Poor Ovarian Stimulation Response in In Vitro Fertilization (IVF) Program

December 22, 2015 updated by: Nadine wagdi maurice, Cairo University

Assessing the Relation Between Hormone Receptors Gene Polymorphism and Ovarian Stimulation Response in In Vitro Fertilization (IVF) Program

The aim of this study is to assess the role of AMH in prediction of poor ovarian response as well as the relation between ESR2 (+1730G>A) (rs4986938), FSHR p.Thr307Ala (c.919A>G, rs6165) and FSHR p.Asn680Ser (c.2039A>G, rs6166) SNPs and the poor response in Egyptian women undergoing IVF procedure. Discovering the genetic variants associated with ovarian response is an important step towards individualized pharmacogenetic protocols of ovarian stimulation.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

In-vitro fertilization treatment safety is highly challenged by the erratic individual variability to controlled ovarian hyperstimulation (COH). One of the diverse predictive factors is the AMH, which is considered to be the most sensitive marker. Nowadays, practices of pharmacogenetics could predict the stimulation success and thus tailoring the treatment reaching advancement in patient care. Since the efficiency of the Follicle stimulating hormone (FSH) dose is greatly related to the success of COH, the FSHR gene is treated as the primary candidate in explaining the difference in COH results.Furthermore, the estrogen receptors are important genes for improvements in the diagnosis and treatment of infertility.

Materials and Methods: Starting June 2013, couples with unexplained infertility, seeking the first attempt IVF/ICSI treatment cycle will be recruited in "AL shark Al-Awsat fertility center".In this prospective study, 216 Couples fulfilling our inclusion criteria will enroll in this study after informed consent. Ovarian stimulation will be performed according to the GnRH antagonist protocol with a fixed daily morning dose of Human menopausal gonadotrophin (HMG) [Merional® 75 IU ampoules, IBSA institut] intra-muscular injection starting on cycle day 2. Based on the patient's body mass index and hormonal profile, the daily dose of HMG will be adjusted to (225 IU) for participants with AMH levels > 1.5 ng/ml and/or FSH levels ≤ 8 mIU/ml and to (300 IU) for participants with AMH levels < 1.5 ng/ml and/or FSH levels > 8 mIU/ml, doses will be increased by 75 IU in cases with BMI > 30 Kg/m2. On day 2 of the menstrual cycle, the dose of HMG will be commenced for all patients and will be maintained for 9-11 days according to each participant individual ovarian response assessed by trans-vaginal ultrasound folliculometry starting on cycle day 7 and continued every other day until the day of Human chorionic gonadotrophin (hCG) injection. On cycle day 7, the GnRH antagonist Cetrorelix 0.25 mg [Cetrotide® 0.25 mg syringes, Merck Serono] will be introduced as daily subcutaneous injections and continued till the day of ovulation triggering. Finally, when at least 3 follicles will reach 17 mm in diameter, ovulation will be triggered by a single intra-muscular injection of 10,000 IU of hCG [Choriomon® 5000 IU ampoules, IBSA institut]. 36 hours later, oocyte retrieval will be performed and will be guided by transvaginal ultrasound. According to our primary outcome, the number of oocytes collected, patients will be classified as poor responders (4 oocytes or less) and will be considered as good responders if they produced 5 or more oocytes. The good responders group will serve as the control group.

Genotyping:Peripheral blood will be collected from each patient in an EDTA-containing tube. Genomic DNA will be extracted from lymphocytes of peripheral blood by fully automated system of QIAcube using QIAamp DNA Blood Mini Kit (250) plus QIAamp DNA Blood Mini Accessory Set B, cat. no. 1043369. Detection of the polymorphisms ESR2 (+1730G>A) (rs4986938), FSHR p.Thr307Ala (c.919A>G, rs6165) and FSHR p.Asn680Ser (c.2039A>G, rs6166) SNPs will be performed using the TaqMan system by real-time polymerase chain reaction (PCR). Primers and probes will be provided by applied biosystem, Life Technologies. Assays will be performed with TaqMan Universal Master Mix.

Statistical analysis: Data will be statistically described in terms of mean and standard deviation, for quantitative data and frequencies (number of cases) and relative frequencies (percentages) for qualitative data. Hardy-Weinberg (H-W) Equilibrium for each polymorphism will be tested using the Chi-square test. Comparison of quantitative variables will be done using unpaired t test when comparing 2 categories and one way analysis of variance (ANOVA) with post hoc test when comparing more than 2 categories.

For comparing categorical data, Chi square test will be performed. Exact test will be used instead when the expected frequency is less than 5.

Genotype and allele frequencies will be compared between the disease and the control groups using chi-square tests. Odds ratio (OR) with 95% confidence intervals will be calculated. A probability value (P value) less than 0.05 will be considered statistically significant. All statistical calculations will be done using SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version 22.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
216

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Early Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

25 years to 35 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Women at or under the age of 35 years.
  • Normal thyroid stimulating hormone and prolactin levels.
  • Normal ovulatory cycles (25-35 interval days), together with proven patent fallopian tubes at hysterosalpingography or laparoscopy done within six cycles preceding the ICSI cycle.
  • Presence of both ovaries with normal findings as assessed by trans-vaginal ultrasound and laparoscopy.
  • All male partners had a normal semen analysis according to WHO criteria (WHO, 2010), done within 6 months preceding the ICSI cycle

Exclusion Criteria

  • Chronic medical disorders such as diabetes.
  • Previous inadequate response to ovulation induction.
  • Polycystic ovary syndrome.
  • Women who performed ovarian surgery and cases of endometriosis diagnosed by laparoscopy or suspected by ultrasound or CA-125 assay.
  • Abnormal pelvic pathology or congenital anomalies.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Poor responders

This group will include women who underwent IVF/ICSI cycle and produced 4 oocytes or less.

intervention:

  1. fixed daily morning dose of Human menopausal gonadotrophin (HMG) Merional® intra-muscular injection ,starting on cycle day 2 and will be maintained for 9-11 days according to each individual ovarian response,at a dose of (300 IU).
  2. On cycle day 7, the GnRH antagonist Cetrorelix 0.25 mg Cetrotide® will be introduced as daily subcutaneous injections and continued till the day of ovulation triggering.
  3. Finally, when at least 3 follicles will reach 17 mm in diameter, ovulation will be triggered by a single intra-muscular injection of 10,000 IU of Human chorionic gonadotrophin (hCG) Choriomon®.
Drug: Human menopausal gonadotrophin (HMG)
[Merional® 75 IU ampoules, IBSA institut]
Other Names:
  • Merional®
Drug: GnRH antagonist Cetrorelix
[Cetrotide® 0.25 mg syringes, Merck Serono]
Other Names:
  • Cetrotide®
Drug: Human chorionic gonadotrophin (hCG)
[Choriomon® 5000 IU ampoules, IBSA institut]
Other Names:
  • Choriomon®
Active Comparator: Good responders

This group will include women who produced (5 or more oocytes) after COH.

Intervention:

  1. fixed daily morning dose of Human menopausal gonadotrophin (HMG) Merional® intra-muscular injection ,starting on cycle day 2 and will be maintained for 9-11 days according to each individual ovarian response,at a dose of (225 IU) for participants with AMH levels > 1.5 ng/ml and/or FSH levels ≤ 8 mIU/ml
  2. On cycle day 7, the GnRH antagonist Cetrorelix 0.25 mg Cetrotide® will be introduced as daily subcutaneous injections and continued till the day of ovulation triggering.
  3. When at least 3 follicles will reach 17 mm in diameter, ovulation will be triggered by a single intra-muscular injection of 10,000 IU of Human chorionic gonadotrophin (hCG) Choriomon®.
Drug: Human menopausal gonadotrophin (HMG)
[Merional® 75 IU ampoules, IBSA institut]
Other Names:
  • Merional®
Drug: GnRH antagonist Cetrorelix
[Cetrotide® 0.25 mg syringes, Merck Serono]
Other Names:
  • Cetrotide®
Drug: Human chorionic gonadotrophin (hCG)
[Choriomon® 5000 IU ampoules, IBSA institut]
Other Names:
  • Choriomon®

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
number of oocytes collected
Time Frame: 3 weeks from of start of ICSI cycle
when at least 3 follicles will reach 17 mm in diameter, ovulation will be triggered by a single intra-muscular injection of 10,000 IU of hCG [Choriomon® 5000 IU ampoules, IBSA institut]. 36 hours later, oocyte retrieval will be performed and will be guided by transvaginal ultrasound.
3 weeks from of start of ICSI cycle

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Detection of the single nucleotide polymorphisms ESR2(+1730G>A) (rs4986938), FSHR p.Thr307Ala (c.919A>G, rs6165) and FSHR p.Asn680Ser (c.2039A>G, rs6166) SNPs will be performed using the TaqMan system by real-time polymerase chain reaction (PCR)
Time Frame: Within 1 week
By using PCR, we will indicate the genotype in each individual and determine the probability of the poor ovarian response.
Within 1 week

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Laboratory analysis of basal follicle stimulating hormone level for each individual will be measured by enzyme-linked immunosorbent assay (ELISA)
Time Frame: Done within 3 months preceeding the ICSI cycle
Based on FSH level, the dose of HMG ( Merional) will be adjusted for each individual.
Done within 3 months preceeding the ICSI cycle
Laboratory analysis of anti-mullerian hormone level (AMH) will be measured by ELISA technique for each individual.
Time Frame: Done within 3 months preceeding the ICSI cycle.
Based on AMH level, the dose of HMG (Merional) will be adjusted for each individual.
Done within 3 months preceeding the ICSI cycle.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Cairo University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

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Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2015

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2015

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 16, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 22, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 29, 2015

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 29, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 22, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • BC (705)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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