Low ResponderNCT03155438
Oxidative Stress-related Gene Expression in Cumulus Cells Among Low Responders
An observational study of Low Responder, run by Chulalongkorn University at 1 site in Thailand.
Trial summary
In Vitro Fertilization is considered one of effective treatment for infertile couple. However, some women do not have adequate response to controlled ovarian hyperstimulation, resulting in low response which defined as less than 5 retrieved oocytes. Read more about this study
- Who is it for?
- Ages 25 to 49 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Low Responder
- What is being tested?
- Oxidative stress-related gene expression (RNA expression) and oocyte competence biomarkers
- How many people
- 56 participants
- Where
- 1 siteThailand
- Study dates
- 1 Jun 2017to 31 May 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 49 years
- Women only
- Healthy volunteers accepted
- Adult
Study population: Women aged 25-49 years old , who receiving care at infertile clinic ,King Chulalongkorn Memorial hospital
Who may be able to join
- Low responder : women aged 25-49 years old with less than 5 oocytes (1-4 oocytes) retrieved during controlled ovarian hyperstimulation
- Normal responder women aged 25-49 years old with 5-15 oocytes retrieved during controlled ovarian hyperstimulation
Who cannot join
- Active ovarian pathology ( ovarian cyst or tumor)
- Basal FSH more than 20 IU/L or Antimullerian hormone less than 0.5 ng/ml
- Ovarian hyperstimulation syndrome
Trial locations and contacts
1 site in 1 country.
Thailand1 site
Faculty of Medicine ,Chulalongkorn University
Bangkok, 10330
Porntip Sirayapiwat, MD, 66818378923, p_siraya@hotmail.com
Nalina Bhupornvivat, MD, 66909908440, nalina88@hotmail.com
About this study
Official title: Oxidative Stress-related Gene Expression in Cumulus Cells Among Low Responders to Controlled Ovarian Hyperstimulation During in Vitro Fertilization
In Vitro Fertilization is considered one of effective treatment for infertile couple. However, some women do not have adequate response to controlled ovarian hyperstimulation, resulting in low response which defined as less than 5 retrieved oocytes. There are studies claiming that live birth rates in these patient lower than normal responder (10-15 retrieved oocytes). Among factors contributing low response, oxidative stress, resulting from increased pro-oxidant and/or reduced antioxidant, is considered to effect the functions of follicles and quality of oocytes. However, there are few studies demonstrating this relation. Objective of our study is to find the difference of oxidative stress-related gene expression in cumulus cell and oocyte competence biomarkers from follicular fluid between low responders and normal responder to controlled ovarian hyperstimulation.
Read the detailed description
Low response to controlled ovarian hyperstimulation (less than 5 retrieved oocytes) is a problem in some of couple receiving treatment for infertility. Studies showed that success rate in treatment for these patients is lower than normal response group. Among many factors contributing low response, oxidative stress is suspected to be involved in malfunction of follicular environment and oocyte maturation. However, direct relationship between oxidative and oocyte function cannot be studied due to ethical concern, so many studies had studied oocyte's surrounding environment such as cumulus cell and follicular fluid instead.
In our study , we aim to study the difference in level of oxidative stress-related gene expression and oocyte competence biomarkers among low responders and normal responders. For oxidative stress-related gene expression of cumulus cell , we will measure mRNA expression by quantitative PCR for Superoxide dismutase 1 (SOD1) , SOD2 , Glutathione peroxidase (GPX) and Inducible nitric oxide synthase (iNOS) . For oocyte competent biomarkers, we will use ELISA technique to measure the level of GDF(, BMP15, Amphiregulin and CoQ10 in follicular fluid.
Sample size calculation was done with data from study performed by Donnabela et al , which found that Mean SOD gene expression in control group was 2.06 2-Δ ΔCT (SD = 0.53) . The formula for comparing two different mean was used with expectation that low responders group would have lower SOD gene expression by 20%.:
n/group = 2(Z α/2 + Z β)2 σ2 / (X̅ 1- X̅ 2)2
α = 0.05 , β = 0.2 Z α/2 = Z0.05/2 = 1.96 (two tail) Z β = Z0.8 = 0.84
Mean in group1 (X̅ 1) = 2.06, SD. in group1 (σ₁) = 0.53 Mean in group2 (X̅ 2) = 1.64, SD. in group2 (σ₂)= 0.53 Sample size: Group1 (n₁) = 25, Group2 (n₂) = 25 Total number is 56 patients (added 10% for possible data loss)
Statistical analysis
- Mean and Standard deviation will be used for descriptive data.
- Mann-Whitney U test , unpaired t-test and chi square will be used as appropriate
- p value less than 0.05 is considered statistical significant.
- Conditions
- Low Responder
- Being tested
- Oxidative stress-related gene expression (RNA expression), oocyte competence biomarkers
- Keywords
- Oxidative stress, Cumulus cell, Controlled ovarian hyperstimulation, In vitro fertilization, Low responder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oxidative stress-related gene expression (RNA expression)Diagnostic test
Oxidative stress-related gene expression (RNA expression),Superoxide dismutase 1 (SOD1) , SOD2 , Glutathione peroxidase (GPX) and Inducible nitric oxide synthase (iNOS) , measured by Real time PCR technique.
oocyte competence biomarkersDiagnostic test
Oocyte competence biomarkers ,GDF9, BMP15, Amphiregulin and CoQ10 measured by ELISA
| Study group | Role | What they receive |
|---|---|---|
| Low responder | Low responder : women aged 25-49 years old with less than 5 oocytes (1-4 oocytes) retrieved during controlled ovarian hyperstimulation
Oxidative stress-related gene expression and oocyte competence biomarkers will be performed to access the difference between low and normal responders. Receives: Diagnostic Test: Oxidative stress-related gene expression (RNA expression); Diagnostic Test: oocyte competence biomarkers | |
| Normal responder | Normal responder women aged 25-49 years old with 5-15 oocytes retrieved during controlled ovarian hyperstimulation
Oxidative stress-related gene expression and oocyte competence biomarkers will be performed to access the difference between low and normal responders. Receives: Diagnostic Test: Oxidative stress-related gene expression (RNA expression); Diagnostic Test: oocyte competence biomarkers |
What is being measured
The primary outcome is the main question the study is designed to answer.
Oxidative stress-related gene expression
mRNA expression by quantitative PCR for Superoxide dismutase 1 (SOD1) SOD2 , Glutathione peroxidase (GPX) and Inducible nitric oxide synthase (iNOS).
Measured: June 2017-May 2018
Secondary outcomes (1)
oocyte competent biomarkers
ELISA technique to measure the level of GDF9, BMP15, Amphiregulin and CoQ10 in follicular fluid.
Measured: June 2017-May 2018
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 May 2017
- Study start1 Jun 2017 (estimated)
- Primary completion30 Mar 2018 (estimated)
- Study completion31 May 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Low ResponderStudies of the same condition, open and under way.
- More trials run by Chulalongkorn UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 56 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Chulalongkorn University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Porntip Sirayapiwat, Chulalongkorn University
- Investigators
- Porntip Sirayapiwat, MD, Principal investigator, Chulalongkorn University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03155438
- Sponsor's protocol ID
- RA60/041
- Other IDs
- Med Chula IRB No.688/59
- Status last verified
- May 2017
- First submitted
- 15 May 2017
- Last updated
- 16 May 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Polyzos NP, Sunkara SK. Sub-optimal responders following controlled ovarian stimulation: an overlooked group? Hum Reprod. 2015 Sep;30(9):2005-8. doi: 10.1093/humrep/dev149. Epub 2015 Jul 21.
PubMed 26202582Oudendijk JF, Yarde F, Eijkemans MJ, Broekmans FJ, Broer SL. The poor responder in IVF: is the prognosis always poor?: a systematic review. Hum Reprod Update. 2012 Jan-Feb;18(1):1-11. doi: 10.1093/humupd/dmr037. Epub 2011 Oct 10.
PubMed 21987525Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012 Jun 29;10:49. doi: 10.1186/1477-7827-10-49.
PubMed 22748101Nunez-Calonge R, Cortes S, Gutierrez Gonzalez LM, Kireev R, Vara E, Ortega L, Caballero P, Rancan L, Tresguerres J. Oxidative stress in follicular fluid of young women with low response compared with fertile oocyte donors. Reprod Biomed Online. 2016 Apr;32(4):446-56. doi: 10.1016/j.rbmo.2015.12.010. Epub 2016 Jan 14.
PubMed 26805046Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril. 2015 Feb;103(2):303-16. doi: 10.1016/j.fertnstert.2014.11.015. Epub 2014 Dec 10.
PubMed 25497448Wu YT, Tang L, Cai J, Lu XE, Xu J, Zhu XM, Luo Q, Huang HF. High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development. Hum Reprod. 2007 Jun;22(6):1526-31. doi: 10.1093/humrep/dem029. Epub 2007 Mar 8.
PubMed 17347167Gode F, Gulekli B, Dogan E, Korhan P, Dogan S, Bige O, Cimrin D, Atabey N. Influence of follicular fluid GDF9 and BMP15 on embryo quality. Fertil Steril. 2011 Jun;95(7):2274-8. doi: 10.1016/j.fertnstert.2011.03.045. Epub 2011 Apr 15.
PubMed 21496799Liu N, Ma Y, Li R, Jin H, Li M, Huang X, Feng HL, Qiao J. Comparison of follicular fluid amphiregulin and EGF concentrations in patients undergoing IVF with different stimulation protocols. Endocrine. 2012 Dec;42(3):708-16. doi: 10.1007/s12020-012-9706-z. Epub 2012 Jun 8.
PubMed 22678853Bergandi L, Basso G, Evangelista F, Canosa S, Dalmasso P, Aldieri E, Revelli A, Benedetto C, Ghigo D. Inducible nitric oxide synthase and heme oxygenase 1 are expressed in human cumulus cells and may be used as biomarkers of oocyte competence. Reprod Sci. 2014 Nov;21(11):1370-7. doi: 10.1177/1933719114525268. Epub 2014 Mar 7.
PubMed 24607880Donabela FC, Meola J, Padovan CC, de Paz CC, Navarro PA. Higher SOD1 Gene Expression in Cumulus Cells From Infertile Women With Moderate and Severe Endometriosis. Reprod Sci. 2015 Nov;22(11):1452-60. doi: 10.1177/1933719115585146. Epub 2015 May 6.
PubMed 25947891
Study at a glance
From the registry record, last updated by the sponsor on 16 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oxidative Stress-related Gene Expression in Cumulus Cells Among Low Responders to Controlled Ovarian Hyperstimulation During in Vitro Fertilization
- ClinicalTrials.gov ID
- NCT03155438
- Acronym / sponsor ID
- RA60/041
- Conditions
- Low Responder
- Keywords
- Oxidative stress, Cumulus cell, Controlled ovarian hyperstimulation, In vitro fertilization, Low responder
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 56 participants (estimated)
- Lead sponsor
- Chulalongkorn UniversityUniversity, hospital or other
- Study start
- 1 Jun 2017 (estimated)
- Primary completion
- 30 Mar 2018 (estimated)
- Study completion
- 31 May 2018 (estimated)
- First posted
- 16 May 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In Vitro Fertilization is considered one of effective treatment for infertile couple. However, some women do not have adequate response to controlled ovarian hyperstimulation, resulting in low response which defined as less than 5 retrieved oocytes. There are studies claiming that live birth rates in these patient lower than normal responder (10-15 retrieved oocytes). Among factors contributing low response, oxidative stress, resulting from increased pro-oxidant and/or reduced antioxidant, is considered to effect the functions of follicles and quality of oocytes. However, there are few studies demonstrating this relation. Objective of our study is to find the difference of oxidative stress-related gene expression in cumulus cell and oocyte competence biomarkers from follicular fluid between low responders and normal responder to controlled ovarian hyperstimulation.
Detailed description
Low response to controlled ovarian hyperstimulation (less than 5 retrieved oocytes) is a problem in some of couple receiving treatment for infertility. Studies showed that success rate in treatment for these patients is lower than normal response group. Among many factors contributing low response, oxidative stress is suspected to be involved in malfunction of follicular environment and oocyte maturation. However, direct relationship between oxidative and oocyte function cannot be studied due to ethical concern, so many studies had studied oocyte's surrounding environment such as cumulus cell and follicular fluid instead.
In our study , we aim to study the difference in level of oxidative stress-related gene expression and oocyte competence biomarkers among low responders and normal responders. For oxidative stress-related gene expression of cumulus cell , we will measure mRNA expression by quantitative PCR for Superoxide dismutase 1 (SOD1) , SOD2 , Glutathione peroxidase (GPX) and Inducible nitric oxide synthase (iNOS) . For oocyte competent biomarkers, we will use ELISA technique to measure the level of GDF(, BMP15, Amphiregulin and CoQ10 in follicular fluid.
Sample size calculation was done with data from study performed by Donnabela et al , which found that Mean SOD gene expression in control group was 2.06 2-Δ ΔCT (SD = 0.53) . The formula for comparing two different mean was used with expectation that low responders group would have lower SOD gene expression by 20%.:
n/group = 2(Z α/2 + Z β)2 σ2 / (X̅ 1- X̅ 2)2
α = 0.05 , β = 0.2 Z α/2 = Z0.05/2 = 1.96 (two tail) Z β = Z0.8 = 0.84
Mean in group1 (X̅ 1) = 2.06, SD. in group1 (σ₁) = 0.53 Mean in group2 (X̅ 2) = 1.64, SD. in group2 (σ₂)= 0.53 Sample size: Group1 (n₁) = 25, Group2 (n₂) = 25 Total number is 56 patients (added 10% for possible data loss)
Statistical analysis
- Mean and Standard deviation will be used for descriptive data.
- Mann-Whitney U test , unpaired t-test and chi square will be used as appropriate
- p value less than 0.05 is considered statistical significant.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Low responder | – | Diagnostic Test: Oxidative stress-related gene expression (RNA expression), Diagnostic Test: oocyte competence biomarkersLow responder : women aged 25-49 years old with less than 5 oocytes (1-4 oocytes) retrieved during controlled ovarian hyperstimulation Oxidative stress-related gene expression and oocyte competence biomarkers will be performed to access the difference between low and normal responders. |
| Normal responder | – | Diagnostic Test: Oxidative stress-related gene expression (RNA expression), Diagnostic Test: oocyte competence biomarkersNormal responder women aged 25-49 years old with 5-15 oocytes retrieved during controlled ovarian hyperstimulation Oxidative stress-related gene expression and oocyte competence biomarkers will be performed to access the difference between low and normal responders. |
Who may qualify
- Ages
- 25 to 49 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
- Study population
- Women aged 25-49 years old , who receiving care at infertile clinic ,King Chulalongkorn Memorial hospital
Key inclusion criteria (2 listed)
- Low responder : women aged 25-49 years old with less than 5 oocytes (1-4 oocytes) retrieved during controlled ovarian hyperstimulation
- Normal responder women aged 25-49 years old with 5-15 oocytes retrieved during controlled ovarian hyperstimulation
Key exclusion criteria (3 listed)
- Active ovarian pathology ( ovarian cyst or tumor)
- Basal FSH more than 20 IU/L or Antimullerian hormone less than 0.5 ng/ml
- Ovarian hyperstimulation syndrome
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oxidative stress-related gene expression (RNA expression)Oxidative stress-related gene expression (RNA expression),Superoxide dismutase 1 (SOD1) , SOD2 , Glutathione peroxidase (GPX) and Inducible nitric oxide synthase (iNOS) , measured by Real time PCR technique. | Diagnostic test | Low responder, Normal responder |
| oocyte competence biomarkersOocyte competence biomarkers ,GDF9, BMP15, Amphiregulin and CoQ10 measured by ELISA | Diagnostic test | Low responder, Normal responder |
Primary outcome
Oxidative stress-related gene expression
Time frame: June 2017-May 2018
mRNA expression by quantitative PCR for Superoxide dismutase 1 (SOD1) SOD2 , Glutathione peroxidase (GPX) and Inducible nitric oxide synthase (iNOS).
1 secondary outcome
oocyte competent biomarkers
Time frame: June 2017-May 2018
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 May 2017.
- Background: PubMed 26202582Polyzos NP, Sunkara SK. Sub-optimal responders following controlled ovarian stimulation: an overlooked group? Hum Reprod. 2015 Sep;30(9):2005-8. doi: 10.1093/humrep/dev149. Epub 2015 Jul 21.
- Background: PubMed 21987525Oudendijk JF, Yarde F, Eijkemans MJ, Broekmans FJ, Broer SL. The poor responder in IVF: is the prognosis always poor?: a systematic review. Hum Reprod Update. 2012 Jan-Feb;18(1):1-11. doi: 10.1093/humupd/dmr037. Epub 2011 Oct 10.
- Background: PubMed 22748101Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012 Jun 29;10:49. doi: 10.1186/1477-7827-10-49.
- Background: PubMed 26805046Nunez-Calonge R, Cortes S, Gutierrez Gonzalez LM, Kireev R, Vara E, Ortega L, Caballero P, Rancan L, Tresguerres J. Oxidative stress in follicular fluid of young women with low response compared with fertile oocyte donors. Reprod Biomed Online. 2016 Apr;32(4):446-56. doi: 10.1016/j.rbmo.2015.12.010. Epub 2016 Jan 14.
- Background: PubMed 25497448Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril. 2015 Feb;103(2):303-16. doi: 10.1016/j.fertnstert.2014.11.015. Epub 2014 Dec 10.
- Background: PubMed 17347167Wu YT, Tang L, Cai J, Lu XE, Xu J, Zhu XM, Luo Q, Huang HF. High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development. Hum Reprod. 2007 Jun;22(6):1526-31. doi: 10.1093/humrep/dem029. Epub 2007 Mar 8.
- Background: PubMed 21496799Gode F, Gulekli B, Dogan E, Korhan P, Dogan S, Bige O, Cimrin D, Atabey N. Influence of follicular fluid GDF9 and BMP15 on embryo quality. Fertil Steril. 2011 Jun;95(7):2274-8. doi: 10.1016/j.fertnstert.2011.03.045. Epub 2011 Apr 15.
- Background: PubMed 22678853Liu N, Ma Y, Li R, Jin H, Li M, Huang X, Feng HL, Qiao J. Comparison of follicular fluid amphiregulin and EGF concentrations in patients undergoing IVF with different stimulation protocols. Endocrine. 2012 Dec;42(3):708-16. doi: 10.1007/s12020-012-9706-z. Epub 2012 Jun 8.
- Background: PubMed 24607880Bergandi L, Basso G, Evangelista F, Canosa S, Dalmasso P, Aldieri E, Revelli A, Benedetto C, Ghigo D. Inducible nitric oxide synthase and heme oxygenase 1 are expressed in human cumulus cells and may be used as biomarkers of oocyte competence. Reprod Sci. 2014 Nov;21(11):1370-7. doi: 10.1177/1933719114525268. Epub 2014 Mar 7.
- Results publication: PubMed 25947891Donabela FC, Meola J, Padovan CC, de Paz CC, Navarro PA. Higher SOD1 Gene Expression in Cumulus Cells From Infertile Women With Moderate and Severe Endometriosis. Reprod Sci. 2015 Nov;22(11):1452-60. doi: 10.1177/1933719115585146. Epub 2015 May 6.
- Individual participant dataSharing planned: No
Related trials for Low Responder
Recruiting
Linear Piezoelectric Low Intensity Shockwave Treatment (LI-SWT) for the Treatment of Erectile Dysfunction in PDE5i Non Responder
Erectile Dysfunction
RecruitingObservational study
Time to BBVNA Relief
Low Back Pain, Vertebrogenic Pain Syndrome
RecruitingPhase 2
Neo IRENIE (NEOadjuvant Ipilimumab, RElatlimab, NIvolumab Evaluation)
Cutaneous Melanoma, Mucosal Melanoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Porntip Sirayapiwat, MD principal investigator
Chulalongkorn University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Low Responder, run by Chulalongkorn University at 1 site in Thailand.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 16 May 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Thailand. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Porntip Sirayapiwat, MD (66-81-8378923, p_siraya@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Oxidative stress-related gene expression (time frame: June 2017-May 2018). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03155438, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2017.