Herjan Coelingh Bennink, M.D.:j: Andre Van Steirteghem, M.D., Ph.D.* Paul Devroey, M.D., Ph.D.*

Transcription

1 J FERTILITY AND Copyright 't; 1996 American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. Premature luteinization in in vitro fertilization cycles using gonadotropin-releasing hormone agonist (CnRH-a) and recombinant follicle-stimulating hormone (FSH) and CnRH-a and urinary FSH Filippo Ubaldi, M.D. *t Michel Camus, M.D. * Johan Smitz, M.D., Ph.D.* Herjan Coelingh Bennink, M.D.:j: Andre Van Steirteghem, M.D., Ph.D.* Paul Devroey, M.D., Ph.D.* Centre for Reproductive Medicine, Dutch-speaking Brussels, Free University, Brussels, Belgium, and Organon International B. V., Oss, The Netherlands Objective: To determine if premature luteinization can occur in GnRH agonist (GnRH-a) and FSH (recombinant FSH and human urinary FSH) IVF cycles and whether premature luteinization affects 1VF and clinical outcome. Design: Retrospective evaluation of 171 1VF-ET cycles. The cycles were divided into two groups according to the P level on the day of hcg: group I (serum P :5 0.9 ng/ml [conversion factor to S1 unit, 3.180]) and group II (serum P 2: 1.1 ng/ml). Main Outcome Measures: Comparison of cycles characteristics and of cumulative exposure offollicular serum E 2, FSH, LH, and P as well as ofivf and clinical outcome were made between the study groups. Results: Twenty-three of 171 cycles (13.4%) demonstrated premature luteinization. The age of the patients, the E 2, and LH exposure were similar between the groups. The number of the ampules of gonadotropins (recombinant FSH and urinary FSH) used and the area under FSH and P curve were higher in cycles with premature luteinization. The area under the FSH curve correlated with the area under the P curve. Similar 1VF and clinical outcomes were observed in cycles with and without premature luteinization. Conclusion: The greater FSH exposure and its correlation with the P exposure suggest that one of the possible factors inducing premature luteinization is the increased FSH-induced LH receptivity in granulosa cells. No adverse effects of premature luteinization on the 1VF and clinical outcome were observed. Fertil Steril 1996;66: Key Words: Recombinant human FSH, urinary human FSH (ufsh), premature luteinization,1vf-et Although pituitary desensitization with GnRH agonists (GnRH-a) is reported to eliminate both immunoactive and bioactive LH surges (1), subtle serum P rise during the late follicular phase can occur when GnRH-a are combined with menotropins for controlled ovarian hyperstimulation (COH) in patients undergoing assisted reproductive techniques (2-6). Received October 4, 1995; revised and accepted March 13, * Department of Obstetrics and Gynecology, Centre for Reproductive Medicine, Dutch-speaking Brussels Free University. t Reprint requests: Filippo Ubaldi, M.D., Centre for Reproductive Medicine, Free University of Brussels, Laarbeeklaan 101, 1090 Brussels, Belgium (FAX: ). t Medical Research and Development Unit, Organon International BV. The etiology of the subtle rise in P is poorly understood. Recently, Copperman et al. (7), comparing women with and without premature luteinization during GnRH-a and hmg IVF cycles, have reported higher hcg serum levels in women who experienced subtle serum P rise, suggesting that premature luteinization, despite pituitary suppression with GnRH-a, may be due to the hcg content ofhmg (8). According to this hypothesis, the use of recombinant human FSH or human urinary FSH in which LH activity is negligible (9) or practically devoid (10) should avoid premature luteinization. Another debatable issue is represented by the consequences of premature luteinization on the IVF and clinical outcome. Reduced implantation and pregnancy rates have been reported by some (2-4) but Ubaidi et al. FSH and premature luteinization 275

2 not all authors (5, 6) (Ubaldi F, Wisanto A, Liu J, Joris H, Smitz J, Van Steirteghem A, et ai., abstract). To assess whether the hcg content of hmg could be the cause or one of the possible causes of subtle P rise and whether subtle P rise could affect IVF and clinical outcome, we measured serum levels of P, E2, LH, and FSH during the follicular phase and we analyzed the IVF and the clinical outcome of women who underwent COH by using GnRH-a in combination with recombinant FSH or urinary FSH for IVF-ET. MATERIALS AND METHODS A total of 171 cycles were studied retrospectively in 110 women selected for a randomized, assessorblind, group comparative multicenter safety and efficiency study of recombinant FSH (75 IU per ampule, Puregon, Org 32489; Organon International, Oss, The Netherlands) and treated by IVF with recombinant FSH or urinary (75 IU per ampule, Metrodin; Serono, Brussels, Belgium), both after pituitary suppression with buserelin acetate (Suprefact; Hoechst, Brussels, Belgium), were included in this study. Age older than 39 years; infertility caused by endocrine abnormalities such as hyperprolactinemia, polycystic ovary syndrome, and absence of ovarian function; and male infertility (sperm concentration <10 X 10 6 /ml, and/or <40% normal morphology, and/or <40% normal motility (11) were considered exclusion criteria. Eligible subjects were randomized by receiving a subject number from a randomization list corresponding with patient boxes in which the medication was kept. The randomization procedure included a ratio between recombinant and urinary FSH of 3:2. Administration of the agonist was started on day 1 of the menstrual cycle with a dose of 100 f.lg administered intranasally six times daily. When pituitary desensitization was obtained (serum E2 and P concentrations, respectively, ::=;40 pg/ml [conversion factor to SI unit, 3.671] and :50.3 ng/ml [conversion factor to SI unit, 3.180)) and when ovarian follicular structures on ultrasound were <8 mm diameter, ovarian stimulation was started with two ampules (150 IU) recombinant FSH or urinary FSH per day for 4 days. Thereafter, the dose was adapted individually according to the serum E2 increment and ultrasound measurements of follicular diameter (12, 13). From day 5 of the stimulated cycle onward, blood samples were taken and assayed for E2, P, LH, and FSH. Criteria for administration of hcg and details of oocyte retrieval were described previously (12, 13) as well as the technique of oocyte insemination with husband sperm and embryo culture (14, 15). The embryos were classified into three categories ac- 276 Ubaldi et al. FSH and premature luteinization cording to the relative proportion of anucleate fragments present in the zona pellucida: [1] type A or excellent-quality embryos, when all blastomeres had an equal or nonequal size without anuclear fragmentation; [2] type B or good-quality embryos, when <20% of the embryo was fragmented; [3] type C or fair-quality embryos when the relative amount of fragments was between 20% and 50%. Up to three embryos were replaced into the uterine cavity 48 hours after follicular aspiration. The luteal phase was supported by means of natural micronized P, 600 mg/d intravaginally in three divided doses (Utrogestan; Piette, Brussels, Belgium), starting on the day after the hcg injection (16). Pregnancy was confirmed by serial rise in serum hcg concentrations on two consecutive occasions 10 to 12 days after embryo replacement. Clinical pregnancy was determined by ultrasound demonstration of cardiac activity at 7 weeks. For the purposes of this study ectopic pregnancies were excluded. Serum E2 and P concentration were assayed using commercially available RIA kits. The sensitivity of the assay was 20 pg/ml for E2 and 0.04 ng/ml for P. Intra-assay and interassay coefficients of variation (CV) were <7% and <10%, respectively, for E2 and <4% and <6% for P within the normal working range. However, in the 1 ng/ml range, the betweenassay CV of P was 10.8%. Serum LH and FSH were measured by immunoradiometric assay (IRMA; bio Merieux, Charbonnieres-Ies-Bains, France). Results were expressed in miu/ml (conversion factor to SI unit, 1.00; First International Reference Preparation 68/40 for LH, Second International Reference Preparation 78/549 for FSH). Intra-assay and interassay CVs were both <7% for LH and <3% and <8% for FSH. The lower limit of assay sensitivity was 0.3 miu/ml for LH and 0.25 miu/ml for FSH. Serum hcg was measured by IRMA (Hybritech, Brussels, Belgium). Results were expressed in miui ml (First International Reference Preparation ). Intra-assay and interassay CVs were <6% and <8% and the lower limit of assay sensitivity was 1.5 miu/ml. The cycles were divided into two groups according to the P level on the day of HCG: group I (serum P :5 0.9 ng/ml) and group II (serum P 2: 1.1 ng/ml). These cut-off values were chosen arbitrarily because previous studies had reported lower pregnancy rates when serum P was >0.9 ng/ml on the day of hcg injection (2-4) and because given the sensitivity of the assay these two values were significantly different without overlap. Moreover, in each group the cycles were divided according to the drug (recombinant FSH versus urinary FSH) used for COH into two subgroups (group I-recombinant FSH, group 1- Fertility and Sterility

3 Table 1 Comparison of the Area Under Serum Follicular E 2, FSH, LH, and P Curve in the Two Groups* Group I (n = 148) 5,989 ± 2,112 Group II (n = 23) 6,669 ± 2,315 Group I-recombinant FSH (n = 93) 6,170 ± 2,051 Group II-recombinant FSH (n = 17) 6,607 ± 2,889 Group I-urinary FSH (n = 55) 5,815 ± 2,061 Group II-urinary FSH (n = 6) 6,844 ± 1,666 * Values are means ± SD. Group I, P :::; 0.9 ng/ml; group II; P ~ 1.1 ng/ml. Conversion factor to SI unit, t p < 0.05, groups I, I-recombinant FSH, I-urinary FSH versus groups II, II-recombinant FSH, II-urinary FSH. E2 FSH LH P ± 53.2t 11.7 ± ± 1.2:j: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 3.1 :j: P < 0.05, groups I, I-recombinant FSH, I-urinary FSH versus groups II, II-recombinant FSH, II-urinary FSH. urinary FSH and group II-recombinant FSH, group II-urinary FSH).. Serum follicular levels of E2, FSH, LH, and P from day -10 to day 0 (day of hcg administration) were measured by area under the curve (AUC). Data are expressed as mean ± SD. Comparisons of cycles between groups I and II were performed using a Student's t-test, AUC, and linear regression analysis. X 2 analysis was used for comparisons ofet, implantation, pregnancy, and miscarriage rates. Statistical significance was defined as P < RESULTS In 148 of 171 cycles (group I), serum P concentrations were ::=;0.9 ng/ml (range 0.1 to 0.9 ng/ml), whereas the remaining 23 cycles (13.4%) demonstrated premature luteinization (P 2:: 1.1 ng/ml, range 1.1 to 9.8 ng/ml). In four patients, serum P concentration on the day of hcg administration was 1.0 ng/ml. These patients were not included in the study. In group I, recombinant FSH was used for COH in 93 cycles (group I-recombinant FSH) and urinary FSH in 55 cycles (group I-urinary FSH), whereas in group II recombinant FSH and urinary FSH were used in 17 and in 6 cycles, respectively (group II-recombinant FSH and group II-urinary FSH). Cycles in group I were similar to group II in age (32.4 ± 3.4 versus 31.6 ± 4.3; mean ± SD), in the number of follicles 2:: 17 mm on the day of hcg administration (6.2 ± 2.4 versus 6.3 ± 2.1), and in the number of days of stimulation (13.1 ± 2.6 versus 13.4 ± 2.8), but the number of ampules of FSH were significantly higher in group II and in group II-recombinant FSH than in group I and in group I-recombinant FSH, respectively (40.3 ± 17 versus 32 ± 16.8, and 38.1 ± 16.9 versus 28.0 ± 14.8, respectively). Table 1 depicts the results of the mean ± SD of the serum follicular E2, FSH, LH, and P, expressed as AUC, in the two groups. There were no significant differences in the mean serum follicular E2 and LH AUC between cycles with premature luteinization and those with serum P levels::=; 0.9 ng/ml. Moreover, mean serum LH concentrations on the day of hcg administration were comparable between group I and group II (1.1 and 1.5 miu/ml, respectively, P = 0.2). On the contrary, the mean serum follicular FSH and P AUC were significantly higher in group II, in group II-urinary FSH, and the group II-recombinant FSH than in the respective groups of cycles with serum P levels::=; 0.9 ng/ml. As expected, the number of ampules of gonadotropins used strongly correlates with serum follicular FSH AUC in group II (r = 0:79, P = ) as does the serum follicular FSH Auc with the serum follicular P AUC (r = 0.43, P = 0.03) (Fig. 1). Oocyte and embryo data are presented in Table 2. The mean number of oocytes retrieved, the numbers of oocytes fertilized, and embryo quality were similar in the cycles with low and high serum P concentrations. The mean number of embryos replaced per cycle and the mean number of cryopreserved embryos per cycle did not differ in groups I and II. Total :J' ~12.5,5 u 10 ::> < ~ o~----~----~----~----~----~--~ FSH AUC (miu/ml) Figure 1 Regression analysis of the serum follicular P AUC as a function of the serum follicular FSH AUC in group II (P ~ 1.1 ng/ml) of cycles (r = 0.43, P = 0.03). Ubaldi et al. FSH and premature luteinization 277

4 Table 2 Comparison of the IVF Outcome in the Two Groups of Patients No. of oocytes retrieved* No. of mature oocytes* Two pronuclear fertilization rate (%) Embryo quality Excellent (type A)* Good (type B)* Fair (type C)* Embryos transferred per cycle* Embryos cryopreserved per cycle* No. of cycles with no ETt * Values are means ± SD. t Values in parentheses are percentages. Follicular serum P :50.9 nglml ;;;,:1.1 nglml (n = 148) (n = 23) 11.2 ± ± ± ± ± ± ± /148 (4.7) 13.6 ± ± ± ± ± ± ± /23 (4.3) pregnancy rates per cycle (including one biochemical pregnancy observed in group I), implantation rates, clinical pregnancy rates per cycle and per transfer, and miscarriage rates as well as delivery rates were similar in both groups (Table 3). DISCUSSION The increasing attention to the premature luteinization, usually defined as serum P levels > 0.9 ng/ ml occurring before hcg administration, is because of the controversy as to whether increased P levels have a detrimental effect on the outcome ofivf-et. Some authors (2-4) reported reduced implantation and pregnancy rates, suggesting reduced fertilization rates and embryo quality (4) or an impaired endometrial environment (2, 3) as a possible cause of this phenomenon. In contrast with these reports, other authors (5, 6) reported similar pregnancy rates in patients with high or low follicular serum P. Similarly, we were not able to observe any difference with regard to oocyte and embryo quality, implantation rates, and pregnancy rates in those two groups of patients (Ubaldi F, Wisanto A, Liu J, Joris H, Smitz J, Van Steirteghem A, et ai., abstract). The etiology of premature luteinization in patients undergoing COH with a combination of urinary gonadotropins and GnRH-a is not clear. Although pituitary desensitization is reported to eliminate both immunoactive and bioactive LH surges 0), in some patients incomplete suppression of bioactive LH occurs. This may be sufficient to stimulate granulosa cells to produce P but inadequate for triggering ovulation (17). Recently, another etiology for premature luteinization in GnRH-a and hmg cycles was suggested. Because the presence of hcg in hmg is.well docu- 278 Ubaldi et al. FSH and premature luteinization mented (8) as well as the possibility of its accumulation in serum during hmg cycles (8), the serum accumulation of hcg from the hmg preparations used for ovarian hyperstimulation could be responsible for premature serum Prise. Copperman et ai. (7) reported higher follicular phase serum concentrations ofhcg, as measured by AUC, in women undergoing GnRH-a and hmg cycles with increased serum P levels before hcg administration. Moreover, in this group of patients, they observed a strong linear correlation (P < 0.001) between the levels of hcg and the serum P levels but not between the serum P and LH and between the serum hcg and the number of ampules ofhmg used. These data suggest that premature luteinization could be due to increased serum hcg accumulation, that most likely it is not related to the number of ampules of hmg administered but to the differences in clearance between individuals or to the differences in the amount of hcg between lots of hmg (9). If this was the unique etiology of premature luteinization, the use of urinary FSH, practically devoid of LH activity (FSH 75 IU and LH < 0.7 IU) (10), or the use of recombinant FSH, with a negligible intrinsic LH bioactivity less than one tenth that of urinary FSH (9), should avoid premature Prise. However, in a previous report (20) and in the present study, we observed premature luteinization in patients who underwent COH by using GnRH-a in combination either with recombinant FSH or urinary FSH for IVF-ET in a similar ratio (23/171 cycles, 13.4%) as reported in previous studies with the use of hmg (2-6). Our results show that in group II (P ~ 1.1 ng/ml), although the number of days of stimulation were similar to group I, the number of ampules of gonadotropins (recombinant FSH and urinary FSH) used were significantly higher (P = 0.05) and strongly correlated (r = 0.79, P = ) with the serum follicular levels of FSH, as measured by AUC, observed in the same group. Similar results Table 3 Comparison of the Clinical Outcome in the Two Groups of Patients Total pregnancy rate per cycle Clinical pregnancy rate per cycle (%) Clinical pregnancy rate per ET (%) Implantation rate (%) Miscarriage rate (%) Delivery rate per cycle (%) Delivery rate per ET (%) Follicular serum P :50.9 nglml ;;;,:1.1 nglml (n = 148) (n = 23) 29.7 (441148) 29.0 (43/148) 30.5 (43/141) 17.2 (59/342) 20.9 (9/43) 22.9 (34/148) 24.1 (341141) 30.4 (7/23) 30.4 (7/23) 31.8 (7/22) 20.3 (11/54) 28.5 (217) 21.7 (5/23) 22.7 (5/22) Fertility and Sterility

5 I J were observed in group II-recombinant FSH (P = 0.01). In group II-urinary FSH, however, though the number of ampules of urinary FSH used was higher when premature luteinization occurred (46.6 ± 19.2 versus 40.2 ± 17.3), statistical significance was not reached, maybe because of the small number of cycles. An analysis of the endocrine parameters during the follicular phase in the cycles with premature luteinization (group II, group II-urinary FSH, and group II-recombinant FSH) revealed higher sustained levels of FSH during the midlate follicular phase, as measured by the AUC (Table 1), that correlated with serum P levels (r = 0.43, P = 0.03) (Fig. 1). These data support the hypothesis that, because LH receptors develop in granulosa cells as a result of FSH stimulation, higher FSH levels, due to an increased amount of gonadotropins administered, might be responsible for an increased LH receptivity, so that P production could be present even in the presence of low levels of serum LH (21). This phenomenon also could be one of the possible factors inducing premature luteinization in hmg cycles. With regard to the controversy as to whether premature luteinization has a detrimental effect on the IVF-ET outcome, in the present study we did not observe differences in the mean number of oocytes retrieved and in the mean number of mature oocytes in the cycles with or without premature luteinization (Table 2). Fertilization rates and the quality of the embryos were similar in the two groups of cycles as well as the mean number of embryos replaced, the mean number of the embryos frozen per cycle, and the number of cycles with no ET (Table 2). Similarly, no differences either in implantation and pregnancy rates or in miscarriage and delivery rates were observed in the two groups of cycles (Table 3). These data confirm those presented by other authors (5, 6). Nevertheless, in several reports, a decrease in pregnancy and implantation rates was observed in patients with premature luteinization (2-5). Recently, it was suggested that a possible decreased implantation rate in patients with premature Prise most likely is related to the decreased endometrial receptivity rather than to the oocyte and, hence, embryo quality (3, 22, 23). In conclusion, the etiology of premature luteinization and the mechanisms through which premature P rise could have a potential adverse effect on pregnancy outcome are not yet clear. From the results of this study it seems that one of the possible factors inducing premature luteinization is the greater integrated FSH exposure, as measured by AUC, due to an increased number of ampules of recombinant FSH and urinary FSH administered. Moreover, once again, the IVF and clinical outcome of the cycles with premature luteinization was similar to the cycles with normal follicular serum P. However, further studies assessing the endometrial receptivity are required. REFERENCES 1. Cedars MI, Surey E, Hamilton F, Lapolt P, Meldrum DR. Leuprolide acetate lowers bioactive luteinizing hormone and testosterone concentrations during ovarian stimulation for oocyte retrieval. Fertil Steril1990;53: Silverberg KM, Burns WN, Olive DL, Riehl RM, Shenken RS. Serum progesterone levels predict success of in vitro fertilization/embryo transfer in patients stimulated with leuprolide acetate and human menopausal gonadotropins. J Clin Endocrinol Metab 1991;73: Fanchin R, de Ziegler D, Taieb J, Hazout A, Frydman R. Premature elevation of plasma progesterone alters pregnancy rates ofin vitro fertilization and embryo transfer. Fertil Steril 1993;59: Harada T, Yoshida S, Katagiri C, Takao N, Ikenari T, Toda T, et al. Reduced implantation rate associated with a subtle rise in serum progesterone concentration during the follicular phase of cycles stimulated with a combination of a GnRH-a and gonadotropin. Hum Reprod 1995;10: Edelstein MC, Seltman HJ, Cox BJ, Robinson SM, Shaw RA, Muasher SJ. Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome. Fertil Steril1990;54: Givens CR, Schriock ED, Dandekar PV, Martin MC. Elevated serum progesterone levels on the day of human chorionic gonadotropin administration do not predict outcome in assisted reproduction cycles. Fertil Steril 1994;62: Copperman AB, Horowitz GM, Kaplan P, Scott RT, Navot D, Hofmann GE. Relationship between circulating human chorionic gonadotropin levels and premature luteinization in cycles of controlled ovarian hyperstimulation. Fertil Steril 1995;63: Stokman PGW, de Leeuw R, van den Wijngaard HAGW, Kloosterboer HJ, Verner HM, Sanders ALM. Human chorionic gonadotropin in commercial human menopausal gonadotropin preparations. Fertil Steril 1993;60: Mannaerts B, De Leeuw R, Geelen J, Van Ravestein A, Van Wezenbeek P, Shuurs A, et al. Comparative in vitro and in vivo studies on the biological characteristics of recombinant human follicle-stimulating hormone. Endocrinology 1991; 129: Shaw RW, Ndukwe G, Imoedemhe DA, Bernard AG, Burford G. Twin pregnancy after pituitary desensitization with LHRH agonist and pure FSH. Lancet 1985;2: World Health Organization. WHO laboratory manual for the examination of human semen and sperm cervical mucus interaction. 3rd ed. New York: Cambridge University Press, Smitz J, Devroey P, Braeckmans P, Camus M, Khan I, Staessen C, et al. Management of failed cycles in an IVF/GIFT programme with the combination of a GnRH analogue and HMG. Hum Reprod 1987;2: Smitz J, Van Den Abbeel E, Bollen N, Camus M, Devroey P, Tournaye H, et al. The effect of gonadotropin-releasing hormone (GnRH) agonist in the follicular phase on in vitro fertilization outcome in normo-ovulatory women. Hum Reprod 1992;7: Ubaldi et al. FSH and premature luteinization 279

6 14. Khan I, Staessen C, Van den Abbeel E, Camus M, Wisanto A, Smitz J, et al. Time of insemination and its effect on invitro fertilization, cleavage and pregnancy rates in GnRH agonistlhmg-stimulated cycles. Hum Reprod 1989;4: Staessen C, Van den Abbeel E, Janssenswillen C, Devroey P, Van Steirteghem A. Controlled comparison of Earle's balanced salt solution with Menezo B2 medium for in-vitro fertilization performance. Hum Reprod 1994;9: Smitz J, Devroey P, Faguer B, Bourgain C, Camus M, Van Steirteghem A. A prospective randomized comparison of intramuscular or intravaginal natural progesterone as luteal phase and early pregnancy supplementation. Hum Reprod 1992;7: Hofmann GE, Bergh PA, Guzman I, Masuku S, Navot D. Premature luteinization is not eliminated by pituitary desensitization with leuprolide acetate in women undergoing gonadotropin stimulation who demonstrated premature luteinization in a prior gonadotrophin-only cycle. Hum Reprod 1993;8: Rodgers M, McLoughlin J, Peers N, Anderson J, Woods P, Mitchell GG, et al. Accumulation of human chorionic gonado- tropin in the serum of patients during in-vitro fertilization treatment cycles with Pergonal. Hum Reprod 1994;9: Stone BA, Quinn K, Quinn P, Vargyas JM, Marrs RP. Responses of patients to different lots of menopausal gonadotropins during controlled ovarian hyperstimulation. Fertil Steril 1989;52: Ubaldi F, Smitz J, Bourgain C, Van Steirteghem AC, Devroey P. Pregnancy and birth after high serum progesterone levels during the follicular phase in an in-vitro fertilization cycle with gonadotropin-releasing hormone agonist suppression. Hum Reprod 1995;1: Channing CP, Kammerman S. Binding of gonadotropins to ovarian cells. BioI Reprod 1974;10: Hofmann GE, Bentzien F, Bergh PA, Garrisi GJ, Williams MC, Guzman I, et al. Premature luteinization in controlled ovarian hyperstimulation has no adverse effect on oocyte and embryo quality. Fertil Steril 1993;60: Legro RS, Ary BR, Paulson RJ, Stanczyk FZ, Sauer MY. Premature luteinization as detected by elevated serum progesterone is associated with a higher pregnancy rate in donor oocyte in-vitro fertilization. Hum Reprod 1993;8: Ubaldi et al. FSH and premature luteinization Fertility and Sterility