney U test was applied for the Student t test when the variables did not pass the normality test. The area under the receiver operating characteristic curve was computed to assess the predictive accuracy of the logistic models. A P value of less than .05 was considered statistically significant.

	RESULTS

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First, we analyzed the FSH test results of 110 patients who were undergoing their first IVF/ICSI. We included 3 patients with cycle cancellation because their cycle cancellations were caused by poor response. Figure 1 shows the distribution of plasma E2 levels on day 7 after administration of 150 IU of FSH daily for 4 days. The mean ± standard deviation (SD) was 265 ± 171 pg/mL. The median was 245 pg/mL (range, 22.1–997). The 10, 25, 75, and 90 percentiles of the test were 77, 134, 387, and 505 pg/mL respectively.

View larger version (45K): [in this window] [in a new window]   Fig. 1. Histogram of the results of the follicle-stimulating hormone (FSH) test. Serum estradiol (E2) levels of 110 patients were measured after administration of 150 IU of FSH daily for 4 days from day 3 in the menstrual cycle. The range of each column is 50 pg/mL. Iwase. FSH Test for Predicting Ovarian Response. Obstet Gynecol 2005.

The result of the FSH test did not show a significant correlation with patient's age (r = –.057, Fig. 2A), basal FSH level (r = –.128, Fig. 2B), or basal LH level (data not shown). We also assessed the correlation between the result of the FSH test and the outcome of IVF/ICSI. The total dose of FSH used for ovarian stimulation showed a negative correlation with the result of the FSH test (r = –.300, P < .001, Fig. 2C). A negative correlation also was found between the duration of stimulation and the result of the FSH test (r = –.238, P = .014, Fig. 2D). Next, we analyzed the correlation between the result of the FSH test and ovarian response to stimulation. The dose of FSH administered for stimulation per retrieved mature oocyte (M II oocyte) showed a significant negative correlation with the result of the FSH test (r = –.308, P < .001, Fig. 2E). Furthermore, we examined whether an elevated LH/FSH ratio had any impact on the FSH test. No patients in our study met the revised diagnostic criteria of polycystic ovary syndrome.¹³ However, 9 patients had inverted FSH-to-LH ratio (LH/FSH > 1). The mean ± SD was 431 ± 270 pg/mL in the patients who showed inverted FSH/LH ratio, whereas it was 251 ± 153 pg/mL in the patients who showed normal FSH/LH ratio (P = .002).

View larger version (30K): [in this window] [in a new window]   Fig. 2. Correlation of age–follicle-stimulating hormone (FSH) test (A, r = .057, P = .555), basal FSH–FSH test (B, r = –.128, P = .183), FSH test–total dose of gonadotropin (C, r = –.300, P < .001), FSH test–duration of stimulation (D, r = –.238, P = .014), and FSH test–dose of gonadotropin per mature oocyte (E, r = –.308, P < .001). The sample sizes were 110 (A and B) and 107 (C, D, and E). The r is the Pearson correlation coefficient. Iwase. FSH Test for Predicting Ovarian Response. Obstet Gynecol 2005.

Critical evaluation of ovarian stimulation protocols is made difficult by the lack of uniformity in the definition of "poor response." However, several investigators have proposed defining poor responders on the basis of variable numbers of mature follicles noted on ultrasound or numbers of mature oocytes retrieved.⁹ In this study, we found that both the result of the FSH test and the basal plasma FSH level showed significant differences (P = .036 and P = .011, respectively) between the 2 types of responders as defined by the number of mature oocytes retrieved (poor responders, n = 31, 4 mature oocytes retrieved; normal responders, n = 79, >5 mature oocytes). However, based on the fact that there was a good correlation between the result of the FSH test and the dose of FSH per M II oocyte, we examined whether there was a correlation between the number of mature oocytes and the dose of FSH per M II oocyte. Figure 3 shows that the dose of FSH per M II oocyte showed a significant inverse correlation with the number of retrieved mature oocytes (r = .967, P = .001). In this correlation, 4 or fewer mature oocytes corresponded to 408 IU or more of FSH administered per M II oocyte. Therefore, in this study, we defined poor responders as patients who were administered doses of FSH of more than 400 IU per M II oocyte or had cycle cancellation attributable to poor follicle growth. Table 1 presents the clinical characteristic, FSH test results, treatment data, and IVF/ICSI outcomes. Thirty-five patients, including 3 patients with cycle cancellation, were diagnosed as poor responders and 75 patients as normal responders. The main cause of infertility of the patients was not significantly different between normal responders and poor responders. In addition, no significant difference existed in the results of the FSH test among the 3 subgroups (tubal 206 ± 139 pg/mL compared with male 273 ± 175 pg/mL compared with unexplained 298 ± 178 pg/mL, P = .255). The mean ± SD of the FSH test in the 37 pregnant women was 263 ± 145 pg/mL, which was almost same as that in the 73 women who were not pregnant (267 ± 183 pg/mL, P = .908).

View larger version (24K): [in this window] [in a new window]   Fig. 3. Correlation between dose of gonadotropin per mature oocyte and the number of mature oocytes retrieved. The r of the inverse correlation was .967 (P = .001). The sample size was 107. Iwase. FSH Test for Predicting Ovarian Response. Obstet Gynecol 2005.

We found that the result of the FSH test showed a significant difference (P = .007) between the 2 types of responders, as did the basal plasma FSH level (P = .041). In addition, we also found a significantly increased total dose of FSH (P < .001) and decreased peak E2 level (P < .001) in the poor responders. No significant differences existed in either clinical pregnancy rate or live birth rate, despite the fact that fewer embryos were transferred to poor responders. The mean embryo quality was similar in the 2 groups (data not shown). The receiver operating characteristic curves were drawn to assess the predictive accuracy of the logistic models for poor responders (Fig. 4). The area under the curve (AUC) indicated that the result of the FSH test (AUC = .661) had similar predictive accuracy as the basal FSH level (AUC = .621, P = .061).

View larger version (24K): [in this window] [in a new window]   Fig. 4. The receiver operating characteristic curves to assess the predictive accuracy of the logistic models using the follicle-stimulating hormone (FSH) test and basal FSH for poor responders who were defined based on the dose of FSH per metaphase II oocyte in IVF. The areas under the curves are .661 and .621, respectively (P = .061). Iwase. FSH Test for Predicting Ovarian Response. Obstet Gynecol 2005.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
A general consensus exists that the ovarian response to stimulation is a major factor in determining the rate of pregnancy using IVF, although several factors can determine the success of using IVF. Moreover, several protocols proposed for clinical management, such as flare-up regimens, may improve ovarian response in poor responders,^9,14 and some authors have proposed that the use of IVF in conjunction with natural cycles should be considered for poor responders.¹⁵ Therefore, identification of women with poor response to stimulation using gonadotropin is important for determining individualized clinical management strategies, including IVF on the natural cycle. Basal FSH levels have been widely used to assess functional ovarian age. Indeed, basal FSH has been reported to be a better predictor than age of ovarian response in IVF cycles stimulated with gonadotropins.^2,4,16 Inhibin-B is another predictor of ovarian response. A recent study showed that women with low day-3 serum inhibin-B concentrations have a poorer response to controlled ovarian hyperstimulation for IVF compared with women with high day-3 inhibin-B concentrations.¹⁷ Moreover, it was recently demonstrated that the serum antimüllerian hormone level can be used as a novel marker for ovarian aging.⁵ However, concerns exist that normal baseline hormonal values do not always guarantee normal ovarian response to stimulation. Indeed, it has been demonstrated that the basal FSH level can show marked intercycle fluctuations¹⁸ and that patients with baseline values in the normal range may have a diminished ovarian reserve.¹⁹ In addition to markers for ovarian reserve, antral follicle counts has been used to predict the response to ovulation induction.²⁰ However, ovaries often are located far from the vaginal fornix and, therefore, antral follicle counts cannot be measured accurately even with transvaginal ultrasound.

To address these problems, some approaches called "ovarian reserve tests" have been proposed. Among them, the clomiphene challenge test has demonstrated a particularly good predictive value for poor response in IVF/ICSI.^7,21 The use of the clomiphene challenge test may improve the predictive value of basal FSH alone; however, the clomiphene challenge test does not provide direct information concerning the ovarian response using exogenous FSH/gonadotropin in IVF. Surprisingly, there have been few reports of attempts to predict ovarian response and outcome in IVF with pretreatment tests using exogenous FSH/gonadotropin. Fanchin et al²² developed an ovarian reserve test named the exogenous FSH ovarian reserve test in which ovarian response in IVF was predicted by E2 response to an injection of 300 IU of FSH. A good correlation between this test and the subsequent quality of the ovarian response in IVF was observed, and the predictive value of this test for good and poor responders was higher than that of basal FSH alone. However, the duration of administration of exogenous FSH/gonadotropin in IVF usually ranges from 7 to 10 days, and some normal responders have slow follicular growth and E2 development. Therefore, it might be difficult to conclude that E2 response 24 hours after 1 injection of FSH reflects the ovarian response in IVF. Compared with the exogenous FSH ovarian reserve test, the hMG test proposed by Fabregues et al²³ is more practical. They assessed E2 response to the administration of 150 IU of hMG for 5 days from the second or third day as a predictor of cycle cancellation in IVF. Their results demonstrated that the hMG test showed a better correlation with cycle cancellation than basal FSH, as assessed by diagnostic accuracy and area under the receiver operating curve. However, they did not provide the results of the hMG test in the canceled group or in a control group. In their study, the cycle was canceled when there were fewer than 3 follicles and when serum E2 levels were less than 500 pg/mL and when all patients had normal ovulatory function. Taken together, this result implies that the control group in their study might have included patients who showed minimal response to stimulation using gonadotropin.

After we started this study, the first report regarding the day-3 E2 level as a prognosticator of ovarian response was published.³ However, most of the patients, including poor responders, in that study had basal E2 levels of less than 75 pg/mL. Considering that the mean E2 levels after the FSH test in normal and poor responders were 293 and 207 pg/mL, respectively, it seems that elevated basal E2 levels do not affect the results of the FSH test very significantly, although measurement of the basal E2 levels in the present study would have made the FSH test more accurate.

In the present study, the difference of predictive accuracy between the FSH test and the basal FSH level was not significant, although the FSH test had a larger area under the receiver operating curve than did the basal FSH level. A study involving a larger number of patients might yield a significant difference. However, the result of the FSH test showed a correlation with the total dose of gonadotropin. The exogenous FSH ovarian reserve test and hMG tests failed to show a correlation with the gonadotropin dose required for stimulation. The initial dose of gonadotropin required for stimulation is important because follicle recruitment depends on the initial dose of gonadotropin. Incrementally higher gonadotropin doses in normal responders resulted in poorer oocyte quality,²⁴ whereas high initial doses of FSH could be successfully used to achieve follicular growth in previously poor responders.^10,11 We also found that the result of the FSH test showed a correlation with the dose of gonadotropin per M II oocyte in the overall patients and not only in poor responders. Poor response generally is defined based on the result of ovarian response to stimulation using FSH/gonadotropin, and the number of mature follicles or retrieved mature oocytes has been used as a criterion to define poor responders in IVF.⁹ However, the total dose of FSH administered for stimulation may affect the number of mature oocytes in protocols in which the dose of FSH is adjusted individually. The criteria we used to define poor responders based on the dose of gonadotropin per M II oocyte, which showed a good inverse correlation with the number of mature oocytes, might be a more appropriate indicator because it reflects both the number of mature oocytes and the dose of gonadotropin. In fact, our results demonstrated that the result of the FSH test was significantly lower in poor responders who needed more than 400 IU of gonadotropin per M II oocyte. Patients who develop a relatively large number of mature oocytes with relatively smaller doses of gonadotropin, which means a low dose of gonadotropin per mature oocyte, may show improved follicular recruitment and growth in response to adjusting the initial dose.

We also found that the lack of difference in the pregnancy rate between normal and poor responders was the result of a lower implantation rate in normal responders, who have higher E2 levels with the FSH test and much higher peak E2 levels in IVF than do poor responders. Uterine receptivity has been reported to be affected by high serum E2 concentrations in high and normal responders.²⁵ Taken together, these findings suggest that there is a possibility that we may avoid high E2 concentrations in IVF, which impair the uterine receptivity, by decreasing the dose of FSH/gonadotropin for possible high responders predicted by the results of the FSH test. All things considered, our results indicate that the result of the FSH test can be indicator a useful for designing individualized and optimized protocols through adjusting the initial dose of gonadotropin (eg, increase or decrease the initial dose of FSH/gonadotropin for stimulation for possible poor or high responders). Further studies are now underway to evaluate whether optimization of the ovarian stimulation protocol (adjusting the initial dose of FSH) based on the results of the FSH test can improve outcomes in IVF.

We conclude that the FSH test is an effective method not only for predicting poor responders to stimulation using FSH/gonadotropin but also for estimating the necessary doses of FSH/gonadotropin. Although further studies of a large number of patients, including comparison with other ovarian reserve tests such as clomiphene challenge test and exogenous FSH ovarian reserve test, or with other markers for ovarian reserve such as antimüllerian hormone, will be required to more accurately evaluate the correlations observed here, the FSH test can be a useful tool for designing individualized clinical management plans and optimizing stimulation protocols in IVF.

	Footnotes

 
Address reprint requests to: Dr. Akira Iwase, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466–8550, Japan; e-mail: akiwase{at}med.nagoya-u.ac.jp

Received June 29, 2004. Received in revised form October 6, 2004. Accepted October 27, 2004.

doi:10.1097/01.AOG.0000152334.23169.32

	REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Iwase, A. Articles by Mizutani, S. Search for Related Content PubMed PubMed Citation Articles by Iwase, A. Articles by Mizutani, S. Related Collections Infertility including ART Reproductive endocrinology