Minimal stimulation using gonadotropin-releasing hormone (GnRH) antagonist and recombinant human follicle-stimulating hormone versus GnRH antagonist multiple-dose protocol in low responders undergoing in vitro fertilization/intracytoplasmic sperm injection

This prospective randomized study was performed to investigate the effectiveness of minimal stimulation using recombinant human FSH (rhFSH) and GnRH antagonist compared with GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection. Our study demonstrated that minimal stimulation in natural cycles provides similar pregnancy rates to the GnRH antagonist MDP with fewer dose and days of rhFSH used and thus can be a cost-effective alternative as a last chance before oocyte donation in low responders. This prospective randomized study was performed to investigate the effectiveness of minimal stimulation using recombinant human FSH (rhFSH) and GnRH antagonist compared with GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection. Our study demonstrated that minimal stimulation in natural cycles provides similar pregnancy rates to the GnRH antagonist MDP with fewer dose and days of rhFSH used and thus can be a cost-effective alternative as a last chance before oocyte donation in low responders. Controlled ovarian stimulation (COS) has contributed to improving the pregnancy rates of women who have undergone IVF by increasing the number of developing follicles and oocytes. However, whatever COS protocol is used, low responders who are characterized by a diminished ovarian reserve (1Pellicer A. Ardiles G. Neuspiller F. Remohi J. Simon C. Bonilla-Musoles F. Evaluation of the ovarian reserve in young low responders with normal basal levels of follicle-stimulating hormone using three-dimensional ultrasonography.Fertil Steril. 1998; 70: 671-675Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar) most commonly require a large dose of gonadotropins and also fail to respond adequately. Therefore, they may benefit from natural cycle IVF treatment (2Bassil S. Godin P.A. Donnez J. Outcome of in-vitro fertilization through natural cycles in poor responders.Hum Reprod. 1999; 14: 1262-1265Crossref PubMed Scopus (91) Google Scholar, 3Feldman B. Seidman D.S. Levron J. Bider D. Shulman A. Shine S. et al.In vitro fertilization following natural cycles in poor responders.Gynecol Endocrinol. 2001; 15: 328-334PubMed Google Scholar). Natural cycle IVF is low risk and patient friendly and moreover allows the transfer of a single embryo into a more physiologic and receptive endometrial environment. However, its efficacy is much reduced by high cancellation rates because of premature LH surge and premature ovulation. These problems can be eliminated by using a GnRH antagonist. Actually, several investigators have reported that minimal stimulation using GnRH antagonists in the late follicular phase may be a feasible alternative in poor responders (4Weghofer A. Margreiter M. Bassim S. Sevelda U. Beilhack E. Feichtinger W. Minimal stimulation using recombinant follicle-stimulation hormone and a gonadotropin-releasing hormone antagonist in women of advanced age.Fertil Steril. 2004; 81: 1002-1006Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Elizur S.E. Aslan D. Shulman A. Weisz B. Bider D. Dor J. Modified natural cycle using GnRH antagonist can be an optional treatment in poor responders undergoing IVF.J Assist Reprod Genet. 2005; 22: 75-79Crossref PubMed Scopus (47) Google Scholar). However, a prospective noncontrolled study by Kolibianakis et al. (6Kolibianakis E. Zikopoulos K. Camus M. Tournaye H. Steirteghem A.V. Devroey P. Modified natural cycle for IVF does not offer a realistic chance of parenthood in poor responders with high day 3 FSH levels, as a last resort prior to oocyte donation.Hum Reprod. 2004; 19: 2545-2549Crossref PubMed Scopus (70) Google Scholar) showed a disappointing pregnancy outcome. So far, there are limited data with inconsistent results on minimal stimulation using GnRH antagonist in low responders. This prospective randomized study was performed to investigate the effectiveness of minimal stimulation using GnRH antagonist and FSH during the late follicular phase compared with the GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection (ICSI) at a university-based infertility clinic at the Asan Medical Center, Seoul, South Korea. The study population consisted of 90 low responders who had undergone 90 IVF/ICSI cycles. A low responder was defined as a patient who failed to produce three or fewer follicles with a mean diameter of at least 16 mm with the result that three or fewer oocytes were retrieved despite the use of a high gonadotropin dose (>2500 IU) in previous failed IVF/ICSI cycles. The Institutional Review Board of the University of Ulsan College of Medicine, Asan Medical Center, approved the study, and all patients provided written informed consent. Patients were randomly allocated into the minimal stimulation group (n = 45) or the GnRH antagonist MDP group (n = 45) by the use of sealed envelopes and a computer-generated list. All patients had regular ovulatory cycles (duration 21–35 days). They were in good health with normal thyroid, hepatic, and renal functions, and they had experienced spontaneous onset of puberty and normal sexual development. None of the subjects had taken any infertility medications (clomiphene and/or gonadotropins) within the preceding 3 months. For the minimal stimulation group, cycle monitoring was started on cycle day 7 or 8 by transvaginal ultrasound and repeated daily or every other day, according to the size of the dominant follicle. SC injections of 0.25 mg GnRH antagonist cetrorelix (Cetrotide, Merck Serono SA, Geneva, Switzerland) and 150 IU recombinant human FSH (rhFSH; Gonal-F, Merck Serono SA) were started concomitantly when the lead follicle reached 13–14 mm in a mean diameter and was continued daily until the day of hCG injection. When the mean diameter of the lead follicle reached 17–18 mm, 250 μg recombinant hCG (rhCG; Ovidrel, Merck Serono SA) was administered SC to induce follicular maturation. For GnRH antagonist MDP group, rhFSH (Gonal-F) at a dose of 225 IU/day was administered daily from the third day of the menstrual cycle. The dose of rhFSH was adjusted according to ovarian response every 3–4 days. When the mean diameter of the lead follicle reached 13 to ∼14 mm, cetrorelix (Cetrotide) at a dose of 0.25 mg/day was started and continued daily up to the day of hCG injection. When the mean diameter of the lead follicle reached 17–18 mm, 250 μg rhCG (Ovidrel) was administered SC. In both groups, transvaginal ultrasound–guided oocyte retrieval was performed 34–35 hours after hCG injection, and one to four embryos after IVF or ICSI were transferred into the uterus on the third day after oocyte retrieval. Luteal support was provided by administering 90 mg of vaginal P gel (Crinone gel 8%, Merck Serono SA) once daily from the day of oocyte retrieval. The mean value was expressed as the mean ± SD. Student's t-test was used to compare the mean values. The χ2-test and Fisher's exact test were used for the comparisons of fractions. Statistical significance was defined as P<.05. All analyses were performed using the SPSS statistical package for Windows, version 11.0 (SPSS Inc., Chicago). There were no differences in the age of patients and spouses, duration of infertility, body mass index, the proportion of nullipara, antral follicle count, and basal endocrine profile between the minimal stimulation and GnRH antagonist MDP groups. In the minimal stimulation group, four out of 45 cycles initiated (8.9%) did not result in oocyte retrieval owing to no follicular development (n = 1) or premature ovulation (n = 3). In four out of 41 cycles (9.8%) in which oocyte retrieval was performed, no oocytes were retrieved. Overall, eight out of 45 cycles initiated (17.8%) had to be cancelled before ET because no oocytes were available. In the GnRH antagonist MDP group, two out of 45 cycles initiated (4.4%) were cancelled before oocyte retrieval owing to no follicular development (n = 1) or premature ovulation (n = 1). In one out of 43 cycles (2.3%) in which oocyte retrieval was performed, no oocytes were obtained. Overall, three out of 45 cycles initiated (6.7%) were cancelled before ET. There was no significant difference in the overall cycle cancellation rate between the two groups, although the former showed a higher value (Table 1). The numbers of oocytes, mature oocytes, fertilized oocytes, grade 1 or 2 embryos, and embryos transferred were also significantly lower in the minimal stimulation group (P<.001, P<.001, P<.001, P=.007, and P<.001, respectively). However, total dose and days of rhFSH required for COS were significantly fewer in the minimal stimulation group than in the GnRH antagonist MDP group (P<.001, P<.001). The duration of GnRH antagonist administration was also shorter in the minimal stimulation group (P=.001). The clinical pregnancy rates per cycle initiated and per cycle ET of the minimal stimulation group were similar to those of the GnRH antagonist MDP group. Live-birth rates per ET and implantation rates were also comparable between the two groups (Table 1).Table 1Comparison of controlled ovarian stimulation results and IVF/ICSI outcome. Minimal stimulationGnRH antagonist MDPPNo. of patients4545No. of cycles initiated4545No. of cycles retrieved (%)41 (91.1)43 (95.6)NSaχ2-test or Fisher's exact test.No. of ET cycles (%)37 (82.2)42 (93.3)NSaχ2-test or Fisher's exact test.Cancellation rate, %17.8 (8/45)6.7 (3/45)NSaχ2-test or Fisher's exact test.No. of cycles with ICSI (%)19 (51.4)19 (45.2)NSaχ2-test or Fisher's exact test.Days of rhFSH4.1 ± 1.010.7 ± 1.6<.001bStudent's t-test.Total dose of rhFSH, IU607.2 ± 147.42652.8 ± 399.7<.001bStudent's t-test.Days of GnRH antagonist4.1 ± 1.05.0 ± 1.3.001bStudent's t-test.Endometrial thickness on hCG day, mm10.2 ± 1.510.4 ± 1.8NSbStudent's t-test.No. of oocytes retrieved (range)1.5 ± 0.9 (0–3)3.1 ± 1.6 (0–7)<.001bStudent's t-test.No. of mature oocytes (range)1.3 ± 0.8 (0–3)2.5 ± 1.4 (0–6)<.001bStudent's t-test.No. of fertilized oocytes (range)1.2 ± 0.8 (0–3)2.4 ± 1.4 (0–5)<.001bStudent's t-test.No. of grade 1, 2 embryos (range)0.8 ± 0.7 (0–2)1.2 ± 0.8 (0–3).007bStudent's t-test.No. of embryos transferred1.3 ± 0.82.2 ± 1.0<.001bStudent's t-test.Clinical PR/cycle initiated (%)13.3 (6/45)17.8 (8/45)NSaχ2-test or Fisher's exact test.Clinical PR/cycle completed (%)16.2 (6/37)19.0 (8/42)NSaχ2-test or Fisher's exact test.Miscarriage rate per clinical pregnancy, %16.7 (1/6)12.5 (1/8)NSaχ2-test or Fisher's exact test.Live birth rate/ET, %13.5 (5/37)16.7 (7/42)NSaχ2-test or Fisher's exact test.Twin PR/clinical pregnancy, %012.5 (1/8)NSaχ2-test or Fisher's exact test.Implantation rate, %12.5 (6/48)9.8 (9/92)NSaχ2-test or Fisher's exact test.Note: Values are means ± SDs. PR = pregnancy rate; NS = not significant.a χ2-test or Fisher's exact test.b Student's t-test. Open table in a new tab Note: Values are means ± SDs. PR = pregnancy rate; NS = not significant. This is the first prospective randomized study to evaluate the effectiveness of minimal stimulation using GnRH antagonist and rhFSH compared with GnRH antagonist MDP in low responders undergoing IVF/ICSI. The management for low responders with diminished ovarian reserve is still a challenge, although many studies have been performed to find a method of efficient COS for infertile women with reduced ovarian reserve. Even the most prevalent COS regimes such as the GnRH agonist low-dose long protocol, GnRH agonist flare-up regimes, and GnRH antagonist protocols in low responders often result in poor clinical outcome and high expenditure due to the large doses of gonadotropins administered. Therefore, the use of natural cycles in IVF-ET has been proposed as a low-risk, low-cost, and patient-friendly approach (2Bassil S. Godin P.A. Donnez J. Outcome of in-vitro fertilization through natural cycles in poor responders.Hum Reprod. 1999; 14: 1262-1265Crossref PubMed Scopus (91) Google Scholar, 3Feldman B. Seidman D.S. Levron J. Bider D. Shulman A. Shine S. et al.In vitro fertilization following natural cycles in poor responders.Gynecol Endocrinol. 2001; 15: 328-334PubMed Google Scholar). However, high cancellation rates due to premature ovulation is a serious disadvantage of natural cycle IVF. To reduce these problems, daily injection of GnRH antagonist was started at a follicle size of 13–14 mm in natural cycles. To avoid retarded follicular growth by an anticipated decline in the E2 level, 150 IU of rhFSH was administered concomitantly. This combined treatment, so-called minimal stimulation, was employed to ensure optimized follicular development and controllable ovulation in natural cycles for IVF. Indeed, premature ovulation was not always prevented, despite the administration of GnRH antagonist. It may result from estrogen levels high enough to induce an LH increase before the start of GnRH antagonist administration. In our prospective study, the cancellation rate in the minimal stimulation group was higher, 17.8%, compared with 6.7% in the GnRH antagonist MDP group, but the difference did not achieve the statistical significance. Our current study revealed that the minimal stimulation in natural cycles can be as efficacious as GnRH antagonist MDP. Moreover, minimal stimulation can benefit the low responders by reducing the amount of gonadotropins and the number of days of stimulation required for follicular maturation, compared with the standard COS regimes. Also, oocyte retrieval is easy and short lasting and can be performed without anesthesia or analgesia because usually only one or two follicles are aspirated. In addition, this method has the merit of allowing the procedure to be carried out again in the following cycle without having a resting cycle after a failed previous cycle. The minimal stimulation can be employed as a last chance before oocyte donation for low responders who failed to respond adequately despite the high dose of gonadotropins administered. Minimal stimulation protocols can also be useful for infertile women who have failed to conceive repeatedly after several IVF-ET cycles using standard COS protocols with the possibility that the high-dose gonadotropins caused an abnormal endometrial environment inhibiting implantation. In conclusion, the present study suggests that the minimal stimulation protocol in natural cycles provides similar pregnancy rates to GnRH antagonist MDP with fewer doses and days of rhFSH and thus can be a patient-friendly and cost-effective alternative in low responders.