IVF treatment should not be postponed for patients with high basal FSH concentrations

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1 Reproductive BioMedicine Online (2010) 21, SHORT COMMUNICATION IVF treatment should not be postponed for patients with high basal FSH concentrations Ettie Maman *, Micha Baum, Ronit Machtinger, Daniel S Seidman, Jehushua Dor, Ariel Hourvitz IVF Unit, Division of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer 52621, Israel * Corresponding author. address: ettiemaman@gmail.com (E Maman). Dr Ettie Maman is a senior physician in the IVF unit, Department of Obstetric and Gynecology, Sheba Medical Center, Tel Aviv University, Israel. She graduated from Ben Gurion University, School of Medicine in Beer Sheba, Israel, in She completed her residency in Obstetrics and Gynecology at the Department of Obstetric and Gynecology, Sheba Medical Center. She worked as a research fellow at the Samuel Lunenfeld Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada. She joined the Sheba Medical Center IVF programme in 2006 and her research interests are related to infertility, in vitro maturation and stem cells. Abstract This study determined the influence of inter-cycle variation of basal FSH concentrations on IVF treatment results, in patients with a history of high basal FSH. Patients underwent at least two IVF cycles, one with basal serum FSH 10 IU/l and the other at least 3 IU/l lower (interval between cycles being <1 year when the second cycle had the elevated FSH). A subanalysis was performed in patients with exceptionally large differences in values (16 IU/l and 12 IU/l). IVF outcomes were compared according to basal FSH concentrations in two consecutive cycles. Seventy-six patients met the inclusion criteria. Mean basal serum FSH were 15.0 ± 3.6 IU/l in the high FSH group (range IU/l) and 9.0 ± 3.0 IU/l in the low FSH group (range 5 14 IU/l). Patient age, oestradiol at HCG administration, number of collected oocytes, fertilization and clinical pregnancy rates were similar for all cycles compared. Analysis of the subgroup with exceptionally large differences of basal FSH concentration yielded similar results. Neither high nor low basal serum FSH values were associated with IVF outcome in patients with reduced ovarian reserve and previously determined high basal FSH concentrations. Ovarian stimulation need not be delayed until FSH declines. RBMOnline ª 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: FSH, IVF, pregnancy rate, reduced ovarian reserve Introduction Basal concentrations of serum FSH are routinely used as a marker for predicting ovarian reserve and as a screening test for patients undergoing IVF. High day-3 basal concentrations of FSH have been shown to be associated with low response to ovarian stimulation (Sharif et al., 1998) and a lower pregnancy rate (Scott et al., 1989). The predictive value of basal FSH concentrations for IVF outcome is influenced by the threshold concentrations that are selected and the methods used to select those thresholds (Scott et al., 2008). It is common practice in many centres to withhold treatment whenever the basal FSH is >20 IU/l (Roberts et al., 2005). Treatment results in patients with a history of elevated basal FSH were compared in several studies. Lass et al. (2000) showed that once the FSH concentrations /$ - see front matter ª 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. doi: /j.rbmo

2 632 E Maman et al. returned to normal in patients with a poor response and a history of high basal FSH values, the same IVF outcome was achieved as that of patients with a poor response and normal FSH results. These studies, however, did not investigate basal FSH fluctuations within the same patient. Abdalla and Thum (2006) compared IVF cycles with high FSH values to cycles with low FSH values and found no significant differences in pregnancy and delivery rates or in other IVF outcome parameters. Those authors, however, took the nearest FSH concentrations and not the basal FSH concentrations within the given cycle. The aim was to evaluate if the success of the IVF treatment cycle in patients with previously determined high basal FSH values is related to the basal FSH concentrations of that treatment cycle. This would be of clinical significance as it may suggest whether IVF treatment should be delayed in patients with reduced ovarian reserve and high FSH concentrations until the concentrations reach lower limits in order to achieve better IVF results. Materials and methods Two consecutive IVF cycles were evaluated in the same patient: one with a documented low basal (day-3) FSH concentration and the other with a documented high basal FSH concentration. Study population A retrospective analysis was performed using the information stored in the database of women with reduced ovarian reserve who underwent assisted reproduction treatment cycles from January 1998 to December Inclusion criteria were two cycles with documented basal serum FSH and serum oestradiol concentrations within the treatment cycle, one cycle with a basal FSH value 10 IU/l and another cycle with a difference of at least 3 IU/l and low serum oestradiol (<200 pmol/l), and the time interval between the two cycles limited to 12 months (if the second cycle was the one with elevated FSH value) in order to avoid the influence of age on the results. A subanalysis was also carried out on a group of patients with exceptionally high FSH differences, i.e. one cycle with a FSH concentration of 16 IU/l and another cycle with a FSH concentration of 12 IU/l. The cycles were divided into those with a high basal FSH concentration and those with a low basal FSH concentration, thus each patient served as her own control. Long agonist protocol treatments were excluded because the study protocol dictated a documented day-3 FSH concentration within the treatment cycle. The treatment protocols followed in this study were gonadotrophin-releasing hormone agonist flare-up or antagonist protocols and a modified natural protocol. Ovarian stimulation was carried out with either recombinant FSH or urinary human menopausal gonadotrophin (HMG). A transvaginal scan was performed prior to ovarian stimulation and a hormonal profile of day- 3 was performed in each cycle. The women underwent a pregnancy test 12 days after embryo transfer. Data analysis Data was analysed using the Statistical Package for Social Sciences version 11 for Windows (SPSS, Chicago, USA). Chi-squared or the Fisher s exact tests for categorical variables and the unpaired two-way Student s t-test for continuous variables were used as appropriate. A P-value of <0.05 was considered significant. Results The study evaluated 8292 cycles that were preformed between January 1998 and December 2007 in the IVF unit of the Sheba Medical Centre. Seventy-six women met the enrolment criteria and were included in the study group. These women underwent a total of 152 IVF cycles, each undergoing one with a high and one with a low serum FSH concentration. Forty patients had elevated concentrations of FSH in the first cycle with a mean interval between the two cycles of 6.2 month (range 1 26 months), while 36 had high FSH concentrations in the second cycle with a mean interval of 5.1 months (range 1 12 months). The only parameter that was significantly different between the two types of cycles was the concentration of FSH, as dictated by study protocol. There were no significant group differences in age, cycle number, dose of gonadotrophins used or type of protocol used. Table 1 presents the patients characteristics of the study group. The IVF treatment outcome parameters were compared between the two cycles, i.e., the one with high FSH concentrations versus the one with low FSH concentrations. The results revealed that there were no significant differences in endometrial thickness, number of collected oocytes, fertilization rate, number of transferred embryos or pregnancy rates (Table 2). A further analysis of the study group according to patients age (<40 years n = 42, >40 years n = 34) similarly showed no significant differences in the outcome of cycles with low and high day-3 FSH concentrations. In the younger group (<40 years), pregnancy rates (per oocyte retrieval) were 16.7% versus 20.4% (low versus high, respectively) and 11.8% versus 9.4% for patients 40 years and older (not significant). In order to evaluate whether exceptionally high differences in FSH concentrations can significantly influence the clinical outcome, the study included a further subanalysis of women with exceptionally high differences in their FSH concentrations. Of the 22 women (44 cycles) who met the stringent enrolment criteria, the high FSH concentration was in the first IVF cycle (with a mean interval of 5.9 months) in 12 of them. These selected cycles did not differ in terms of the patients characteristics (Table 3) or the main IVF outcome parameters that were analysed (Table 4). Discussion The significance of basal serum FSH concentrations on the outcome of IVF has been studied extensively. Most investigations have evaluated the effect of FSH concentrations on the likelihood of a successful IVF procedure, but the prognostic significance of fluctuations in FSH concentrations in the same patient has not been investigated in depth. The aim in the present study was to compare treatment

3 History of high basal FSH concentration and outcome of IVF 633 Table 1 Characteristic Cycle characteristics of the study group. Low FSH concentration High FSH concentration Age (years) 38.4 ± ± 5.2 FSH (IU/l) 9.0 ± ± 3.6 Oestradiol (pmol/l) ± ± 65.0 Cycle (n) 6.4 ± ± 5.4 Gonadotrophins used (ampoules/day) 4.8 ± ± 1.5 Number of stimulation days 8.9 ± ± 2.3 Antagonist Flare-up Modified natural Values are mean ± SD or percentage. FSH concentrations significantly different (P < 0.01). In other parameters there were no statistically significant differences between the two groups. Table 2 IVF treatment outcome of the study group. Low FSH concentration High FSH concentration Oestradiol on day of HCG (pmol/l) 907 ± ± 593 Endometrial thickness (%) 7 mm >7 mm Oocytes collected 4.4 ± ± 3.3 Fertilization rate (%) Embryos transferred 2.3 ± ± 1.3 Pregnancy rate Per oocyte retrieval 14.5 (11) 15.8 (12) Per embryo transfer 15.2 (10) 20.3 (13) Clinical pregnancy rate Per oocyte retrieval 5.3 (4) 13.2 (10) Per embryo transfer 6.1 (4) 15.6 (10) Values are mean ± SD or percentage (n) unless otherwise indicated. HCG = human chorionic gonadotrophin. outcome in the same patient in cycles with a high FSH concentration versus those with a low FSH concentration. According to these findings, repeated testing of basal FSH has limited clinical benefit for IVF patients with high day-3 FSH concentrations. These finding are in concordance with a review by Scott and Hofmann (1995) who suggested that serial screening of FSH concentrations to select the optimal cycle for stimulation may be of limited value. The current results are also in accordance with the findings of Abdalla and Thum (2006); however, those results were criticized by El-Toukhy and Taranissi (2006) regarding the use of nearest FSH concentrations to treatment evaluated, but not the day-3 FSH of the same cycle. In the current study, intracycle day-3 FSH concentrations were used, avoiding this criticism. As for the patients age, some studies proposed that the significance of high FSH in younger patients may be different from that for older ones. Roberts et al. (2005) compared IVF patients with previous high FSH concentrations (>20 IU/l) and showed that patients younger than 40 years had a lower oocyte yield, but that there was no difference in pregnancy or implantation rates. Women aged 40 years or more had both compromised ovarian response and poor embryo quality compared with those with normal FSH concentrations (Roberts et al., 2005). Luna et al. (2007) showed that patients aged 40 years or more with high basal FSH concentrations had a poorer IVF outcome than patients in the same age group who had normal basal FSH concentrations. There was no difference in clinical pregnancy rates between younger and older patients in their study. Previous studies did not, however, evaluate the age effect and the fluctuations in the basal FSH of the same patient. The FSH cut-off concentrations and their relation to IVF prognosis and patients age were evaluated by Watt et al. (2000). Their study on

4 634 E Maman et al. Table 3 Cycle characteristics of the subgroup of women with high variations in basal serum FSH concentrations. FSH 12 IU/l FSH 16 IU/l Age (years) 38.8 ± ± 5.3 FSH (IU/l) 9.6 ± ± 2.5 Oestradiol (pmol/l) ± ± 56.3 Cycles 4.3 ± ± 2.9 Gonadotrophins used (ampoules/day) 5.0 ± ± 1.7 Stimulation days 9.0 ± ± 2.4 Antagonist Flare-up Modified natural Values are mean ± SD or percentage. FSH concentrations significantly different (P < 0.01). In other parameters there were no statistically significant differences between the two groups. Table 4 IVF treatment outcome of the subgroup of women with high variations in basal serum FSH concentrations. FSH 12 IU/l FSH 16 IU/l Oestradiol on day of HCG (pmol/l) 807 ± ± 629 Endometrial thickness (%) 7 mm >7 mm Oocytes collected 4.1 ± ± 2.2 Fertilization rate (%) Embryos transferred 2.0 ± ± 0.9 Pregnancy rate Per oocyte retrieval 22.7 (5) 18.2 (4) Per embryo transfer 25.0 (5) 22.2 (4) Clinical pregnancy rate Per oocyte retrieval 13.6 (3) 9.1 (2) Per embryo transfer 15.0 (3) 11.1 (2) Values are mean ± SD or percentage (n) unless otherwise indicated. HCG = human chorionic gonadotrophin. There were no statistically significant differences between the two groups. patients over 40 years old found that no pregnancies were achieved in cases where the day-3 FSH concentration was >11.1 IU/l. They did not address the issue of fluctuations in FSH values. The current study evaluated the effect of age on the results and demonstrated that although better IVF treatment outcomes were achieved in the younger group, those women will not clearly benefit from waiting to initiate ovarian stimulation treatment until their FSH concentrations are low. It is therefore concluded that consultation for younger patients on fluctuating basal FSH concentrations and treatment delays should be the same as that for older ones. Two methods were used to examine this study s hypothesis. First, it was shown that when the FSH concentration is higher than the normal cut-off for IVF good prognosis (defined in this study as >10 IU/l), waiting for it to drop bestows no apparent benefit. Second, it was questioned whether exceptionally high variability in FSH basal concentrations would make a significant difference on IVF prognosis and outcome. Observations on a selected group of 22 patients with exceptionally high differences in basal FSH concentrations similarly showed no difference, further supporting the suggestion that delaying treatment has no benefit whatsoever. These observations are consistent with those of Scott et al. (1990), but the question of whether this assumption can be extrapolated for application to even higher (>25 IU/l) basal FSH concentrations remains unclear and needs further study. One other question that arose from the results of this study is whether there is a better marker that can aid the

5 History of high basal FSH concentration and outcome of IVF 635 clinician when deciding on whether to delay treatment and wait for a better-prognosis cycle in a patient who has intercycle variability. This study shows that inter-cycle variability in basal FSH concentrations are not useful for this purpose. The answer may lie in the results of studies on other ovarian reserve markers, such as antral follicle count, anti-müllerian hormone and inhibin B. Acknowledgement Esther Eshkol is thanked for editorial assistance. References Abdalla, H., Thum, M.Y., Repeated testing of basal FSH levels has no predictive value for IVF outcome in women with elevated basal FSH. Hum. Reprod. 21, El-Toukhy, T., Taranissi, M., Which is more counterproductive: a brief delay or start anyway? Hum. Reprod. 21, (author reply ). Lass, A., Gerrard, A., Abusheikha, N., Akagbosu, F., Brinsden, P., IVF performance of women who have fluctuating early follicular FSH levels. J. Assist. Reprod. Genet. 17, Luna, M., Grunfeld, L., Mukherjee, T., Sandler, B., Copperman, A.B., Moderately elevated levels of basal folliclestimulating hormone in young patients predict low ovarian response, but should not be used to disqualify patients from attempting in vitro fertilization. Fertil. Steril. 87, Roberts, J.E., Spandorfer, S., Fasouliotis, S.J., Kashyap, S., Rosenwaks, Z., Taking a basal follicle-stimulating hormone history is essential before initiating in vitro fertilization. Fertil. Steril. 83, Scott Jr., R.T., Hofmann, G.E., Prognostic assessment of ovarian reserve. Fertil. Steril. 63, Scott, R.T., Toner, J.P., Muasher, S.J., Oehninger, S., Robinson, S., Rosenwaks, Z., Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil. Steril. 51, Scott Jr., R.T., Hofmann, G.E., Oehninger, S., Muasher, S.J., Intercycle variability of day 3 follicle-stimulating hormone levels and its effect on stimulation quality in in vitro fertilization. Fertil. Steril. 54, Scott Jr., R.T., Elkind-Hirsch, K.E., Styne-Gross, A., Miller, K.A., Frattarelli, J.L., The predictive value for in vitro fertility delivery rates is greatly impacted by the method used to select the threshold between normal and elevated basal folliclestimulating hormone. Fertil. Steril. 89, Sharif, K., Elgendy, M., Lashen, H., Afnan, M., Age and basal follicle stimulating hormone as predictors of in vitro fertilisation outcome. Br. J. Obstet. Gynaecol. 105, Watt, A.H., Legedza, A.T., Ginsburg, E.S., Barbieri, R.L., Clarke, R.N., Hornstein, M.D., The prognostic value of age and follicle-stimulating hormone levels in women over forty years of age undergoing in vitro fertilization. J. Assist. Reprod. Genet. 17, Declaration: The authors report no financial or commercial conflicts of interest. Received 20 October 2009; refereed 15 May 2010; accepted 18 May 2010.