<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02979886</url>
  </required_header>
  <id_info>
    <org_study_id>FirstZhongshanMU</org_study_id>
    <nct_id>NCT02979886</nct_id>
  </id_info>
  <brief_title>Effects of SNP of GnRH Receptor Genes in IVF Patients</brief_title>
  <official_title>Effects of Single Nucleotide Polymorphism of GnRH Receptor Genes on Clinical Response to Pituitary Down Regulation in IVF Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Miao benyu</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>First Affiliated Hospital of Zhongshan Medical University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Gonadotropin-releasing hormone analogue (GnRH-a) &quot;long protocol&quot; is a protocol for pituitary&#xD;
      down-regulation in IVF. However, it is common in clinic that some patients are hypersensitive&#xD;
      to pituitary down-regulation and have pituitary oversuppression, resulting in prolonged&#xD;
      ovarian stimulation and increased consumption of exogenous gonadotropin(Gn). On the other&#xD;
      hand, some patients may have insufficient pituitary down-regulation, which can affect the&#xD;
      synchronization of ovarian follicles and consequently reduce the number of oocytes&#xD;
      retrievable and lower the pregnancy rate. The differences in responses to GnRH-a among&#xD;
      patients may be associated with the SNP of their GnRH receptor genes. It has been reported&#xD;
      that mutations in GnRH receptor genes could change their binding affinity to the ligands,&#xD;
      thus affecting the outcome of pituitary down-regulation. So far 20 non-synonymous mutations&#xD;
      on the GnRH receptor genes have been reported, which can affect the function of GnRH receptor&#xD;
      and are highly associated with disorders such as endometriosis and sexual precocity. However,&#xD;
      the correlation between the SNP of GnRH receptor genes and the outcome of pituitary&#xD;
      down-regulation in IVF has not been reported.&#xD;
&#xD;
      The purpose of this study is to analyze the correlation between single nucleotide&#xD;
      polymorphism (SNP) of GnRH receptor genes in infertile female patients and the extent of&#xD;
      pituitary down-regulation by short-acting GnRH-a long protocol, with the goal to achieve&#xD;
      individual down-regulation protocols based on the patients' SNP haplotypes of GnRH receptor&#xD;
      genes and to improve the success rate of assisted reproductive technology.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Short-acting GnRH-a will be administered daily since the mid-luteal phase for pituitary&#xD;
      down-regulation. 14 days after down-regulation,serum levels of follicle stimulating hormone&#xD;
      (FSH), luteinizing hormone (LH) and E2 will be measured. Meanwhile, about 2ml of peripheral&#xD;
      blood will be preserved for SNP analysis of the GnRH receptor genes. Once the patients are&#xD;
      judged to achieve pituitary down-regulation, ovarian stimulation will be started. B-mode&#xD;
      ultrasonography and determination of hormone levels will be performed regularly according to&#xD;
      the course of follicle maturation. An appropriate dose of human menopause gonadotropin (HMG)&#xD;
      (75~150IU) will be added when follicles are larger than 12~14mm in diameter. When one leading&#xD;
      follicle is &gt;18mm in diameter, or two follicles are &gt;17mm in diameter, or three follicles are&#xD;
      &gt;16mm in diameter, final ovulation will be triggered by a single injection of human chorionic&#xD;
      gonadotropin (HCG) 4,000~10,000 IU or Ovidrel® 250μg (equivalent to HCG 6,500IU).Oocyte&#xD;
      retrieval guided by vaginal ultrasonography will be conducted 35~36 hours after HCG or&#xD;
      Ovidrel®injection.Fertilization and embryo culture will be performed according to the&#xD;
      standard IVF or intracytoplasmic sperm injection (ICSI) protocol.Embryo transfer and&#xD;
      cryopreservation will be performed 3~5 days after oocyte retrieval. Luteal support will be&#xD;
      provided after embryo transfer according to the Center's routine practice. Serum β-HCG level&#xD;
      will be measured 12~14 days after embryo transfer to determine biochemical pregnancy, and&#xD;
      transvaginal ultrasonography will be performed 4~5 weeks after embryo transfer to determine&#xD;
      clinical pregnancy.&#xD;
&#xD;
      For data analysis, patients will be divided into two groups according to their serum LH level&#xD;
      on day 14 after pituitary down-regulation - one group of patients with an LH level above the&#xD;
      median of the group and another group of patients with an LH level below the median of the&#xD;
      group.Comparisons will be made between the two groups in the following aspects: 1) age; BMI;&#xD;
      basal levels of LH, FSH and prolactin (PRL); serum levels of FSH, LH, E2 and progesterone on&#xD;
      the day of HCG injection; the numbers of oocytes retrieved, the number of cleavage, the&#xD;
      number of transferrable embryos, the number of embryos transferred and the clinical pregnancy&#xD;
      rate; and 2) genotyping results at the 11 SNP loci of the GnRH receptor genes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Enrolling by invitation</last_known_status>
  <start_date>January 2017</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">June 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Screening</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>the evidence of the correlation between single nucleotide polymorphism (SNP) of GnRH receptor genes in infertile female patients and the extent of pituitary down-regulation by short-acting GnRH-a long protocol</measure>
    <time_frame>two years</time_frame>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">1500</enrollment>
  <condition>Infertility, Female</condition>
  <arm_group>
    <arm_group_label>triptorelin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>GnRH-a will be given everyday to the patient undergoing IVF treatment from middle luteal phase to the day of HCG. After 14 days of injection, serum FSH/LH/E2 will be checked. Then ovarian stimulation will be started by giving daily subcutaneous injection of recombinant FSH 150~300 IU. An appropriate dose of HMG (75~150 IU) will be added when follicles are larger than 12~14mm in diameter. When one leading follicle is &gt;18mm in diameter, or two follicles are &gt;17mm in diameter, or three follicles are &gt;16mm in diameter, final ovulation will be triggered by a single injection of HCG 4,000~10,000 IU or Ovidrel® 250μg (equivalent to HCG 6,500 IU)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GnRH-a</intervention_name>
    <description>the hormone reaction to the down regulation of the patients</description>
    <arm_group_label>triptorelin</arm_group_label>
    <other_name>triptorelin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Human Menopausal Gonadotropins</intervention_name>
    <description>the effects on the serum LH level of day of HCG</description>
    <arm_group_label>triptorelin</arm_group_label>
    <other_name>menopur</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  regular periods of spontaneous menstruation (23~35 days)&#xD;
&#xD;
          -  basal serum FSH &lt;12 IU/L&#xD;
&#xD;
          -  use of short-acting GnRH-a long protocol for pituitary down-regulation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  polycystic ovary syndrome (PCOS)&#xD;
&#xD;
          -  hypothalamic-pituitary lesions&#xD;
&#xD;
          -  use of oral contraceptives&#xD;
&#xD;
          -  treated with a GnRH-a within 3 months before the start of GnRH-a treatment for this&#xD;
             study&#xD;
&#xD;
          -  failure to sign informed consent form.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>benyu miao</last_name>
    <role>Study Director</role>
    <affiliation>the first affiliated hosptial of zhongshan university</affiliation>
  </overall_official>
  <results_reference>
    <citation>Noel SD, Kaiser UB. G protein-coupled receptors involved in GnRH regulation: molecular insights from human disease. Mol Cell Endocrinol. 2011 Oct 22;346(1-2):91-101. doi: 10.1016/j.mce.2011.06.022. Epub 2011 Jun 29.</citation>
    <PMID>21736917</PMID>
  </results_reference>
  <results_reference>
    <citation>Valkenburg O, Uitterlinden AG, Piersma D, Hofman A, Themmen AP, de Jong FH, Fauser BC, Laven JS. Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Hum Reprod. 2009 Aug;24(8):2014-22. doi: 10.1093/humrep/dep113. Epub 2009 Apr 29.</citation>
    <PMID>19403562</PMID>
  </results_reference>
  <results_reference>
    <citation>Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes VA, Seminara SB, Boepple PA, Sidis Y, Crowley WF Jr, Martin KA, Hall JE, Pitteloud N. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med. 2011 Jan 20;364(3):215-25. doi: 10.1056/NEJMoa0911064.</citation>
    <PMID>21247312</PMID>
  </results_reference>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>November 27, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <last_update_submitted>December 1, 2016</last_update_submitted>
  <last_update_submitted_qc>December 1, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 5, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>First Affiliated Hospital of Zhongshan Medical University</investigator_affiliation>
    <investigator_full_name>Miao benyu</investigator_full_name>
    <investigator_title>the associated professor</investigator_title>
  </responsible_party>
  <keyword>single nucleotide polymorphism,GnRH receptor, IVF</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Infertility, Female</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Triptorelin Pamoate</mesh_term>
    <mesh_term>Menotropins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02979886
org study id: FirstZhongshanMU
nct id: NCT02979886
lead sponsor: 
has dmc: No
Gonadotropin-releasing hormone analogue (GnRH-a) "long protocol" is a protocol for pituitary
      down-regulation in IVF. However, it is common in clinic that some patients are hypersensitive
      to pituitary down-regulation and have pituitary oversuppression, resulting in prolonged
      ovarian stimulation and increased consumption of exogenous gonadotropin(Gn). On the other
      hand, some patients may have insufficient pituitary down-regulation, which can affect the
      synchronization of ovarian follicles and consequently reduce the number of oocytes
      retrievable and lower the pregnancy rate. The differences in responses to GnRH-a among
      patients may be associated with the SNP of their GnRH receptor genes. It has been reported
      that mutations in GnRH receptor genes could change their binding affinity to the ligands,
      thus affecting the outcome of pituitary down-regulation. So far 20 non-synonymous mutations
      on the GnRH receptor genes have been reported, which can affect the function of GnRH receptor
      and are highly associated with disorders such as endometriosis and sexual precocity. However,
      the correlation between the SNP of GnRH receptor genes and the outcome of pituitary
      down-regulation in IVF has not been reported.

      The purpose of this study is to analyze the correlation between single nucleotide
      polymorphism (SNP) of GnRH receptor genes in infertile female patients and the extent of
      pituitary down-regulation by short-acting GnRH-a long protocol, with the goal to achieve
      individual down-regulation protocols based on the patients' SNP haplotypes of GnRH receptor
      genes and to improve the success rate of assisted reproductive technology.
Short-acting GnRH-a will be administered daily since the mid-luteal phase for pituitary
      down-regulation. 14 days after down-regulation,serum levels of follicle stimulating hormone
      (FSH), luteinizing hormone (LH) and E2 will be measured. Meanwhile, about 2ml of peripheral
      blood will be preserved for SNP analysis of the GnRH receptor genes. Once the patients are
      judged to achieve pituitary down-regulation, ovarian stimulation will be started. B-mode
      ultrasonography and determination of hormone levels will be performed regularly according to
      the course of follicle maturation. An appropriate dose of human menopause gonadotropin (HMG)
      (75~150IU) will be added when follicles are larger than 12~14mm in diameter. When one leading
      follicle is >18mm in diameter, or two follicles are >17mm in diameter, or three follicles are
      >16mm in diameter, final ovulation will be triggered by a single injection of human chorionic
      gonadotropin (HCG) 4,000~10,000 IU or Ovidrel® 250μg (equivalent to HCG 6,500IU).Oocyte
      retrieval guided by vaginal ultrasonography will be conducted 35~36 hours after HCG or
      Ovidrel®injection.Fertilization and embryo culture will be performed according to the
      standard IVF or intracytoplasmic sperm injection (ICSI) protocol.Embryo transfer and
      cryopreservation will be performed 3~5 days after oocyte retrieval. Luteal support will be
      provided after embryo transfer according to the Center's routine practice. Serum β-HCG level
      will be measured 12~14 days after embryo transfer to determine biochemical pregnancy, and
      transvaginal ultrasonography will be performed 4~5 weeks after embryo transfer to determine
      clinical pregnancy.

      For data analysis, patients will be divided into two groups according to their serum LH level
      on day 14 after pituitary down-regulation - one group of patients with an LH level above the
      median of the group and another group of patients with an LH level below the median of the
      group.Comparisons will be made between the two groups in the following aspects: 1) age; BMI;
      basal levels of LH, FSH and prolactin (PRL); serum levels of FSH, LH, E2 and progesterone on
      the day of HCG injection; the numbers of oocytes retrieved, the number of cleavage, the
      number of transferrable embryos, the number of embryos transferred and the clinical pregnancy
      rate; and 2) genotyping results at the 11 SNP loci of the GnRH receptor genes.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Screening
masking: None (Open Label)
measure: the evidence of the correlation between single nucleotide polymorphism (SNP) of GnRH receptor genes in infertile female patients and the extent of pituitary down-regulation by short-acting GnRH-a long protocol
time frame: two years
arm group label: triptorelin
arm group type: Experimental
description: GnRH-a will be given everyday to the patient undergoing IVF treatment from middle luteal phase to the day of HCG. After 14 days of injection, serum FSH/LH/E2 will be checked. Then ovarian stimulation will be started by giving daily subcutaneous injection of recombinant FSH 150~300 IU. An appropriate dose of HMG (75~150 IU) will be added when follicles are larger than 12~14mm in diameter. When one leading follicle is >18mm in diameter, or two follicles are >17mm in diameter, or three follicles are >16mm in diameter, final ovulation will be triggered by a single injection of HCG 4,000~10,000 IU or Ovidrel® 250μg (equivalent to HCG 6,500 IU)
intervention type: Drug
intervention name: GnRH-a
description: the hormone reaction to the down regulation of the patients
arm group label: triptorelin
other name: triptorelin
intervention type: Drug
intervention name: Human Menopausal Gonadotropins
description: the effects on the serum LH level of day of HCG
arm group label: triptorelin
other name: menopur
criteria: 
gender: Female
minimum age: 20 Years
maximum age: 40 Years
healthy volunteers: No
last name: benyu miao
role: Study Director
affiliation: the first affiliated hosptial of zhongshan university
citation: Noel SD, Kaiser UB. G protein-coupled receptors involved in GnRH regulation: molecular insights from human disease. Mol Cell Endocrinol. 2011 Oct 22;346(1-2):91-101. doi: 10.1016/j.mce.2011.06.022. Epub 2011 Jun 29.
PMID: 21736917
citation: Valkenburg O, Uitterlinden AG, Piersma D, Hofman A, Themmen AP, de Jong FH, Fauser BC, Laven JS. Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Hum Reprod. 2009 Aug;24(8):2014-22. doi: 10.1093/humrep/dep113. Epub 2009 Apr 29.
PMID: 19403562
citation: Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes VA, Seminara SB, Boepple PA, Sidis Y, Crowley WF Jr, Martin KA, Hall JE, Pitteloud N. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med. 2011 Jan 20;364(3):215-25. doi: 10.1056/NEJMoa0911064.
PMID: 21247312
responsible party type: Sponsor-Investigator
investigator affiliation: First Affiliated Hospital of Zhongshan Medical University
investigator full name: Miao benyu
investigator title: the associated professor
mesh term: Infertility
mesh term: Infertility, Female
mesh term: Triptorelin Pamoate
mesh term: Menotropins
sharing ipd: No