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A prospective, randomized, controlled study to compare two doses of recombinant human chorionic gonadotropin in serum and follicular fluid in woman with high body mass index

2009; Elsevier BV; Volume: 93; Issue: 6 Linguagem: Inglês

10.1016/j.fertnstert.2009.08.026

1556-5653

Semra Kahraman, G. Karlikaya, Mustecep Kavrut, H. Karagozoglu,

Assisted Reproductive Technology and Twin Pregnancy

This prospective, randomized, controlled study compares the efficiency of 250 μg or 500 μg of recombinant hCG in serum and follicular fluid (FF) levels and pregnancy rates (PR) in women with high body mass index (BMI) (≥26 kg/m2) undergoing assisted reproduction treatment (ART). Treatment outcomes are similar between the two groups. This prospective, randomized, controlled study compares the efficiency of 250 μg or 500 μg of recombinant hCG in serum and follicular fluid (FF) levels and pregnancy rates (PR) in women with high body mass index (BMI) (≥26 kg/m2) undergoing assisted reproduction treatment (ART). Treatment outcomes are similar between the two groups. Final maturation of the oocytes is achieved through the administration of a timed injection of hCG. The success of mature oocyte retrieval is dependent on serum concentrations of hormone reaching values capable of initiating meiosis and triggering the release of the cumulus–oocyte complex into the follicular fluid (FF) (1Salha O. Dada T. Sharma V. Influence of body mass index and self-administration of hCH on the outcome of IVF cycles: a prospective cohort study.Hum Fertil. 2001; 4: 37-42Crossref Scopus (48) Google Scholar). For decades hCG derived from urine was available and used during IVF cycles. More recently recombinant hCG became available. Several clinical studies have shown that the two hCG preparations had a similar results in terms of obtained number of oocytes, clinical and ongoing pregnancies, delivery and miscarriage rates (2Driscoll G.L. Tyler J.P.P. Hangan J.T. Fisher P.R. Birdsall M.A. Knight D.C. A prospective, randomized, controlled, double-blind, double-dummy comparison of recombinant and urinary HCG for inducing oocyte maturation and follicular luteinization in ovarian stimulation.Hum Reprod. 2000; 15: 1305-1310Crossref PubMed Scopus (74) Google Scholar, 3Chang P. Kenley S. Burns T. Denton G. Currie K. DeVane G. et al.Recombinant human chorionic gonadotropin (rhCG) in assisted reproductive technology: results of a clinical trial comparing two doses of rhCG (Ovidrel®) to urinary hCG (Profasi®) for induction of final follicular maturation in in vitro fertilization–embryo transfer.Fertil Steril. 2001; 76: 67-74Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 4The European Recombinant Human Chorionic Gonadotrophin Study GroupInduction of final follicular maturation and early luteinization in woman undergoing ovulation induction for assisted reproduction treatment-recombinant HCG versus urinary HCG.Hum Reprod. 2000; 15: 1446-1451Crossref PubMed Google Scholar, 5Al-Inany H. Aboulghar M.A. Mansour R.T. Proctor M. Recombinant versus urinary gonadotrophins for triggering ovulation in assisted conception.Hum Reprod. 2005; 20: 2061-2073Crossref PubMed Scopus (37) Google Scholar, 6The International Recombinant Human Chorionic Gonadotropin Study GroupInduction of ovulation in World Health Organization group II anovulatory women undergoing follicular stimulation with recombinant human follicle-stimulating hormone: a comparison of recombinant human chorionic gonadotropin (rhCG) and urinary hCG.Fertil Steril. 2001; 75: 1111-1118Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 7Kovacs P. Kovats T. Bernard A. Zadori J. Szmatona G. Kaali S.G. Comparison of serum and follicular fluid hormone levels with recombinant and urinary human chorionic gonadotropin during in vitro fertilization.Fertil Steril. 2008; 90: 2133-2137Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). The effectiveness of 250 and 500 μg of recombinant hCG, which represented the lower and upper limits of the dose range, were compared to induce final oocyte maturation during IVF/intracytoplasmic sperm injection (ICSI) cycles and were found to be equally effective (8Chan C.C.W. Ng E.H.Y. Tang O.S. Yeung W.S.B. Lau E.Y.L. Ho P.C. A prospective, randomized, double-blind study to compare two doses of recombinant human chorionic gonadotropin in inducing final oocyte maturity and the hormonal profile during the luteal phase.J Clin Endocrinol Metab. 2005; 90: 3933-3938Crossref PubMed Scopus (26) Google Scholar). However, the problem of high body mass index (BMI) and response in obese patients to a standard amount of hCG may be an inherent problem of obesity and there are no data available yet on the use of recombinant hCG in obese patients (5Al-Inany H. Aboulghar M.A. Mansour R.T. Proctor M. Recombinant versus urinary gonadotrophins for triggering ovulation in assisted conception.Hum Reprod. 2005; 20: 2061-2073Crossref PubMed Scopus (37) Google Scholar). It may not be solved by a recombinant product as with urinary hCG. The adverse effect of obesity on natural fecundity has been reported (9Harlass F.F. Plymate S.R. Fariss B.L. Belts R.P. Weight loss is associated with correction of gonadotropin and sex steroid abnormalities in the obese anovulatory female.Fertil Steril. 1984; 42: 649-652Abstract Full Text PDF PubMed Google Scholar, 10Hollmann M. Runnebaum B. Gerhard I. Effects of weight loss on the hormonal profile in obese, infertile women.Hum Reprod. 1996; 11: 1884-1891Crossref PubMed Scopus (137) Google Scholar). In women undergoing assisted reproduction techniques (ART), obesity has been associated with the need for higher doses of gonadotropins, increased cycle cancellation rates, and fewer oocytes retrieved (11Fedorcsak P. Dale P.O. Storeng R. Ertzeid G. Bjercke S. Oldereid N. et al.Impact of overweight and underweight on assisted reproduction treatment.Hum Reprod. 2004; 19: 2523-2528Crossref PubMed Scopus (389) Google Scholar). Lower rates of embryo transfer, pregnancy, and live birth have also been reported, as have higher miscarriage rates (11Fedorcsak P. Dale P.O. Storeng R. Ertzeid G. Bjercke S. Oldereid N. et al.Impact of overweight and underweight on assisted reproduction treatment.Hum Reprod. 2004; 19: 2523-2528Crossref PubMed Scopus (389) Google Scholar, 12Wang J.X. Davies M. Norman R.J. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study.BMJ. 2000; 321: 1320-1321Crossref PubMed Scopus (280) Google Scholar). Therefore it is not clear which dose of recombinant hCG, 250 μg or 500 μg, is an effective dose to induce final oocyte maturation in obese patients, as there is no data in the literature. The aim of our study is to compare two doses of recombinant hCG in women with high BMI. To our knowledge this is the first study comparing the effectiveness of two recombinant hCG doses in obese woman in terms of serum and FF hCG levels, total and metaphase II (MII) oocytes obtained, and clinical parameters achieved. This prospective, controlled randomized study was done between December 2007 and December 2008 in Istanbul Memorial Hospital. The study was approved by the Institutional Review Board (IRB) of our institution and written consent was obtained from all participants. Patients with a BMI of 26 kg/m2 or higher (range 26–38 kg/m2) were accepted as eligible for the trial. Exclusion criteria included polycystic ovary syndrome (PCOS), a history of bad response to controlled ovarian hyperstimulation (COH), and a high basal FSH level >12 IU/mL. Patients underwent ovarian stimulation by standard midluteal phase GnRH agonist (Lucrin; Abbott, Abbott Park, IL) or GnRH antagonist (Cetrotide; Merck Serono, Istanbul, Turkey). Ovarian stimulation was administrated as recombinant FSH (Gonal-F; Merck Serono). When two or more follicles had attained a minimum mean diameter of 18 mm, follicular maturation was achieved using either 250 mg of recombinant hCG SC (Ovitrelle; Merck Serono, Geneva, Switzerland) or 500 mg of recombinant hCG SC according to a computer-based randomization list. Transvaginal ultrasound (TVUS)-guided oocyte retrieval was performed 36 hours after administration of recombinant hCG injection. After the retrieval, the oocytes were evaluated for maturity and ICSI was used for fertilization. The embryos were cultured 3–5 days before the transfer. The day of transfer and the number of embryos transferred were decided by the physician based on patient and cycle characteristics. Progesteron supplementation was continued until week 10 of pregnancy. Blood samples were taken from the antecubital vein just before the oocyte retrieval for determination of hCG concentration using an automated system. Follicular fluid aspirates were collected from several follicles. Pooled samples were stored at -20°C. Thawed aspirates of each patient's pooled FF were centriufigated to remove blood and granulosa cells (GC). To analyze serum and each patient's pooled FF concentrations of hCG, an automated chemiluminescence immunoassay (cobas; Roche Diagnostics, Indianapolis, IN) was used. The lower detection level of hCG was <0.1 mIU/mL. The primary end points were the mean number of oocytes retrieved per patient and the secondary end points were the serum and intrafollicular hCG levels on oocyte retrievel day, the mean number of mature oocytes, fertilization and pregnancy rates (PR), and ovarian hyperstimulation syndrome (OHSS) risks. All statistical analyses were performed using the SPSS 12.0 statistical package (SPSS Inc., Chicago, IL). Descriptive statistics were given as mean, median, SD, minimum, maximum for numeric variables, and also were given as number and percent for categorical variables. The χ2 test and Fisher's exact test were used to compare categorical variables between groups. Mann-Whitney U test was used to compare independent numerical variables because of abnormal distribution. Statistical significance was established if P≤.05. A total of 105 cycles were randomized and available for analysis. Of these, 54 hCG subjects with high BMI were injected SC with 250 μg of recombinant hCG and 51 cases received 500 μg of recombinant hCG SC. Baseline characteristics were comparable in the two groups (Table 1). Thus, the two recombinant hCG groups were essentially identical with respect to age, BMI, number of previous trial, FSH levels on day 3, duration of induction, the type of protocols used, and the total dose of gonadotropin injected. Also, the mean number of total and MII oocytes and their ratio, the mean number of fertilization with two pronuclei (2PN), and the mean number of embryos transferred was found not to be significantly different. Serum hCG levels were significantly lower in patients receiving 250 μg of recombinant hCG than in patients receiving 500 μg of recombinant hCG (P<.001). Similarly, the FF hCG levels on ovum pick-up day were significantly lower in the 250-μg recombinant hCG group than the 500-μg recombinant hCG group (P<.01). However the ratios of FF-to-serum hCG were identical in both groups. The overall PR was 57.4% in the 250-μg recombinant hCG group and 54.9% in the 500-μg recombinant hCG group. There was no significant difference in the PRs. Clinical PRs were 50% in the 250-μg recombinant hCG group versus 47.1% in the 500-μg recombinant hCG group (P=.763).Table 1Comparison of demographic and IVF outcomes of the study groups between two doses of recombinant hCG in woman with high body mass index (BMI).250μg (n = 54)500μg (n = 51)P valueAge (y)31.2 ± 4.332.2 ± 4.3.120aP values for Student's t-test.BMI29.7 ± 3.129.4 ± 2.9.599bP values for Mann-Whitney U test.No. of cycles2.3 ± 1.92.8 ± 2.2.167bP values for Mann-Whitney U test.Baseline FSH (IU/L)6.1 ± 2.57.5 ± 4.1.380aP values for Student's t-test.No. of days of stimulation9.2 ± 1.49.4 ± 1.2.326aP values for Student's t-test.Total dose of gonadotropin injected3,093.8 ± 1,335.43,157.6 ± 1,319.5.569No. of oocytes13.2 ± 5.212.6 ± 5.2.583aP values for Student's t-test.No. of MII oocytes10.3 ± 49.6 ± 4.5.290bP values for Mann-Whitney U test.MII/total oocytes0.8 ± 0.150.78 ± 0.18.772bP values for Mann-Whitney U test.No. of fertilized oocytes7.8 ± 3.77 ± 3.8.173bP values for Mann-Whitney U test.No. of transferred embryos2.4 ± 0.72.5 ± 0.7.522bP values for Mann-Whitney U test.Serum hCG levels on OPU day73.9 ± 18.8146 ± 48.1<.001aP values for Student's t-test.FF hCG levels on OPU day16 ± 12.435.9 ± 25.5<.001bP values for Mann-Whitney U test.Ratios of FF/serum hCG0.21 ± 0.170.24 ± 0.13.118bP values for Mann-Whitney U test.Pregnancy rate57.4%54.9%.796cP values for χ2 test.Clinical pregnancy rate50.0%47.1%.763cP values for χ2 test.Implantation rate0.60 ± 0.270.60 ± 0.26.937aP values for Student's t-test.Spontaneous abortion rate14.8%20.8%.574cP values for χ2 test.OHSS2 (3.7%)1 (1.9%)Note: Data are presented as mean ± SD.FF = follicular fluid; OHSS = ovarian hyperstimulation syndrome; BMI = body mass index; OPU = ovum pick-up; MII = metaphase II.a P values for Student's t-test.b P values for Mann-Whitney U test.c P values for χ2 test. Open table in a new tab Note: Data are presented as mean ± SD. FF = follicular fluid; OHSS = ovarian hyperstimulation syndrome; BMI = body mass index; OPU = ovum pick-up; MII = metaphase II. Similarly, implantation rates (28% at 250 μg vs. 26% at 500 μg recombinant hCG) were not significantly different. The ratio of moderate and severe OHSS was not significant (3.7% vs 1.9%, respectively). The lower dose generally did not allow serum levels to decrease less than 50 mIU/mL. When the patients were categorized according to their BMI (26–30 kg/m2 [mean BMI=28 kg/m2] and >30 kg/m2 [mean BMI=33 kg/m2]), there was no significant difference in the distribution of hCG doses between the groups. When 250 μg recombinant hCG was used, a significant difference was observed in the 26–30 kg/m2 (mean BMI=28 kg/m2) group compared to the >30 kg/m2 (mean BMI=33 kg/m2) group in terms of total oocytes and MII oocytes (P<.038 and P<.032). However, this difference was not strong statistically and did not affect the PRs. The ratio of MII oocytes-to-total ocytes, total pregnancy, implantation rates and clinical PRs were not significant in different BMI groups whether 250 μg or 500 μg recombinant hCG was injected. The lowest and the highest serum and FF hCG levels in patients where pregnancy was achieved were 43.3 mIU/mL and 95.5 mIU/mL in the 250-μg group and 59.3 mIU/mL and 252.8 mIU/mL in the 500-μg group, respectively, in serum, and 1.84 mIU/mL and 38.15 mIU/mL in the 250-μg group and 10 mIU/mL and 88.5 mIU/mL in the 500-μg group in FF, respectively. In infertile women undergoing ovulation induction, the use of hCG to achieve final follicular maturation and triggering follicular rupture is well established. Recombinant hCG is as effective as urinary hCG for induction of final follicular maturation as judged by several published studies (1Salha O. Dada T. Sharma V. Influence of body mass index and self-administration of hCH on the outcome of IVF cycles: a prospective cohort study.Hum Fertil. 2001; 4: 37-42Crossref Scopus (48) Google Scholar, 2Driscoll G.L. Tyler J.P.P. Hangan J.T. Fisher P.R. Birdsall M.A. Knight D.C. A prospective, randomized, controlled, double-blind, double-dummy comparison of recombinant and urinary HCG for inducing oocyte maturation and follicular luteinization in ovarian stimulation.Hum Reprod. 2000; 15: 1305-1310Crossref PubMed Scopus (74) Google Scholar, 3Chang P. Kenley S. Burns T. Denton G. Currie K. DeVane G. et al.Recombinant human chorionic gonadotropin (rhCG) in assisted reproductive technology: results of a clinical trial comparing two doses of rhCG (Ovidrel®) to urinary hCG (Profasi®) for induction of final follicular maturation in in vitro fertilization–embryo transfer.Fertil Steril. 2001; 76: 67-74Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 4The European Recombinant Human Chorionic Gonadotrophin Study GroupInduction of final follicular maturation and early luteinization in woman undergoing ovulation induction for assisted reproduction treatment-recombinant HCG versus urinary HCG.Hum Reprod. 2000; 15: 1446-1451Crossref PubMed Google Scholar, 5Al-Inany H. Aboulghar M.A. Mansour R.T. Proctor M. Recombinant versus urinary gonadotrophins for triggering ovulation in assisted conception.Hum Reprod. 2005; 20: 2061-2073Crossref PubMed Scopus (37) Google Scholar, 6The International Recombinant Human Chorionic Gonadotropin Study GroupInduction of ovulation in World Health Organization group II anovulatory women undergoing follicular stimulation with recombinant human follicle-stimulating hormone: a comparison of recombinant human chorionic gonadotropin (rhCG) and urinary hCG.Fertil Steril. 2001; 75: 1111-1118Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Another study compared the effects of 250 μg of recombinant hCG, 500 μg of recombinant hCG, and 10,000 IU of urinary hCG. It was shown that recombinant hCG is effective and well tolerated in the induction of final follicular maturation and luteinization in women undergoing ART. Recombinant hCG (250 μg) SC is equivalent to 10,000 IU of urinary hCG. In this study the numbers of 2PN fertilized oocytes, 2PN, and cleaved embryos on the day of embryo transfer were significantly higher with 500 μg of recombinant hCG than with the lower dose. However, the incidence of adverse events also tended to be higher with this dose (3Chang P. Kenley S. Burns T. Denton G. Currie K. DeVane G. et al.Recombinant human chorionic gonadotropin (rhCG) in assisted reproductive technology: results of a clinical trial comparing two doses of rhCG (Ovidrel®) to urinary hCG (Profasi®) for induction of final follicular maturation in in vitro fertilization–embryo transfer.Fertil Steril. 2001; 76: 67-74Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). A recent prospective randomized study has also found similar clinical outcomes with 250 μg of recombinant hCG or 7,500 IU urinary hCG during IVF treatment in normal responder patients (7Kovacs P. Kovats T. Bernard A. Zadori J. Szmatona G. Kaali S.G. Comparison of serum and follicular fluid hormone levels with recombinant and urinary human chorionic gonadotropin during in vitro fertilization.Fertil Steril. 2008; 90: 2133-2137Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). However, there is no data in the literature comparing two doses of recombinant hCG in women with a high BMI. In women undergoing ART, obesity has been associated with the need for higher doses of gonadotropins, increased cycle cancellation rates, and fever oocytes retrieved (11Fedorcsak P. Dale P.O. Storeng R. Ertzeid G. Bjercke S. Oldereid N. et al.Impact of overweight and underweight on assisted reproduction treatment.Hum Reprod. 2004; 19: 2523-2528Crossref PubMed Scopus (389) Google Scholar). Lower rates of embryo transfer, PR, and live birth have also been reported, as have higher miscarriage rates (11Fedorcsak P. Dale P.O. Storeng R. Ertzeid G. Bjercke S. Oldereid N. et al.Impact of overweight and underweight on assisted reproduction treatment.Hum Reprod. 2004; 19: 2523-2528Crossref PubMed Scopus (389) Google Scholar, 12Wang J.X. Davies M. Norman R.J. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study.BMJ. 2000; 321: 1320-1321Crossref PubMed Scopus (280) Google Scholar). However, other studies have been unable to find any negative impact of obesity on ART outcome (13Lashen H. Ledger W. Bernal A.L. Barlow D. Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilization.Hum Reprod. 1999; 14: 712-715Crossref PubMed Scopus (175) Google Scholar, 14Dechaud H. Anahory T. Reyftmann L. Loup V. Hamamah S. Hedon B. Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer.Euro J Obstet Gynecol Reprod Biol. 2006; 127: 88-93Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 15Esinler I. Bozdağ G. Yarali H. Impact of isolated obesity on ICSI outcome.RBM Online. 2008; 17: 583-587Scopus (78) Google Scholar). There are little data on the impact of isolated obesity on IVF/ICSI outcome without commonly associated disorders such as PCOS. Therefore, the results of the present study aim to evaluate the effects of using 250 μg or 500 μg of recombinant hCG on serum and intrafollicular hCG levels and PRs in woman with BMI ≥26 kg/m2. We have been able to provide an estimate of the difference between two the BMI groups (BMI 26–30 kg/m2 [mean BMI=28 kg/m2] vs. >30 kg/m2 [mean BMI=33 kg/m2]). We have considered BMI as a marker of obesity and patients with isolated obesity only were included. Presence of PCOS was accepted as an exclusion criterion. No difference in terms of obtained total or MII oocytes and cycle parameters was observed in patients with high BMI (≥26 kg/m2) whether 250 μg or 500 μg of recombinant hCG was injected for the final maturation of follicles. However, when the BMI was further categorized (BMI 26–30 kg/m2 vs. >30 kg/m2), a higher number of total and MII oocytes was obtained in patients given 250 μg of recombinant hCG, but the other cycle parameters were not effected. Furthermore, although FF and serum hCG levels were found to be markedly elevated in the 500-μg recombinant hCG group, the number of total and MII oocytes and the other cycle parameters remained unchanged. Similarly, cycle parameters, such as clinical pregnancy, implantation, and the occurance of moderate and severe OHSS, were also found to be nonsignificant in both total and categorized BMI groups. The risk of OHSS was not higher when higher doses of recombinant hCG was given. Within the parameters of this prospective randomized study we can conclude that 250 μg of recombinant hCG is sufficient and safe to trigger ovulation, even in women with a BMI higher than 26 kg/m2. No clinical or statistical advantage could be demonstrated for the higher dose of recombinant hCG in obese patients. However, well-designed, additional studies are necessary to draw a final conclusion.