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IRCT201108044339N8 IRCT 2011-09-15 Yazd Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences Estradiol administration for patients with a history of poor IVFresponse IVF Comparsion of luteal estradiol administration during GnRH antagonist protocol versus microdose GnRH agonist protocol for patients with a history of poor IVF out come 2011-03-01 anticipated 116 Complete https://irct.ir/trial/4622 interventional Randomization: Randomized, Blinding: Single blinded, Placebo: Not used, Assignment: Parallel, Purpose: Treatment, Randomization description: Patients are admitted to two groups of 58 patients based on permutation block method. Therapeutic tasks within the blocks are determined in such a way that they are random, but the desired allocation ratio is achieved in each block. 29 blocks of 4 are considered. Generate random codes using random block allocation method which will be generated with the help of Random allocation software version 1. The first person eligible to enter the study is given number one and so on until the last eligible person is given number 116. Using a table generated by random allocation software by number, people receive intervention A or B. In order to be blind, the random allocation of this list is given to another person outside the study, and by sending a text message before assigning the type of treatment, the eligible person is asked according to the number, and thus the people enter the study, Blinding description: The physicians performing the follicular aspiration blinded to the stimulation protocol. 2 Female infertility. Intervention 1: Fifty eight randomly selected women underwent IVF using the E2/antagonist protocol (E2/ANT group). In this group, estradiol (Aburaihan Pharmaceutical Co., Tehran, Iran) 2 mg was started orally twice a day on the 21st luteal day and continued until menstruation. Once menses began, estradiol was discontinued and gonadotropin stimulation was started on the2nd day of the menstrual cycle. Gonal-F (Gonal-F, Serono, Italy) at 225-300 IU/day was initiated from the second day of menses and was adjusted according to serum E2 concentrations and the ovarian response as noted by ultrasound. When the leading follicle reached 14 mm in diameter‚ Cetrorelix (Merck- Serono Germany) 0.25 mg SC was added and continued every day until and including the day of hCG administration. In both groups, 10,000 IU of hCG (pregnyl, Daropakhsh, Iran) was administered IM when at least two follicles reached ≥ 18 mm in diameter. The follicles were followed 36 hours later by ultrasound-guided transvaginal oocyte retrieval. The IVF and intracytoplasmic sperm injection (ICSI) procedures were performed, and the embryos were transferred on the third day after retrieval with a Labotect catheter (Labotect, Gotting, Germany). A good-quality embryo was defined as seven or more blastomeres on day 3‚equally sized blastomeres and < 20% fragmentation’ and poor-quality embryos consist of all the rest. The number of transferred embryos depended on the embryo quality and the patient’s age. All the patients received 100 mg of progesterone (Aburaihan Pharmaceutical Co., Tehran, Iran) IM per day for luteal support, which was initiated on the day of oocyte retrieval. Serum B-hCG was checked 14 days after the embryo transfer .If the patient was pregnant‚ progesterone was continued until the 10th week of pregnancy. Chemical pregnancy was defined as serum B-hCG >50 IU/L after 14 days from embryo transfer. Clinical pregnancy was defined as the presence of a gestational sac with heart beat identified by ultrasound five weeks after the embryo transfer. The implantation rate was defined as the ratio of gestational sacs to the number of embryos transferred and Clinical abortion rate was determined as clinically recognized pregnancy losses before 20 weeks of gestation. Criteria for cycle cancellation due to poor ovarian response included the presence of fewer than two growing follicles on ultrasound’ with an E2 level < 200 pg/ ml on day 7 of stimulation. Intervention 2: Control group consisted of 58 women who underwent ovarian stimulation for IVF using micro dose agonist protocol (micro dose group).In these patients, low-dose OCP (30 mcg Ethinyl Estradiol and 0.3mg Norgestrel, Aburaihan Pharmaceutical Co., Tehran, Iran) was started on the 2nd day of the previous cycle for 21 days. On the second day of menstruation, Suprefact (Buserelin acetate, Aventis Pharma Deutschland, Germany) 50 µg SC was started and continued twice a day until the day of hCG administration. After two days (on the fourth day of menstruation) Gonal-F was started at 225-300 IU/day .In these patients, like in the other group, the dose of Gonal –F was adjusted according to serum E2 concentrations and ovarian responses as noted by ultrasound. In both groups, 10,000 IU of hCG (pregnyl, Daropakhsh, Iran) was administered IM when at least two follicles reached ≥ 18 mm in diameter. The follicles were followed 36 hours later by ultrasound-guided transvaginal oocyte retrieval. The IVF and intracytoplasmic sperm injection (ICSI) procedures were performed, and the embryos were transferred on the third day after retrieval with a Labotect catheter (Labotect, Gotting, Germany). A good-quality embryo was defined as seven or more blastomeres on day 3‚equally sized blastomeres and < 20% fragmentation’ and poor-quality embryos consist of all the rest. The number of transferred embryos depended on the embryo quality and the patient’s age. All the patients received 100 mg of progesterone (Aburaihan Pharmaceutical Co., Tehran, Iran) IM per day for luteal support, which was initiated on the day of oocyte retrieval. Serum B-hCG was checked 14 days after the embryo transfer .If the patient was pregnant‚ progesterone was continued until the 10th week of pregnancy. Chemical pregnancy was defined as serum B-hCG >50 IU/L after 14 days from embryo transfer. Clinical pregnancy was defined as the presence of a gestational sac with heart beat identified by ultrasound five weeks after the embryo transfer. The implantation rate was defined as the ratio of gestational sacs to the number of embryos transferred and Clinical abortion rate was determined as clinically recognized pregnancy losses before 20 weeks of gestation. Criteria for cycle cancellation due to poor ovarian response included the presence of fewer than two growing follicles on ultrasound’ with an E2 level < 200 pg/ ml on day 7 of stimulation. https://link.springer.com/article/10.1007%2Fs00404-012-2522-0 Purpose This study aims to verify if luteal estradiol pre-treatment improves IVF/ICSI outcomes in a GnRH antagonist protocol as compared with a micro dose GnRH agonist protocol in poor-responding patients. Methods A total of 116 IVF/ICSI cycles were included in this prospective randomized single blind clinical trial. The selected women were randomly assigned to receive an estradiol pre-treatment in a GnRH antagonist protocol (daily oral Estradiol Valerate 4 mg preceding the IVF cycle from the 21st day until the first day of the next cycle) or in oral contraceptive pill micro dose GnRH agonist protocol. Results The patients in the luteal estradiol protocol required more days of stimulation (10.9 ± 1.6 vs. 10.2 ± 1.8) and a greater gonadotropin requirement (3,247.8 ± 634.6 vs. 2,994.8 ± 611 IU), yet similar numbers of oocytes were retrieved and fertilized. There was no significant difference between the two groups in terms of the implantation rates (9.8 vs. 7.9 %) and the clinical pregnancy rates per transfer (16.3 vs. 15.6 %). Conclusion This study demonstrates that the use of estradiol during a preceding luteal phase in a GnRH antagonist protocol can provide similar IVF outcomes when compared to a micro dose GnRH agonist protocol. Undecided - It is not yet known if there will be a plan to make this available Justification or reason for indecision in sharing IPD is Due to the privacy of patients
public Dr Mozhgan Rahsepar
Yazd Research and Clinical Center for Infertility, Booali Street, Safaieh, Yazd
Yazd Iran (Islamic Republic of) 8916877391 +98 35 1824 7085 drrahsepar@hotmail.com Yazd Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences scientific Dr Robab Davar
Yazd Research and Clinical Center for Infertility, Booali Street, Safaieh, Yazd
Yazd Iran (Islamic Republic of) 8916877391 +98 35 1824 7085 r_davar@yahoo.com Yazd Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences Iran (Islamic Republic of) A history of poor response in a prior cycle (≤3 oocytes retrieved, poor-quality oocytes, Cycle cancellation due to inadequate ovarian response Women anticipated to be a poor responder based on initial testing (third-day FSH level of 10 mIU/mL, or a basal antral follicle count <5) no limit no limit Female Stage III–IV endometriosis Autoimmune or chromosomal disorders Endocrine or metabolic diseases Existence of only one ovary Patients exhibiting a day 3 serum FSH level greater than 15 mIU/mL Sever male factor (patients with azoospermia and normal morphology of sperm <4%) Hydrosalpinx N97 Female infertility Treatment - Drugs Treatment - Drugs Fifty eight randomly selected women underwent IVF using the E2/antagonist protocol (E2/ANT group). In this group, estradiol (Aburaihan Pharmaceutical Co., Tehran, Iran) 2 mg was started orally twice a day on the 21st luteal day and continued until menstruation. Once menses began, estradiol was discontinued and gonadotropin stimulation was started on the2nd day of the menstrual cycle. Gonal-F (Gonal-F, Serono, Italy) at 225-300 IU/day was initiated from the second day of menses and was adjusted according to serum E2 concentrations and the ovarian response as noted by ultrasound. When the leading follicle reached 14 mm in diameter‚ Cetrorelix (Merck- Serono Germany) 0.25 mg SC was added and continued every day until and including the day of hCG administration. In both groups, 10,000 IU of hCG (pregnyl, Daropakhsh, Iran) was administered IM when at least two follicles reached ≥ 18 mm in diameter. The follicles were followed 36 hours later by ultrasound-guided transvaginal oocyte retrieval. The IVF and intracytoplasmic sperm injection (ICSI) procedures were performed, and the embryos were transferred on the third day after retrieval with a Labotect catheter (Labotect, Gotting, Germany). A good-quality embryo was defined as seven or more blastomeres on day 3‚equally sized blastomeres and < 20% fragmentation’ and poor-quality embryos consist of all the rest. The number of transferred embryos depended on the embryo quality and the patient’s age. All the patients received 100 mg of progesterone (Aburaihan Pharmaceutical Co., Tehran, Iran) IM per day for luteal support, which was initiated on the day of oocyte retrieval. Serum B-hCG was checked 14 days after the embryo transfer .If the patient was pregnant‚ progesterone was continued until the 10th week of pregnancy. Chemical pregnancy was defined as serum B-hCG >50 IU/L after 14 days from embryo transfer. Clinical pregnancy was defined as the presence of a gestational sac with heart beat identified by ultrasound five weeks after the embryo transfer. The implantation rate was defined as the ratio of gestational sacs to the number of embryos transferred and Clinical abortion rate was determined as clinically recognized pregnancy losses before 20 weeks of gestation. Criteria for cycle cancellation due to poor ovarian response included the presence of fewer than two growing follicles on ultrasound’ with an E2 level < 200 pg/ ml on day 7 of stimulation. Control group consisted of 58 women who underwent ovarian stimulation for IVF using micro dose agonist protocol (micro dose group).In these patients, low-dose OCP (30 mcg Ethinyl Estradiol and 0.3mg Norgestrel, Aburaihan Pharmaceutical Co., Tehran, Iran) was started on the 2nd day of the previous cycle for 21 days. On the second day of menstruation, Suprefact (Buserelin acetate, Aventis Pharma Deutschland, Germany) 50 µg SC was started and continued twice a day until the day of hCG administration. After two days (on the fourth day of menstruation) Gonal-F was started at 225-300 IU/day .In these patients, like in the other group, the dose of Gonal –F was adjusted according to serum E2 concentrations and ovarian responses as noted by ultrasound. In both groups, 10,000 IU of hCG (pregnyl, Daropakhsh, Iran) was administered IM when at least two follicles reached ≥ 18 mm in diameter. The follicles were followed 36 hours later by ultrasound-guided transvaginal oocyte retrieval. The IVF and intracytoplasmic sperm injection (ICSI) procedures were performed, and the embryos were transferred on the third day after retrieval with a Labotect catheter (Labotect, Gotting, Germany). A good-quality embryo was defined as seven or more blastomeres on day 3‚equally sized blastomeres and < 20% fragmentation’ and poor-quality embryos consist of all the rest. The number of transferred embryos depended on the embryo quality and the patient’s age. All the patients received 100 mg of progesterone (Aburaihan Pharmaceutical Co., Tehran, Iran) IM per day for luteal support, which was initiated on the day of oocyte retrieval. Serum B-hCG was checked 14 days after the embryo transfer .If the patient was pregnant‚ progesterone was continued until the 10th week of pregnancy. Chemical pregnancy was defined as serum B-hCG >50 IU/L after 14 days from embryo transfer. Clinical pregnancy was defined as the presence of a gestational sac with heart beat identified by ultrasound five weeks after the embryo transfer. The implantation rate was defined as the ratio of gestational sacs to the number of embryos transferred and Clinical abortion rate was determined as clinically recognized pregnancy losses before 20 weeks of gestation. Criteria for cycle cancellation due to poor ovarian response included the presence of fewer than two growing follicles on ultrasound’ with an E2 level < 200 pg/ ml on day 7 of stimulation. The number of oocyte retrival. Timepoint: Day of punctuer. Method of measurement: Counting by microscope. Clinical pregnancy rates. Timepoint: 5 weeks after the embryo transfer. Method of measurement: Presence of a gestational sac with heart beat identified byultrasound. The cycle length. Timepoint: From the start of the drug until the day of the puncture. Method of measurement: Calendar. The total dose of gonadotropin. Timepoint: From the start of the drug until the day of the puncture. Method of measurement: International unit. The implantation rate. Timepoint: 5 weeks after the embryo transfer. Method of measurement: The number of pregnancy sacs divided by the number of transferred embryos multiplied by 100. Yazd Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences Approved 2011-06-20 Yazd Research and Clinical Center for Infertility Yazd Research and Clinical Center for Infertility, Booali Street, Safaieh, Yazd Yazd Yazd Iran (Islamic Republic of)