Protocol summary
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Study aim
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Better ovarian stimulation in patients with poor ovarian responses
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Design
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Clinical trial with a randomized parallel control group with 116 patients, participating in the study between June 2011 to April 2012 (follow-up time is up to 20 weeks of pregnancy)
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Settings and conduct
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Clinical trial with a single-blind random control group , between June 2011 and April 2012 at Yazd Infertility Research and Treatment Center, Shahid Sadoughi University of Medical Sciences, Yazd
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Participants/Inclusion and exclusion criteria
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Inclusion criteria: 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).
exclusion criteria: 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
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Intervention groups
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For fifty eight randomly estradiol (Aburaihan Pharmaceutical Co., Tehran, Iran) 2 mg is 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. 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. Another group consisted of 58 women who underwent ovarian stimulation for IVF using micro dose agonist protocol.
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Main outcome variables
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Results of ovulation stimulation
General information
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Reason for update
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update as result
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Acronym
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IVF
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IRCT registration information
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IRCT registration number:
IRCT201108044339N8
Registration date:
2011-09-15, 1390/06/24
Registration timing:
registered_while_recruiting
Last update:
2021-04-19, 1400/01/30
Update count:
1
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Registration date
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2011-09-15, 1390/06/24
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Registrant information
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Recruitment status
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Recruitment complete
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Funding source
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مرکز تحقیقاتی و درمانی ناباروری یزد
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Expected recruitment start date
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2011-03-01, 1389/12/10
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Expected recruitment end date
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2011-10-28, 1390/08/06
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Actual recruitment start date
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2011-03-01, 1389/12/10
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Actual recruitment end date
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2011-10-28, 1390/08/06
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Trial completion date
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2012-03-30, 1391/01/11
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Scientific title
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Comparsion of luteal estradiol administration during GnRH antagonist protocol versus microdose GnRH agonist protocol for patients with a history of poor IVF out come
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Public title
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Estradiol administration for patients with a history of poor IVFresponse
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Purpose
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Treatment
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Inclusion/Exclusion criteria
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Inclusion criteria:
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)
Exclusion criteria:
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
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Age
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No age limit
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Gender
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Female
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Phase
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2
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Groups that have been masked
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Sample size
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Target sample size:
116
Actual sample size reached:
116
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Randomization (investigator's opinion)
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Randomized
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Randomization description
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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.
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Blinding (investigator's opinion)
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Single blinded
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Blinding description
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The physicians performing the follicular aspiration blinded to the stimulation protocol.
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Placebo
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Not used
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Assignment
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Parallel
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Other design features
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Ethics committees
1
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Ethics committee
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Approval date
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2011-06-20, 1390/03/30
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Ethics committee reference number
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933
Health conditions studied
1
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Description of health condition studied
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Female infertility
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ICD-10 code
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N97
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ICD-10 code description
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Female infertility
Primary outcomes
1
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Description
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The number of oocyte retrival
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Timepoint
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Day of punctuer
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Method of measurement
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Counting by microscope
2
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Description
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Clinical pregnancy rates
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Timepoint
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5 weeks after the embryo transfer
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Method of measurement
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Presence of a gestational sac with heart beat identified byultrasound
Secondary outcomes
1
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Description
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The cycle length
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Timepoint
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From the start of the drug until the day of the puncture
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Method of measurement
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Calendar
2
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Description
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The total dose of gonadotropin
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Timepoint
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From the start of the drug until the day of the puncture
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Method of measurement
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International unit
3
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Description
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The implantation rate
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Timepoint
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5 weeks after the embryo transfer
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Method of measurement
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The number of pregnancy sacs divided by the number of transferred embryos multiplied by 100
Intervention groups
1
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Description
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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.
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Category
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Treatment - Drugs
2
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Description
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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.
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Category
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Treatment - Drugs
1
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Sponsor
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Grant name
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Grant code / Reference number
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Is the source of funding the same sponsor organization/entity?
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Yes
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Title of funding source
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Yazd Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences
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Proportion provided by this source
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100
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Public or private sector
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Public
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Domestic or foreign origin
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Domestic
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Category of foreign source of funding
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empty
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Country of origin
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Type of organization providing the funding
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Academic
Sharing plan
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Deidentified Individual Participant Data Set (IPD)
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Undecided - It is not yet known if there will be a plan to make this available
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Study Protocol
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Yes - There is a plan to make this available
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Statistical Analysis Plan
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Yes - There is a plan to make this available
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Informed Consent Form
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Undecided - It is not yet known if there will be a plan to make this available
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Clinical Study Report
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No - There is not a plan to make this available
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Analytic Code
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No - There is not a plan to make this available
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Data Dictionary
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No - There is not a plan to make this available
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Title and more details about the data/document
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Information on the main outcome
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When the data will become available and for how long
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6 months after printing the results
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To whom data/document is available
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Editor-in-Chief
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Under which criteria data/document could be used
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Use in the retrospective study
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From where data/document is obtainable
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Yazd Research and Clinical Center for Infertility
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What processes are involved for a request to access data/document
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Request from the Research Deputy, submitted to the Research Council of the Center if the request accepts its referral to the security and after completion of the relevant forms, request is referred to the research experts and then get the data.
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Comments
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Trial results
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Please tick if results have been published
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Yes
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Summary result posting date
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2021-04-19, 1400/01/30
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Table of baseline comparison
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Participant flow diagram
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Table of variable outcomes' results
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Table of adverse events
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First publication date
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2012-08-26, 1391/06/05
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Abstract of published paper
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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.