<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/NCT02969590</url>
  </required_header>
  <id_info>
    <org_study_id>OHSU IRB 11532</org_study_id>
    <nct_id>NCT02969590</nct_id>
  </id_info>
  <brief_title>Regulation of Cervical Mucus Secretion</brief_title>
  <official_title>Regulation of Cervical Mucus Secretion</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oregon Health and Science University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Society of Family Planning</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Oregon Health and Science University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to help us determine how hormones impact the production of&#xD;
      cervical mucus which is a fluid secreted by the opening of the uterus, also called the&#xD;
      cervix. During a normal menstrual cycle, cervical mucus changes in response to two hormones&#xD;
      that the ovaries make: estrogen and progesterone. Many of the birth control methods women use&#xD;
      thicken mucus and make it less likely for sperm to enter the uterus. The goal of this study&#xD;
      is to better understand the effects estrogen and progesterone have on the cervical mucus in&#xD;
      the body. To do this, the investigators will be using a drug that suppresses natural hormone&#xD;
      production for 3 months. Estrogen and progesterone will be artificially replaced to better&#xD;
      understand their effects. The investigators will also be studying the effect of a common&#xD;
      birth control pill that may work by thickening cervical mucus. Last, the investigators will&#xD;
      study some of the cells in the cervix that produce mucus.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This proposed study is to evaluate the temporal changes in human cervical mucus in response&#xD;
      to progesterone and progestins as an initial step toward clarifying these relationships. Our&#xD;
      hypothesis is that direct effects of progesterone on the endocervix, independent of estrogen&#xD;
      withdrawal, cause contraceptive changes to cervical mucus. To study this, a randomized,&#xD;
      prospective, crossover study will be conducted by examining cervical mucus changes in a small&#xD;
      cohort of women in whom investigators will suppress circulating hormonal levels by&#xD;
      administering a GnRH antagonist. Investigators will then artificially replace Estrogen and&#xD;
      Progesterone in order to differentiate their effects on clinical and laboratory measurements&#xD;
      of mucus quality. The investigators will be looking closely at the immediate changes in mucus&#xD;
      when .35 mg of norethindrone, a marketed drug is administered in this experimental setting.&#xD;
      Cervical cell samples will also be collected at various time points and perform RT-PCR to&#xD;
      determine whether genes for membrane bound progesterone receptor are expressed and regulated&#xD;
      by Estrogen and Progesterone.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 29, 2015</start_date>
  <completion_date type="Actual">August 23, 2017</completion_date>
  <primary_completion_date type="Actual">August 23, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Median Cervical Mucus Score - Baseline</measure>
    <time_frame>Baseline</time_frame>
    <description>Measurement of median cervical mucus scores at baseline. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Sperm Penetration Scores</measure>
    <time_frame>Approximately one year</time_frame>
    <description>Measuring sperm penetration scores in different hormonal conditions</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Median Cervical Mucus Score - 2 Hour</measure>
    <time_frame>2 hours</time_frame>
    <description>Measurement of median cervical mucus scores 2 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Median Cervical Mucus Score - 6 Hour</measure>
    <time_frame>6 hours</time_frame>
    <description>Measurement of median cervical mucus scores 6 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Median Cervical Mucus Score - 24 Hour</measure>
    <time_frame>24 hours</time_frame>
    <description>Measurement of median cervical mucus scores 24 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in PGRMC1 During Menstrual Cycle</measure>
    <time_frame>1 month</time_frame>
    <description>Measuring the mean transcript change of membrane bound progestin receptors (PGRMC1) from follicular phase to ovulation to luteal phase of spontaneous menstrual cycle.&#xD;
Total RNA (ribonucleic acid) was isolated from endocervical cell samples and analyzed for expression of PGRMC1 using real-time PCR (polymerase chain reaction) relative to levels of ribosomal (S10) RNA. An endocervical brush will be inserted into the os and then immediately rinsed into a special RNA preserving reagent. After total RNA is isolated and purified, it will be reverse transcribed into cDNA using primers.&#xD;
Ratio of PGRMC1 to 18s RNA&#xD;
Gene expression of membrane bound progesterone receptors in endocervical cells</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Fertility</condition>
  <condition>Contraception</condition>
  <arm_group>
    <arm_group_label>No Intervention: Spontaneous Cycle (1 month)</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>In order to qualify for the intervention phase, subjects needed to demonstrate favorable mucus at ovulation (Insler score of greater than or equal to 10 within 24h of an LH surge) and progesterone level in the luteal phase consistent with ovulation (a single P4 of greater than or equal to 3ng/ ml between days 18-35 of menstrual cycle).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>NET Arm - Norethindrone (4 months)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>E2WD Arm - Estradiol (4 months)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches ; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leuprolide acetate</intervention_name>
    <description>Following this spontaneous cycle, participants received a single intramuscular injection of leuprolide acetate (11.25mg, LupronVR; Abbvie, Chicago, IL), a dose documented to suppress ovarian function for at least 3 months. Ovarian suppression is confirmed with serum E2 less than or equal to 35 pg/ml 21-28 day post-injection.</description>
    <arm_group_label>E2WD Arm - Estradiol (4 months)</arm_group_label>
    <arm_group_label>NET Arm - Norethindrone (4 months)</arm_group_label>
    <other_name>Lupron</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Estrogen and Progesterone Replacement</intervention_name>
    <description>Replace hormones exogenously to create an artificial cycle</description>
    <arm_group_label>E2WD Arm - Estradiol (4 months)</arm_group_label>
    <arm_group_label>NET Arm - Norethindrone (4 months)</arm_group_label>
    <other_name>Estradiol (vivelle-dot)</other_name>
    <other_name>Progesterone (prometrium, progestin)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Progestin</intervention_name>
    <description>Synthetic progestin to assess effects on cervical mucus.</description>
    <arm_group_label>E2WD Arm - Estradiol (4 months)</arm_group_label>
    <arm_group_label>NET Arm - Norethindrone (4 months)</arm_group_label>
    <other_name>Norethindrone</other_name>
    <other_name>NET</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Normal menstrual cycles of 25-35 days in length for at least previous 3 cycles&#xD;
&#xD;
          -  21-40 years of age&#xD;
&#xD;
          -  BMI &gt;18, &lt;30&#xD;
&#xD;
          -  Serum P4 ≥ 3 ng/ml on single sample collected between days 18-25 of self-reported&#xD;
             menstrual cycle&#xD;
&#xD;
          -  Flexible schedule allowing morning blood draws on less than 48 hour notice&#xD;
&#xD;
          -  In good general health&#xD;
&#xD;
          -  Commit to remain on stable diet during study period (no changes to normal dietary&#xD;
             habits)&#xD;
&#xD;
          -  Commit to using non-hormonal contraceptive methods during study period except those&#xD;
             prescribed in the experimental protocol&#xD;
&#xD;
          -  No objections to taking study drugs&#xD;
&#xD;
          -  No objections to refraining from intercourse the night before any sampling and willing&#xD;
             to using condoms during vaginal intercourse.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Oral contraceptive use or other hormone supplement within the preceding 2 months&#xD;
&#xD;
          -  Women with current cervical infection&#xD;
&#xD;
          -  Evidence of abnormal cervical cytology&#xD;
&#xD;
          -  Use of Paragard IUD for contraception&#xD;
&#xD;
          -  Long-acting hormonal contraceptive use in the past 12 months (e.g., Depo-Provera®)&#xD;
&#xD;
          -  Contraindications to study drugs&#xD;
&#xD;
          -  Current or past pregnancy within the previous 6 months or currently trying to conceive&#xD;
&#xD;
          -  Desiring to conceive in the next 8 months&#xD;
&#xD;
          -  Breastfeeding in the past 2 months&#xD;
&#xD;
          -  Diagnosed Diabetes or Metabolic Syndrome&#xD;
&#xD;
          -  Current or previous use of cholesterol lowering drugs within the preceding 12 months&#xD;
&#xD;
          -  Diagnosed Polycystic Ovary Syndrome&#xD;
&#xD;
          -  History of, or self-reported, substance abuse&#xD;
&#xD;
          -  Smoker&#xD;
&#xD;
          -  Previous infertility treatment excluding male factor issues&#xD;
&#xD;
          -  Use of an investigational drug within the past 2 months&#xD;
&#xD;
          -  History of excisional or ablative treatment procedure on cervix (ie. LEEP,&#xD;
             Cryotherapy, Cold Knife Cone)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Leo Han, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Oregon Health and Science University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>May 27, 2015</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <results_first_submitted>April 4, 2019</results_first_submitted>
  <results_first_submitted_qc>October 16, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">October 18, 2019</results_first_posted>
  <last_update_submitted>October 16, 2019</last_update_submitted>
  <last_update_submitted_qc>October 16, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Oregon Health and Science University</investigator_affiliation>
    <investigator_full_name>Leo Han</investigator_full_name>
    <investigator_title>Instructor</investigator_title>
  </responsible_party>
  <keyword>Contraception</keyword>
  <keyword>Mucus</keyword>
  <keyword>Cervix</keyword>
  <keyword>progestin</keyword>
  <keyword>hormones</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leuprolide</mesh_term>
    <mesh_term>Norethindrone</mesh_term>
    <mesh_term>Estradiol</mesh_term>
    <mesh_term>Estrogens</mesh_term>
    <mesh_term>Progesterone</mesh_term>
    <mesh_term>Progestins</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 12, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/90/NCT02969590/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>In order to qualify for the intervention phase, subjects needed to demonstrate an ovulatory menstrual cycle during the Screening Period.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Spontaneous Cycle</title>
          <description>In order to qualify for the intervention phase, subjects needed to demonstrate favorable mucus at ovulation (Insler score of greater than or equal to 10 within 24h of an LH surge) and progesterone level in the luteal phase consistent with ovulation (a single P4 of greater than or equal to 3ng/ ml between days 18-35 of menstrual cycle).</description>
        </group>
        <group group_id="P2">
          <title>NET Arm - Norethindrone, Then Estradiol Withdrawal</title>
          <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
        </group>
        <group group_id="P3">
          <title>E2WD Arm - Estradiol Withdrawal, Then Norethindrone</title>
          <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Screening Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Hormones not suppressed post Lupron</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Treatment Period 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Treatment Period 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Norethindrone, Then Estradiol Withdrawal</title>
          <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
        </group>
        <group group_id="B2">
          <title>Estradiol Withdrawal, Then Norethindrone</title>
          <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
            <count group_id="B2" value="2"/>
            <count group_id="B3" value="4"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Median Cervical Mucus Score - Baseline</title>
        <description>Measurement of median cervical mucus scores at baseline. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
        <time_frame>Baseline</time_frame>
        <population>Data from one (1) subject were excluded from analyses because estradiol (E2) levels were consistent with patch noncompliance</population>
        <group_list>
          <group group_id="O1">
            <title>Norethindrone</title>
            <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol</title>
            <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Cervical Mucus Score - Baseline</title>
          <description>Measurement of median cervical mucus scores at baseline. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
          <population>Data from one (1) subject were excluded from analyses because estradiol (E2) levels were consistent with patch noncompliance</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11" lower_limit="9" upper_limit="12"/>
                    <measurement group_id="O2" value="13" lower_limit="12" upper_limit="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Sperm Penetration Scores</title>
        <description>Measuring sperm penetration scores in different hormonal conditions</description>
        <time_frame>Approximately one year</time_frame>
        <population>Outcome not analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>Norethindrone</title>
            <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol</title>
            <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
        </group_list>
        <measure>
          <title>Sperm Penetration Scores</title>
          <description>Measuring sperm penetration scores in different hormonal conditions</description>
          <population>Outcome not analyzed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in PGRMC1 During Menstrual Cycle</title>
        <description>Measuring the mean transcript change of membrane bound progestin receptors (PGRMC1) from follicular phase to ovulation to luteal phase of spontaneous menstrual cycle.&#xD;
Total RNA (ribonucleic acid) was isolated from endocervical cell samples and analyzed for expression of PGRMC1 using real-time PCR (polymerase chain reaction) relative to levels of ribosomal (S10) RNA. An endocervical brush will be inserted into the os and then immediately rinsed into a special RNA preserving reagent. After total RNA is isolated and purified, it will be reverse transcribed into cDNA using primers.&#xD;
Ratio of PGRMC1 to 18s RNA&#xD;
Gene expression of membrane bound progesterone receptors in endocervical cells</description>
        <time_frame>1 month</time_frame>
        <population>PGRMC1 data was analyzed for the 4 subjects who demonstrate ovarian suppression following leuprolide injection and continued to intervention phase of the study. Outcome was only evaluated during spontaneous menstrual cycle (1 month).&#xD;
One participant corresponds to one cycle.</population>
        <group_list>
          <group group_id="O1">
            <title>Spontaneous Cycle</title>
            <description>In order to qualify for the intervention phase, subjects needed to demonstrate favorable mucus at ovulation (Insler score of greater than or equal to 10 within 24h of an LH surge) and progesterone level in the luteal phase consistent with ovulation (a single P4 of greater than or equal to 3ng/ ml between days 18-35 of menstrual cycle).&#xD;
Prior to the intervention cycle, each subject was observed over the normal natural cycle during which time we collected menstrual data including serum sex-steroid levels, mucus and cytology brushings for PGRMC1 analysis.</description>
          </group>
          <group group_id="O2">
            <title>Norethindrone</title>
            <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
          <group group_id="O3">
            <title>Estradiol</title>
            <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in PGRMC1 During Menstrual Cycle</title>
          <description>Measuring the mean transcript change of membrane bound progestin receptors (PGRMC1) from follicular phase to ovulation to luteal phase of spontaneous menstrual cycle.&#xD;
Total RNA (ribonucleic acid) was isolated from endocervical cell samples and analyzed for expression of PGRMC1 using real-time PCR (polymerase chain reaction) relative to levels of ribosomal (S10) RNA. An endocervical brush will be inserted into the os and then immediately rinsed into a special RNA preserving reagent. After total RNA is isolated and purified, it will be reverse transcribed into cDNA using primers.&#xD;
Ratio of PGRMC1 to 18s RNA&#xD;
Gene expression of membrane bound progesterone receptors in endocervical cells</description>
          <population>PGRMC1 data was analyzed for the 4 subjects who demonstrate ovarian suppression following leuprolide injection and continued to intervention phase of the study. Outcome was only evaluated during spontaneous menstrual cycle (1 month).&#xD;
One participant corresponds to one cycle.</population>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Follicular Phase</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.2" spread="0.38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ovulation Phase</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.0" spread="2.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Luteal Phase</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.02" spread="0.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Median Cervical Mucus Score - 2 Hour</title>
        <description>Measurement of median cervical mucus scores 2 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
        <time_frame>2 hours</time_frame>
        <population>Data from one (1) subject were excluded from analyses because estradiol (E2) levels were consistent with patch noncompliance</population>
        <group_list>
          <group group_id="O1">
            <title>Norethindrone</title>
            <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol</title>
            <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Cervical Mucus Score - 2 Hour</title>
          <description>Measurement of median cervical mucus scores 2 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
          <population>Data from one (1) subject were excluded from analyses because estradiol (E2) levels were consistent with patch noncompliance</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.5" lower_limit="4" upper_limit="9"/>
                    <measurement group_id="O2" value="10.5" lower_limit="10" upper_limit="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Median Cervical Mucus Score - 6 Hour</title>
        <description>Measurement of median cervical mucus scores 6 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
        <time_frame>6 hours</time_frame>
        <population>Data from one (1) subject were excluded from analyses because estradiol (E2) levels were consistent with patch noncompliance</population>
        <group_list>
          <group group_id="O1">
            <title>Norethindrone</title>
            <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol</title>
            <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Cervical Mucus Score - 6 Hour</title>
          <description>Measurement of median cervical mucus scores 6 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
          <population>Data from one (1) subject were excluded from analyses because estradiol (E2) levels were consistent with patch noncompliance</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.5" lower_limit="6" upper_limit="8"/>
                    <measurement group_id="O2" value="8.5" lower_limit="8" upper_limit="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Median Cervical Mucus Score - 24 Hour</title>
        <description>Measurement of median cervical mucus scores 24 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
        <time_frame>24 hours</time_frame>
        <population>Data from one (1) subject were excluded from analyses because estradiol (E2) levels were consistent with patch noncompliance</population>
        <group_list>
          <group group_id="O1">
            <title>Norethindrone</title>
            <description>This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol</title>
            <description>This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Cervical Mucus Score - 24 Hour</title>
          <description>Measurement of median cervical mucus scores 24 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered &quot;mucus favoring penetration&quot; and scores below 10 are considered to be &quot;unfavorable to penetration.&quot;</description>
          <population>Data from one (1) subject were excluded from analyses because estradiol (E2) levels were consistent with patch noncompliance</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8" lower_limit="7" upper_limit="8"/>
                    <measurement group_id="O2" value="10.5" lower_limit="8" upper_limit="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>4 months</time_frame>
      <desc>Crossover study. One participant corresponds to one cycle.</desc>
      <group_list>
        <group group_id="E1">
          <title>Spontaneous Cycle</title>
          <description>Adverse Events experienced by subjects during Spontaneous Cycle.&#xD;
In order to qualify for the intervention phase, subjects needed to demonstrate favorable mucus at ovulation (Insler score of greater than or equal to 10 within 24h of an LH surge) and progesterone level in the luteal phase consistent with ovulation (a single P4 of greater than or equal to 3ng/ ml between days 18-35 of menstrual cycle).</description>
        </group>
        <group group_id="E2">
          <title>Norethindrone (NET)</title>
          <description>Adverse Events experienced by subjects for the Norethindrone intervention (while in the Norethindrone (NET) arm of study).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
        </group>
        <group group_id="E3">
          <title>Estradiol (E2)</title>
          <description>Adverse Events experienced by subjects for the Estradiol (E2) intervention (while in the estradiol (E2) arm of study).&#xD;
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.&#xD;
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.&#xD;
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Ob/Gyn Regulatory Specialist</name_or_title>
      <organization>Oregon Health &amp; Science University</organization>
      <phone>5034940757</phone>
      <email>mccrimmo@ohsu.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02969590
org study id: OHSU IRB 11532
nct id: NCT02969590
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this study is to help us determine how hormones impact the production of
      cervical mucus which is a fluid secreted by the opening of the uterus, also called the
      cervix. During a normal menstrual cycle, cervical mucus changes in response to two hormones
      that the ovaries make: estrogen and progesterone. Many of the birth control methods women use
      thicken mucus and make it less likely for sperm to enter the uterus. The goal of this study
      is to better understand the effects estrogen and progesterone have on the cervical mucus in
      the body. To do this, the investigators will be using a drug that suppresses natural hormone
      production for 3 months. Estrogen and progesterone will be artificially replaced to better
      understand their effects. The investigators will also be studying the effect of a common
      birth control pill that may work by thickening cervical mucus. Last, the investigators will
      study some of the cells in the cervix that produce mucus.
This proposed study is to evaluate the temporal changes in human cervical mucus in response
      to progesterone and progestins as an initial step toward clarifying these relationships. Our
      hypothesis is that direct effects of progesterone on the endocervix, independent of estrogen
      withdrawal, cause contraceptive changes to cervical mucus. To study this, a randomized,
      prospective, crossover study will be conducted by examining cervical mucus changes in a small
      cohort of women in whom investigators will suppress circulating hormonal levels by
      administering a GnRH antagonist. Investigators will then artificially replace Estrogen and
      Progesterone in order to differentiate their effects on clinical and laboratory measurements
      of mucus quality. The investigators will be looking closely at the immediate changes in mucus
      when .35 mg of norethindrone, a marketed drug is administered in this experimental setting.
      Cervical cell samples will also be collected at various time points and perform RT-PCR to
      determine whether genes for membrane bound progesterone receptor are expressed and regulated
      by Estrogen and Progesterone.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Single (Investigator)
measure: Median Cervical Mucus Score - Baseline
time frame: Baseline
description: Measurement of median cervical mucus scores at baseline. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered "mucus favoring penetration" and scores below 10 are considered to be "unfavorable to penetration."
measure: Sperm Penetration Scores
time frame: Approximately one year
description: Measuring sperm penetration scores in different hormonal conditions
measure: Median Cervical Mucus Score - 2 Hour
time frame: 2 hours
description: Measurement of median cervical mucus scores 2 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered "mucus favoring penetration" and scores below 10 are considered to be "unfavorable to penetration."
measure: Median Cervical Mucus Score - 6 Hour
time frame: 6 hours
description: Measurement of median cervical mucus scores 6 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered "mucus favoring penetration" and scores below 10 are considered to be "unfavorable to penetration."
measure: Median Cervical Mucus Score - 24 Hour
time frame: 24 hours
description: Measurement of median cervical mucus scores 24 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered "mucus favoring penetration" and scores below 10 are considered to be "unfavorable to penetration."
measure: Change in PGRMC1 During Menstrual Cycle
time frame: 1 month
description: Measuring the mean transcript change of membrane bound progestin receptors (PGRMC1) from follicular phase to ovulation to luteal phase of spontaneous menstrual cycle.
Total RNA (ribonucleic acid) was isolated from endocervical cell samples and analyzed for expression of PGRMC1 using real-time PCR (polymerase chain reaction) relative to levels of ribosomal (S10) RNA. An endocervical brush will be inserted into the os and then immediately rinsed into a special RNA preserving reagent. After total RNA is isolated and purified, it will be reverse transcribed into cDNA using primers.
Ratio of PGRMC1 to 18s RNA
Gene expression of membrane bound progesterone receptors in endocervical cells
arm group label: No Intervention: Spontaneous Cycle (1 month)
arm group type: No Intervention
description: In order to qualify for the intervention phase, subjects needed to demonstrate favorable mucus at ovulation (Insler score of greater than or equal to 10 within 24h of an LH surge) and progesterone level in the luteal phase consistent with ovulation (a single P4 of greater than or equal to 3ng/ ml between days 18-35 of menstrual cycle).
arm group label: NET Arm - Norethindrone (4 months)
arm group type: Active Comparator
description: This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD).
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.
arm group label: E2WD Arm - Estradiol (4 months)
arm group type: Active Comparator
description: This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET).
On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects.
On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches ; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four.
Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.
intervention type: Drug
intervention name: Leuprolide acetate
description: Following this spontaneous cycle, participants received a single intramuscular injection of leuprolide acetate (11.25mg, LupronVR; Abbvie, Chicago, IL), a dose documented to suppress ovarian function for at least 3 months. Ovarian suppression is confirmed with serum E2 less than or equal to 35 pg/ml 21-28 day post-injection.
arm group label: E2WD Arm - Estradiol (4 months)
arm group label: NET Arm - Norethindrone (4 months)
other name: Lupron
intervention type: Drug
intervention name: Estrogen and Progesterone Replacement
description: Replace hormones exogenously to create an artificial cycle
arm group label: E2WD Arm - Estradiol (4 months)
arm group label: NET Arm - Norethindrone (4 months)
other name: Estradiol (vivelle-dot)
other name: Progesterone (prometrium, progestin)
intervention type: Drug
intervention name: Progestin
description: Synthetic progestin to assess effects on cervical mucus.
arm group label: E2WD Arm - Estradiol (4 months)
arm group label: NET Arm - Norethindrone (4 months)
other name: Norethindrone
other name: NET
criteria: 
gender: Female
minimum age: 21 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Leo Han, MD
role: Principal Investigator
affiliation: Oregon Health and Science University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Oregon Health and Science University
investigator full name: Leo Han
investigator title: Instructor
mesh term: Leuprolide
mesh term: Norethindrone
mesh term: Estradiol
mesh term: Estrogens
mesh term: Progesterone
mesh term: Progestins
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 