<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/NCT03252223</url>
  </required_header>
  <id_info>
    <org_study_id>170684</org_study_id>
    <secondary_id>P50HD012303</secondary_id>
    <secondary_id>K12HD001259</secondary_id>
    <nct_id>NCT03252223</nct_id>
  </id_info>
  <brief_title>Ovarian Response to Recombinant Follicle Stimulating Hormone in Women With PCOS</brief_title>
  <official_title>Ovarian Function in Women With Polycystic Ovary Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Diego</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Diego</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Women with PCOS suffer from anovulation and, as a result, infertility. Efforts to clinically&#xD;
      induce ovulation in these women using follicle stimulating hormone (FSH) administered&#xD;
      subcutaneously seemingly requires prolonged administration compared to that of ovulatory&#xD;
      women without PCOS. The apparent differing ovarian responsiveness to FSH between PCOS and&#xD;
      normal women has not been carefully studied. We propose to address this issue by performing a&#xD;
      dose-response study and examine ovarian follicle (estrogen, E2) responses to FSH administered&#xD;
      subcutaneously in women with PCOS compared to responses observed in normal women.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In women with polycystic ovary syndrome (PCOS) androgen excess is fundamental to the clinical&#xD;
      and physiological alterations of this disorder. In particular, androgen overproduction&#xD;
      induces distinctive PCO morphology and appears to influence follicle function. Studies&#xD;
      conducted in animals and nonhuman primates have demonstrated that androgens increase follicle&#xD;
      number and in small antral follicles enhance granulosa cell (GC) responsiveness to&#xD;
      gonadotropin stimulation. However, androgens also have been shown to clearly inhibit GC&#xD;
      aromatase activity, and in PCOS follicular fluid, androgen content is abnormally increased.&#xD;
      Efforts to reconcile these differences are nonexistent. Moreover, appropriate clinical&#xD;
      studies to examine the effects of androgen on follicle health in women are lacking. Excessive&#xD;
      androgen exposure in women due to functional tumors or high-dose testosterone treatment in&#xD;
      F-M transsexuals has been associated with PCO morphology. Use of androgen therapy to promote&#xD;
      follicle growth prior to ovarian hyperstimulation in women undergoing in vitro fertilization&#xD;
      has not provided consistent results. However, in these studies GC responses to FSH were not&#xD;
      carefully assessed, study populations were exclusively women with previously poor ovarian&#xD;
      responses to FSH, and women with PCOS were not included. In fact, there are essentially no&#xD;
      clinical studies that have addressed in detail the impact of androgen on follicle function in&#xD;
      normal or PCOS women. We hypothesize that androgen facilitates GC responses to FSH in normal&#xD;
      women and androgen excess further amplifies follicle growth and function in women with PCOS.&#xD;
      We propose to study the effect of increased ovarian androgen on follicle function by&#xD;
      increasing intraovarian androgen accumulation using aromatase inhibition followed by FSH&#xD;
      stimulation. The experiments in this project are designed to provide insight into whether&#xD;
      androgen excess facilitates or interferes with follicle function and ovulation in women with&#xD;
      PCOS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2, 2017</start_date>
  <completion_date type="Actual">June 30, 2021</completion_date>
  <primary_completion_date type="Actual">June 30, 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in granulosa cell function in 24 hours intervals following FSH administration</measure>
    <time_frame>Serum levels will be assessed daily during each 3 day FSH stimulation test and for five days following the initial FSH administration</time_frame>
    <description>Granulosa function will be assessed using estradiol and inhibin levels</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in follicle count in following FSH administration</measure>
    <time_frame>With each dose tested, a pelvic ultrasound will be done before and 3 days after commencing FSH</time_frame>
    <description>Number of ovarian follicles will be assessed by pelvic ultrasound</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in follicular size in following FSH administration</measure>
    <time_frame>With each dose tested, a pelvic ultrasound will be done before and 3 days after commencing FSH</time_frame>
    <description>Size of ovarian follicles will be assessed by pelvic ultrasound</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Polycystic Ovary Syndrome</condition>
  <condition>Healthy</condition>
  <condition>Anovulation</condition>
  <condition>Hyperandrogenism</condition>
  <arm_group>
    <arm_group_label>Women with normal menses</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Women with Polycystic Ovary Syndrome</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Recombinant Follicle Stimulating Hormone</intervention_name>
    <description>A modified dose-response study will be done using recombinant FSH (r-FSH), injected sc for 3 days at any one dose. r-FSH will be administered at weight-adjusted doses equivalent to 37.5, 75, and 150 IU based on an average weight of 70 kg, which approximates the weight of the average woman in the United States according to the Centers for Disease Control. Therefore, the actual dose of r-FSH will be 0.53 IU/kg for the 37.5 dose group. Accordingly, r-FSH will be repeated at doses of 1.1 IU/kg and 2.2 IU/kg that are equivalent to 75 and 150 IU for a 70 kg subject. Each FSH stimulation test will be assigned randomly and be separated by an interval of 8 weeks.</description>
    <arm_group_label>Women with Polycystic Ovary Syndrome</arm_group_label>
    <arm_group_label>Women with normal menses</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects determined to have PCOS based on clinical history of irregular menses and&#xD;
             clinical or laboratory evidence of hyperandrogenism and polycystic ovaries on&#xD;
             ultrasound OR&#xD;
&#xD;
          -  Subjects determined to have a clinical history of regular periods.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Women with hemoglobin less than 11 gm/dl at screening evaluation&#xD;
&#xD;
          2. Women with untreated thyroid abnormalities&#xD;
&#xD;
          3. Pregnant women or women who are nursing&#xD;
&#xD;
          4. Women with BMI &gt; 37&#xD;
&#xD;
          5. Women with known sensitivity to the agents being used&#xD;
&#xD;
          6. Women with diabetes, or renal, liver, or heart disease&#xD;
&#xD;
          7. Women with any hormonal therapy or metformin for at least 2 months prior to study&#xD;
             start.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>37 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>R. Jeffrey Chang, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Diego</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, San Diego</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92037</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>August 8, 2017</study_first_submitted>
  <study_first_submitted_qc>August 14, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 17, 2017</study_first_posted>
  <last_update_submitted>September 6, 2021</last_update_submitted>
  <last_update_submitted_qc>September 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Diego</investigator_affiliation>
    <investigator_full_name>Jeffrey Chang, MD</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>polycystic ovary syndrome</keyword>
  <keyword>anovulation</keyword>
  <keyword>hyperandrogenism</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Polycystic Ovary Syndrome</mesh_term>
    <mesh_term>Hyperandrogenism</mesh_term>
    <mesh_term>Anovulation</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hormones</mesh_term>
    <mesh_term>Follicle Stimulating Hormone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>March 1, 2022</submitted>
    <returned>March 25, 2022</returned>
  </pending_results>
  <!-- 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/NCT03252223
org study id: 170684
secondary id: P50HD012303
secondary id: K12HD001259
nct id: NCT03252223
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
Women with PCOS suffer from anovulation and, as a result, infertility. Efforts to clinically
      induce ovulation in these women using follicle stimulating hormone (FSH) administered
      subcutaneously seemingly requires prolonged administration compared to that of ovulatory
      women without PCOS. The apparent differing ovarian responsiveness to FSH between PCOS and
      normal women has not been carefully studied. We propose to address this issue by performing a
      dose-response study and examine ovarian follicle (estrogen, E2) responses to FSH administered
      subcutaneously in women with PCOS compared to responses observed in normal women.
In women with polycystic ovary syndrome (PCOS) androgen excess is fundamental to the clinical
      and physiological alterations of this disorder. In particular, androgen overproduction
      induces distinctive PCO morphology and appears to influence follicle function. Studies
      conducted in animals and nonhuman primates have demonstrated that androgens increase follicle
      number and in small antral follicles enhance granulosa cell (GC) responsiveness to
      gonadotropin stimulation. However, androgens also have been shown to clearly inhibit GC
      aromatase activity, and in PCOS follicular fluid, androgen content is abnormally increased.
      Efforts to reconcile these differences are nonexistent. Moreover, appropriate clinical
      studies to examine the effects of androgen on follicle health in women are lacking. Excessive
      androgen exposure in women due to functional tumors or high-dose testosterone treatment in
      F-M transsexuals has been associated with PCO morphology. Use of androgen therapy to promote
      follicle growth prior to ovarian hyperstimulation in women undergoing in vitro fertilization
      has not provided consistent results. However, in these studies GC responses to FSH were not
      carefully assessed, study populations were exclusively women with previously poor ovarian
      responses to FSH, and women with PCOS were not included. In fact, there are essentially no
      clinical studies that have addressed in detail the impact of androgen on follicle function in
      normal or PCOS women. We hypothesize that androgen facilitates GC responses to FSH in normal
      women and androgen excess further amplifies follicle growth and function in women with PCOS.
      We propose to study the effect of increased ovarian androgen on follicle function by
      increasing intraovarian androgen accumulation using aromatase inhibition followed by FSH
      stimulation. The experiments in this project are designed to provide insight into whether
      androgen excess facilitates or interferes with follicle function and ovulation in women with
      PCOS.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: Change in granulosa cell function in 24 hours intervals following FSH administration
time frame: Serum levels will be assessed daily during each 3 day FSH stimulation test and for five days following the initial FSH administration
description: Granulosa function will be assessed using estradiol and inhibin levels
measure: Change in follicle count in following FSH administration
time frame: With each dose tested, a pelvic ultrasound will be done before and 3 days after commencing FSH
description: Number of ovarian follicles will be assessed by pelvic ultrasound
measure: Change in follicular size in following FSH administration
time frame: With each dose tested, a pelvic ultrasound will be done before and 3 days after commencing FSH
description: Size of ovarian follicles will be assessed by pelvic ultrasound
arm group label: Women with normal menses
arm group type: Active Comparator
arm group label: Women with Polycystic Ovary Syndrome
arm group type: Active Comparator
intervention type: Drug
intervention name: Recombinant Follicle Stimulating Hormone
description: A modified dose-response study will be done using recombinant FSH (r-FSH), injected sc for 3 days at any one dose. r-FSH will be administered at weight-adjusted doses equivalent to 37.5, 75, and 150 IU based on an average weight of 70 kg, which approximates the weight of the average woman in the United States according to the Centers for Disease Control. Therefore, the actual dose of r-FSH will be 0.53 IU/kg for the 37.5 dose group. Accordingly, r-FSH will be repeated at doses of 1.1 IU/kg and 2.2 IU/kg that are equivalent to 75 and 150 IU for a 70 kg subject. Each FSH stimulation test will be assigned randomly and be separated by an interval of 8 weeks.
arm group label: Women with Polycystic Ovary Syndrome
arm group label: Women with normal menses
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 37 Years
healthy volunteers: Accepts Healthy Volunteers
last name: R. Jeffrey Chang, MD
role: Principal Investigator
affiliation: University of California, San Diego
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of California, San Diego
investigator full name: Jeffrey Chang, MD
investigator title: Professor
mesh term: Polycystic Ovary Syndrome
mesh term: Hyperandrogenism
mesh term: Anovulation
mesh term: Syndrome
mesh term: Hormones
mesh term: Follicle Stimulating Hormone
sharing ipd: No
submitted: March 1, 2022
returned: March 25, 2022