<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/NCT04458662</url>
  </required_header>
  <id_info>
    <org_study_id>DEP2016-75387-P</org_study_id>
    <nct_id>NCT04458662</nct_id>
  </id_info>
  <brief_title>Iron and Muscular Damage: FEmale Metabolism and Menstrual Cycle During Exercise</brief_title>
  <acronym>IronFEMME</acronym>
  <official_title>Iron and Muscular Damage: FEmale Metabolism and Menstrual Cycle During Exercise</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universidad Politecnica de Madrid</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministerio de Economía y Competitividad, Spain</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Universidad Politecnica de Madrid</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This project is an observational controlled randomized counterbalance study. One hundred and&#xD;
      three physically active and healthy women were selected to participate in the IronFEMME&#xD;
      Study, of which 57 were eumenorrheic, 30 were oral contraceptive users (OCP) and 16 were&#xD;
      postmenopausal women. The project consisted on two sections carrying out at the same time:&#xD;
      Iron metabolism (Study I) and Muscle damage (Study II). For the study I, the exercise&#xD;
      protocol consisted on an interval running test (8 bouts of 3 min at 85% of the maximal&#xD;
      aerobic speed), whereas the study II protocol was based on an eccentric-based resistance&#xD;
      exercise protocol (10 sets of 10 repetitions of plate-loaded barbell parallel back squats at&#xD;
      60% of their 1RM with 2 min of rest between sets). In both studies, eumenorrheic participants&#xD;
      were evaluated at three specific moments of the menstrual cycle: Early-follicular phase,&#xD;
      late-follicular phase and mid-luteal phase; OCP performed the trial at two moments:&#xD;
      Withdrawal phase and active pill phase. Lastly, postmenopausal women were tested only once,&#xD;
      since their hormonal status does not fluctuate. The three-step method was used to verify the&#xD;
      menstrual cycle phase: calendar counting, blood analyses confirmation and urine-based&#xD;
      ovulation kits. Blood samples were obtained to measure sexual hormones (e.g., 17β-Estradiol,&#xD;
      Progesterone), iron metabolism parameters (e.g., Hepcidin, Iron, Ferritin, Transferrin) and&#xD;
      muscle damage related markers (e.g., Creatine Kinase, Myoglobin, Lactate Dehydrogenase).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2017</start_date>
  <completion_date type="Actual">June 1, 2020</completion_date>
  <primary_completion_date type="Actual">March 31, 2019</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <target_duration>2 Months</target_duration>
  <primary_outcome>
    <measure>Hepcidin</measure>
    <time_frame>pre-exercise</time_frame>
    <description>Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hepcidin</measure>
    <time_frame>0 hours post-exercise</time_frame>
    <description>Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hepcidin</measure>
    <time_frame>3 hours post-exercise</time_frame>
    <description>Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hepcidin</measure>
    <time_frame>24 hours post-exercise</time_frame>
    <description>Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Creatine kinase</measure>
    <time_frame>pre-exercise</time_frame>
    <description>It is an enzyme that helps regulate the concentration of adenosine triphosphate within a cell. To do so, creatine kinase catalyzes the movement of a phosphate group from ATP to creatine, forming phosphocreatine. This molecules stores the phosphate group in a stable form, acting as an energy reservoir in cells.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Creatine kinase</measure>
    <time_frame>2 hours post-exercise</time_frame>
    <description>It is an enzyme that helps regulate the concentration of adenosine triphosphate within a cell. To do so, creatine kinase catalyzes the movement of a phosphate group from ATP to creatine, forming phosphocreatine. This molecules stores the phosphate group in a stable form, acting as an energy reservoir in cells.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Creatine kinase</measure>
    <time_frame>24 hours post-exercise</time_frame>
    <description>It is an enzyme that helps regulate the concentration of adenosine triphosphate within a cell. To do so, creatine kinase catalyzes the movement of a phosphate group from ATP to creatine, forming phosphocreatine. This molecules stores the phosphate group in a stable form, acting as an energy reservoir in cells.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Creatine kinase</measure>
    <time_frame>48 hours post-exercise</time_frame>
    <description>It is an enzyme that helps regulate the concentration of adenosine triphosphate within a cell. To do so, creatine kinase catalyzes the movement of a phosphate group from ATP to creatine, forming phosphocreatine. This molecules stores the phosphate group in a stable form, acting as an energy reservoir in cells.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Iron</measure>
    <time_frame>pre-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Iron</measure>
    <time_frame>0 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Iron</measure>
    <time_frame>3 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Iron</measure>
    <time_frame>24 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transferrin</measure>
    <time_frame>pre-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transferrin</measure>
    <time_frame>0 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transferrin</measure>
    <time_frame>3 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transferrin</measure>
    <time_frame>24 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ferritin</measure>
    <time_frame>pre-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ferritin</measure>
    <time_frame>0 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ferritin</measure>
    <time_frame>3 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ferritin</measure>
    <time_frame>24 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mioglobin</measure>
    <time_frame>pre-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mioglobin</measure>
    <time_frame>2 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mioglobin</measure>
    <time_frame>24 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mioglobin</measure>
    <time_frame>48 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LDH</measure>
    <time_frame>pre-exercise</time_frame>
    <description>Lactate deshidrogenase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LDH</measure>
    <time_frame>2 hours post-exercise</time_frame>
    <description>Lactate deshidrogenase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LDH</measure>
    <time_frame>24 hours post-exercise</time_frame>
    <description>Lactate deshidrogenase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LDH</measure>
    <time_frame>48 hours post-exercise</time_frame>
    <description>Lactate deshidrogenase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TNF-alfa</measure>
    <time_frame>pre-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TNF-alfa</measure>
    <time_frame>2 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TNF-alfa</measure>
    <time_frame>24 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TNF-alfa</measure>
    <time_frame>48 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interleukin-6</measure>
    <time_frame>pre-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interleukin-6</measure>
    <time_frame>0 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interleukin-6</measure>
    <time_frame>2 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interleukin-6</measure>
    <time_frame>24 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interleukin-6</measure>
    <time_frame>48 hours post-exercise</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CRP</measure>
    <time_frame>pre-exercise</time_frame>
    <description>C-reactive protein</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CRP</measure>
    <time_frame>0 hours post-exercise</time_frame>
    <description>C-reactive protein</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CRP</measure>
    <time_frame>2 hours post-exercise</time_frame>
    <description>C-reactive protein</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CRP</measure>
    <time_frame>24 hours post-exercise</time_frame>
    <description>C-reactive protein</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CRP</measure>
    <time_frame>48 hours post-exercise</time_frame>
    <description>C-reactive protein</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">103</enrollment>
  <condition>Iron-deficiency</condition>
  <condition>Inflammation</condition>
  <condition>Exercise Induced Iron-deficiency</condition>
  <condition>Exercise Induced Muscle Damage</condition>
  <condition>Regulation of Sex Hormones on Hepcidin</condition>
  <condition>Regulation of Sex Hormones on Muscle Damage</condition>
  <condition>Iron Metabolism Disorders</condition>
  <arm_group>
    <arm_group_label>Eumenorrheic women</arm_group_label>
    <description>The project consisted on two sections carrying out at the same time: Iron physiology (Study I) and Muscle damage (Study II).&#xD;
For the study I, the exercise protocol consisted on an interval running test. 5 min warm-up at 60% of the vVO2peak followed by 8 bouts of 3 min at 85% of the vVO2peak with 90 secs recovery at 30% of the vVO2peak between bouts. Finally, a 5 min cool down was performed at 30% of the vVO2peak.&#xD;
The study II protocol was based on an eccentric-based resistance exercise protocol consisted on 10 sets of 10 reps of plate-loaded parallel back squats at 60% of their previously calculated 1RM with 2 mins recoveries between sets.&#xD;
In both studies, eumenorrheic participants were evaluated at three specific moments of the menstrual cycle: Early-follicular phase (EFP), late-follicular phase (LFP) and mid-luteal phase (MLP);</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Oral contraceptive users</arm_group_label>
    <description>The project consisted on two sections carrying out at the same time: Iron physiology (Study I) and Muscle damage (Study II).&#xD;
For the study I, the exercise protocol consisted on an interval running test. 5 min warm-up at 60% of the vVO2peak followed by 8 bouts of 3 min at 85% of the vVO2peak with 90 secs recovery at 30% of the vVO2peak between bouts. Finally, a 5 min cool down was performed at 30% of the vVO2peak.&#xD;
The study II protocol was based on an eccentric-based resistance exercise protocol consisted on 10 sets of 10 reps of plate-loaded parallel back squats at 60% of their previously calculated 1RM with 2 mins recoveries between sets.&#xD;
Oral contraceptive users performed the trial at two moments: Withdrawal phase (WP) and active pill phase (APP).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Postmenopausal women</arm_group_label>
    <description>he project consisted on two sections carrying out at the same time: Iron physiology (Study I) and Muscle damage (Study II).&#xD;
For the study I, the exercise protocol consisted on an interval running test. 5 min warm-up at 60% of the vVO2peak followed by 8 bouts of 3 min at 85% of the vVO2peak with 90 secs recovery at 30% of the vVO2peak between bouts. Finally, a 5 min cool down was performed at 30% of the vVO2peak.&#xD;
The study II protocol was based on an eccentric-based resistance exercise protocol consisted on 10 sets of 10 reps of plate-loaded parallel back squats at 60% of their previously calculated 1RM with 2 mins recoveries between sets.&#xD;
Postmenopausal women were tested only once, since their hormonal status does not fluctuate.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Interval running protocol / eccentric-based resistance exercise protocol</intervention_name>
    <arm_group_label>Eumenorrheic women</arm_group_label>
    <arm_group_label>Oral contraceptive users</arm_group_label>
    <arm_group_label>Postmenopausal women</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Physically active and healthy women. Study I, 37 eumenorrheic women (30.0±6.3 yrs;&#xD;
        59.8±15.7 kg; 163.7±6.3 cm): endurance training (ET) experience of 7.7 yrs and training&#xD;
        volume of 5.5±0.9 h/week. Study II, 20 eumenorrheic women (28.8±6.2 yrs; 57.5±13.8 kg;&#xD;
        163.9±6.4 cm): strength training (ST) experience of 6.4±4.1 yrs and training volume of&#xD;
        7.5±2.1 h/week. Eumenorrheic women selected to participate in Study I and II were&#xD;
        different, whereas oral contraceptive users and postmenopausal women participated in both&#xD;
        studies. 30 oral contraceptive users (25.1±4.3 yrs; 56.2±10.9 kg; 163.1±5.5 cm): ET&#xD;
        experience of 7.3±5.5 yrs and training volume of 3.4±1.5 h/week; ST experience of 3.1±1.9&#xD;
        yrs and training volume of 2.5±1.4 h/week. 16 postmenopausal women (51.4±3.7 yrs; 56.7±8.3&#xD;
        kg; 161.7±4.9 cm): ET experience of 7.9±3.4 yrs and training volume of 4.1±1.2 h/week; ST&#xD;
        experience of 3.1±1.9 yrs and training volume of 1.6±0.9 h/week&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Participants were required to meet the following criteria:&#xD;
&#xD;
          -  Healthy adult females between 18 and 40 years old for eumerroheic and oral&#xD;
             contraceptive groups or under 60 years old for postmenopausal women.&#xD;
&#xD;
          -  Presenting with healthy iron parameters (serum ferritin &gt;20μg/l, haemoglobin &gt;115 μg/l&#xD;
             and transferrin saturation &gt;16%).&#xD;
&#xD;
          -  Performing endurance training between 5 and 12 h per week (study I) or experienced in&#xD;
             resistance training performing at least 1 h session two times per week during a&#xD;
             minimum of a year (study II).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        The exclusion criteria included:&#xD;
&#xD;
          -  Irregular menstrual cycles.&#xD;
&#xD;
          -  Any existing disease and/or metabolic or hormonal disorder.&#xD;
&#xD;
          -  Any musculoskeletal injury in the last six months prior to the beginning of the&#xD;
             project.&#xD;
&#xD;
          -  Any surgery interventions (e.g. ovariectomy) or other medical conditions that would be&#xD;
             exacerbated by an eccentric resistance exercise protocol.&#xD;
&#xD;
          -  Regular use of medication or dietary supplements that could affect the results (e.g.&#xD;
             nonsteroidal anti-inflammatory drugs).&#xD;
&#xD;
          -  Taking medication that alters vascular function (e.g. tricyclic antidepressants,&#xD;
             α-blockers, β-blockers, etc.).&#xD;
&#xD;
          -  Pregnancies in the year preceding.&#xD;
&#xD;
          -  Smoking.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ana Belén Peinado</last_name>
    <role>Study Director</role>
    <affiliation>LFE Research Group. Universidad Politécnica de Madrid</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Laboratorio de Fisiología Del Esfuerzo. Facultad de Ciencias de La Actividad Física Y Del Deporte. Universidad Politécnica de Madrid.</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <link>
    <url>https://ironfemme.com</url>
    <description>IronFEMME project official web page</description>
  </link>
  <reference>
    <citation>Lehtihet M, Bonde Y, Beckman L, Berinder K, Hoybye C, Rudling M, Sloan JH, Konrad RJ, Angelin B. Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans. PLoS One. 2016 Feb 11;11(2):e0148802. doi: 10.1371/journal.pone.0148802. eCollection 2016.</citation>
    <PMID>26866603</PMID>
  </reference>
  <reference>
    <citation>Hou Y, Zhang S, Wang L, Li J, Qu G, He J, Rong H, Ji H, Liu S. Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. Gene. 2012 Dec 15;511(2):398-403. doi: 10.1016/j.gene.2012.09.060. Epub 2012 Oct 3.</citation>
    <PMID>23041085</PMID>
  </reference>
  <reference>
    <citation>Ikeda Y, Tajima S, Izawa-Ishizawa Y, Kihira Y, Ishizawa K, Tomita S, Tsuchiya K, Tamaki T. Estrogen regulates hepcidin expression via GPR30-BMP6-dependent signaling in hepatocytes. PLoS One. 2012;7(7):e40465. doi: 10.1371/journal.pone.0040465. Epub 2012 Jul 11.</citation>
    <PMID>22792339</PMID>
  </reference>
  <reference>
    <citation>Li X, Rhee DK, Malhotra R, Mayeur C, Hurst LA, Ager E, Shelton G, Kramer Y, McCulloh D, Keefe D, Bloch KD, Bloch DB, Peterson RT. Progesterone receptor membrane component-1 regulates hepcidin biosynthesis. J Clin Invest. 2016 Jan;126(1):389-401. doi: 10.1172/JCI83831. Epub 2015 Dec 14.</citation>
    <PMID>26657863</PMID>
  </reference>
  <reference>
    <citation>Yang Q, Jian J, Katz S, Abramson SB, Huang X. 17beta-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. Endocrinology. 2012 Jul;153(7):3170-8. doi: 10.1210/en.2011-2045. Epub 2012 Apr 25.</citation>
    <PMID>22535765</PMID>
  </reference>
  <reference>
    <citation>Thompson B, Almarjawi A, Sculley D, Janse de Jonge X. The Effect of the Menstrual Cycle and Oral Contraceptives on Acute Responses and Chronic Adaptations to Resistance Training: A Systematic Review of the Literature. Sports Med. 2020 Jan;50(1):171-185. doi: 10.1007/s40279-019-01219-1.</citation>
    <PMID>31677121</PMID>
  </reference>
  <reference>
    <citation>McClung JP. Iron status and the female athlete. J Trace Elem Med Biol. 2012 Jun;26(2-3):124-6. doi: 10.1016/j.jtemb.2012.03.006. Epub 2012 May 7.</citation>
    <PMID>22572041</PMID>
  </reference>
  <reference>
    <citation>Kendall B, Eston R. Exercise-induced muscle damage and the potential protective role of estrogen. Sports Med. 2002;32(2):103-23. doi: 10.2165/00007256-200232020-00003.</citation>
    <PMID>11817996</PMID>
  </reference>
  <reference>
    <citation>Tiidus PM, Lowe DA, Brown M. Estrogen replacement and skeletal muscle: mechanisms and population health. J Appl Physiol (1985). 2013 Sep 1;115(5):569-78. doi: 10.1152/japplphysiol.00629.2013. Epub 2013 Jul 18.</citation>
    <PMID>23869062</PMID>
  </reference>
  <reference>
    <citation>Sim M, Dawson B, Landers G, Swinkels DW, Tjalsma H, Yeap BB, Trinder D, Peeling P. Oral contraception does not alter typical post-exercise interleukin-6 and hepcidin levels in females. J Sci Med Sport. 2015 Jan;18(1):8-12. doi: 10.1016/j.jsams.2013.11.008. Epub 2013 Nov 28.</citation>
    <PMID>24373771</PMID>
  </reference>
  <reference>
    <citation>Sipaviciene S, Daniuseviciute L, Kliziene I, Kamandulis S, Skurvydas A. Effects of estrogen fluctuation during the menstrual cycle on the response to stretch-shortening exercise in females. Biomed Res Int. 2013;2013:243572. doi: 10.1155/2013/243572. Epub 2013 Sep 12.</citation>
    <PMID>24151587</PMID>
  </reference>
  <reference>
    <citation>Janse DE Jonge X, Thompson B, Han A. Methodological Recommendations for Menstrual Cycle Research in Sports and Exercise. Med Sci Sports Exerc. 2019 Dec;51(12):2610-2617. doi: 10.1249/MSS.0000000000002073.</citation>
    <PMID>31246715</PMID>
  </reference>
  <results_reference>
    <citation>Romero-Parra N, Barba-Moreno L, Rael B, Alfaro-Magallanes VM, Cupeiro R, Diaz AE, Calderon FJ, Peinado AB. Influence of the Menstrual Cycle on Blood Markers of Muscle Damage and Inflammation Following Eccentric Exercise. Int J Environ Res Public Health. 2020 Mar 2;17(5):1618. doi: 10.3390/ijerph17051618.</citation>
    <PMID>32131554</PMID>
  </results_reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>June 29, 2020</study_first_submitted>
  <study_first_submitted_qc>July 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>July 2, 2020</last_update_submitted>
  <last_update_submitted_qc>July 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 7, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Universidad Politecnica de Madrid</investigator_affiliation>
    <investigator_full_name>ANA BELEN PEINADO LOZANO</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Hepcidin</keyword>
  <keyword>Iron deficiency</keyword>
  <keyword>Menstrual cycle</keyword>
  <keyword>Muscle damage</keyword>
  <keyword>Creatine kinase</keyword>
  <keyword>Female</keyword>
  <keyword>Exercise</keyword>
  <keyword>Estrogen</keyword>
  <keyword>Progesterone</keyword>
  <keyword>Oral contraceptives</keyword>
  <keyword>Postmenopausal women</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Iron-Deficiency</mesh_term>
    <mesh_term>Iron Deficiencies</mesh_term>
    <mesh_term>Metabolic Diseases</mesh_term>
    <mesh_term>Iron Metabolism Disorders</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04458662
org study id: DEP2016-75387-P
nct id: NCT04458662
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This project is an observational controlled randomized counterbalance study. One hundred and
      three physically active and healthy women were selected to participate in the IronFEMME
      Study, of which 57 were eumenorrheic, 30 were oral contraceptive users (OCP) and 16 were
      postmenopausal women. The project consisted on two sections carrying out at the same time:
      Iron metabolism (Study I) and Muscle damage (Study II). For the study I, the exercise
      protocol consisted on an interval running test (8 bouts of 3 min at 85% of the maximal
      aerobic speed), whereas the study II protocol was based on an eccentric-based resistance
      exercise protocol (10 sets of 10 repetitions of plate-loaded barbell parallel back squats at
      60% of their 1RM with 2 min of rest between sets). In both studies, eumenorrheic participants
      were evaluated at three specific moments of the menstrual cycle: Early-follicular phase,
      late-follicular phase and mid-luteal phase; OCP performed the trial at two moments:
      Withdrawal phase and active pill phase. Lastly, postmenopausal women were tested only once,
      since their hormonal status does not fluctuate. The three-step method was used to verify the
      menstrual cycle phase: calendar counting, blood analyses confirmation and urine-based
      ovulation kits. Blood samples were obtained to measure sexual hormones (e.g., 17β-Estradiol,
      Progesterone), iron metabolism parameters (e.g., Hepcidin, Iron, Ferritin, Transferrin) and
      muscle damage related markers (e.g., Creatine Kinase, Myoglobin, Lactate Dehydrogenase).
observational model: Cohort
time perspective: Cross-Sectional
measure: Hepcidin
time frame: pre-exercise
description: Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals
measure: Hepcidin
time frame: 0 hours post-exercise
description: Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals
measure: Hepcidin
time frame: 3 hours post-exercise
description: Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals
measure: Hepcidin
time frame: 24 hours post-exercise
description: Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals
measure: Creatine kinase
time frame: pre-exercise
description: It is an enzyme that helps regulate the concentration of adenosine triphosphate within a cell. To do so, creatine kinase catalyzes the movement of a phosphate group from ATP to creatine, forming phosphocreatine. This molecules stores the phosphate group in a stable form, acting as an energy reservoir in cells.
measure: Creatine kinase
time frame: 2 hours post-exercise
description: It is an enzyme that helps regulate the concentration of adenosine triphosphate within a cell. To do so, creatine kinase catalyzes the movement of a phosphate group from ATP to creatine, forming phosphocreatine. This molecules stores the phosphate group in a stable form, acting as an energy reservoir in cells.
measure: Creatine kinase
time frame: 24 hours post-exercise
description: It is an enzyme that helps regulate the concentration of adenosine triphosphate within a cell. To do so, creatine kinase catalyzes the movement of a phosphate group from ATP to creatine, forming phosphocreatine. This molecules stores the phosphate group in a stable form, acting as an energy reservoir in cells.
measure: Creatine kinase
time frame: 48 hours post-exercise
description: It is an enzyme that helps regulate the concentration of adenosine triphosphate within a cell. To do so, creatine kinase catalyzes the movement of a phosphate group from ATP to creatine, forming phosphocreatine. This molecules stores the phosphate group in a stable form, acting as an energy reservoir in cells.
measure: Iron
time frame: pre-exercise
measure: Iron
time frame: 0 hours post-exercise
measure: Iron
time frame: 3 hours post-exercise
measure: Iron
time frame: 24 hours post-exercise
measure: Transferrin
time frame: pre-exercise
measure: Transferrin
time frame: 0 hours post-exercise
measure: Transferrin
time frame: 3 hours post-exercise
measure: Transferrin
time frame: 24 hours post-exercise
measure: Ferritin
time frame: pre-exercise
measure: Ferritin
time frame: 0 hours post-exercise
measure: Ferritin
time frame: 3 hours post-exercise
measure: Ferritin
time frame: 24 hours post-exercise
measure: Mioglobin
time frame: pre-exercise
measure: Mioglobin
time frame: 2 hours post-exercise
measure: Mioglobin
time frame: 24 hours post-exercise
measure: Mioglobin
time frame: 48 hours post-exercise
measure: LDH
time frame: pre-exercise
description: Lactate deshidrogenase
measure: LDH
time frame: 2 hours post-exercise
description: Lactate deshidrogenase
measure: LDH
time frame: 24 hours post-exercise
description: Lactate deshidrogenase
measure: LDH
time frame: 48 hours post-exercise
description: Lactate deshidrogenase
measure: TNF-alfa
time frame: pre-exercise
measure: TNF-alfa
time frame: 2 hours post-exercise
measure: TNF-alfa
time frame: 24 hours post-exercise
measure: TNF-alfa
time frame: 48 hours post-exercise
measure: Interleukin-6
time frame: pre-exercise
measure: Interleukin-6
time frame: 0 hours post-exercise
measure: Interleukin-6
time frame: 2 hours post-exercise
measure: Interleukin-6
time frame: 24 hours post-exercise
measure: Interleukin-6
time frame: 48 hours post-exercise
measure: CRP
time frame: pre-exercise
description: C-reactive protein
measure: CRP
time frame: 0 hours post-exercise
description: C-reactive protein
measure: CRP
time frame: 2 hours post-exercise
description: C-reactive protein
measure: CRP
time frame: 24 hours post-exercise
description: C-reactive protein
measure: CRP
time frame: 48 hours post-exercise
description: C-reactive protein
arm group label: Eumenorrheic women
description: The project consisted on two sections carrying out at the same time: Iron physiology (Study I) and Muscle damage (Study II).
For the study I, the exercise protocol consisted on an interval running test. 5 min warm-up at 60% of the vVO2peak followed by 8 bouts of 3 min at 85% of the vVO2peak with 90 secs recovery at 30% of the vVO2peak between bouts. Finally, a 5 min cool down was performed at 30% of the vVO2peak.
The study II protocol was based on an eccentric-based resistance exercise protocol consisted on 10 sets of 10 reps of plate-loaded parallel back squats at 60% of their previously calculated 1RM with 2 mins recoveries between sets.
In both studies, eumenorrheic participants were evaluated at three specific moments of the menstrual cycle: Early-follicular phase (EFP), late-follicular phase (LFP) and mid-luteal phase (MLP);
arm group label: Oral contraceptive users
description: The project consisted on two sections carrying out at the same time: Iron physiology (Study I) and Muscle damage (Study II).
For the study I, the exercise protocol consisted on an interval running test. 5 min warm-up at 60% of the vVO2peak followed by 8 bouts of 3 min at 85% of the vVO2peak with 90 secs recovery at 30% of the vVO2peak between bouts. Finally, a 5 min cool down was performed at 30% of the vVO2peak.
The study II protocol was based on an eccentric-based resistance exercise protocol consisted on 10 sets of 10 reps of plate-loaded parallel back squats at 60% of their previously calculated 1RM with 2 mins recoveries between sets.
Oral contraceptive users performed the trial at two moments: Withdrawal phase (WP) and active pill phase (APP).
arm group label: Postmenopausal women
description: he project consisted on two sections carrying out at the same time: Iron physiology (Study I) and Muscle damage (Study II).
For the study I, the exercise protocol consisted on an interval running test. 5 min warm-up at 60% of the vVO2peak followed by 8 bouts of 3 min at 85% of the vVO2peak with 90 secs recovery at 30% of the vVO2peak between bouts. Finally, a 5 min cool down was performed at 30% of the vVO2peak.
The study II protocol was based on an eccentric-based resistance exercise protocol consisted on 10 sets of 10 reps of plate-loaded parallel back squats at 60% of their previously calculated 1RM with 2 mins recoveries between sets.
Postmenopausal women were tested only once, since their hormonal status does not fluctuate.
intervention type: Procedure
intervention name: Interval running protocol / eccentric-based resistance exercise protocol
arm group label: Eumenorrheic women
arm group label: Oral contraceptive users
arm group label: Postmenopausal women
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ana Belén Peinado
role: Study Director
affiliation: LFE Research Group. Universidad Politécnica de Madrid
facility: 
country: Spain
url: https://ironfemme.com
description: IronFEMME project official web page
citation: Lehtihet M, Bonde Y, Beckman L, Berinder K, Hoybye C, Rudling M, Sloan JH, Konrad RJ, Angelin B. Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans. PLoS One. 2016 Feb 11;11(2):e0148802. doi: 10.1371/journal.pone.0148802. eCollection 2016.
PMID: 26866603
citation: Hou Y, Zhang S, Wang L, Li J, Qu G, He J, Rong H, Ji H, Liu S. Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. Gene. 2012 Dec 15;511(2):398-403. doi: 10.1016/j.gene.2012.09.060. Epub 2012 Oct 3.
PMID: 23041085
citation: Ikeda Y, Tajima S, Izawa-Ishizawa Y, Kihira Y, Ishizawa K, Tomita S, Tsuchiya K, Tamaki T. Estrogen regulates hepcidin expression via GPR30-BMP6-dependent signaling in hepatocytes. PLoS One. 2012;7(7):e40465. doi: 10.1371/journal.pone.0040465. Epub 2012 Jul 11.
PMID: 22792339
citation: Li X, Rhee DK, Malhotra R, Mayeur C, Hurst LA, Ager E, Shelton G, Kramer Y, McCulloh D, Keefe D, Bloch KD, Bloch DB, Peterson RT. Progesterone receptor membrane component-1 regulates hepcidin biosynthesis. J Clin Invest. 2016 Jan;126(1):389-401. doi: 10.1172/JCI83831. Epub 2015 Dec 14.
PMID: 26657863
citation: Yang Q, Jian J, Katz S, Abramson SB, Huang X. 17beta-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. Endocrinology. 2012 Jul;153(7):3170-8. doi: 10.1210/en.2011-2045. Epub 2012 Apr 25.
PMID: 22535765
citation: Thompson B, Almarjawi A, Sculley D, Janse de Jonge X. The Effect of the Menstrual Cycle and Oral Contraceptives on Acute Responses and Chronic Adaptations to Resistance Training: A Systematic Review of the Literature. Sports Med. 2020 Jan;50(1):171-185. doi: 10.1007/s40279-019-01219-1.
PMID: 31677121
citation: McClung JP. Iron status and the female athlete. J Trace Elem Med Biol. 2012 Jun;26(2-3):124-6. doi: 10.1016/j.jtemb.2012.03.006. Epub 2012 May 7.
PMID: 22572041
citation: Kendall B, Eston R. Exercise-induced muscle damage and the potential protective role of estrogen. Sports Med. 2002;32(2):103-23. doi: 10.2165/00007256-200232020-00003.
PMID: 11817996
citation: Tiidus PM, Lowe DA, Brown M. Estrogen replacement and skeletal muscle: mechanisms and population health. J Appl Physiol (1985). 2013 Sep 1;115(5):569-78. doi: 10.1152/japplphysiol.00629.2013. Epub 2013 Jul 18.
PMID: 23869062
citation: Sim M, Dawson B, Landers G, Swinkels DW, Tjalsma H, Yeap BB, Trinder D, Peeling P. Oral contraception does not alter typical post-exercise interleukin-6 and hepcidin levels in females. J Sci Med Sport. 2015 Jan;18(1):8-12. doi: 10.1016/j.jsams.2013.11.008. Epub 2013 Nov 28.
PMID: 24373771
citation: Sipaviciene S, Daniuseviciute L, Kliziene I, Kamandulis S, Skurvydas A. Effects of estrogen fluctuation during the menstrual cycle on the response to stretch-shortening exercise in females. Biomed Res Int. 2013;2013:243572. doi: 10.1155/2013/243572. Epub 2013 Sep 12.
PMID: 24151587
citation: Janse DE Jonge X, Thompson B, Han A. Methodological Recommendations for Menstrual Cycle Research in Sports and Exercise. Med Sci Sports Exerc. 2019 Dec;51(12):2610-2617. doi: 10.1249/MSS.0000000000002073.
PMID: 31246715
citation: Romero-Parra N, Barba-Moreno L, Rael B, Alfaro-Magallanes VM, Cupeiro R, Diaz AE, Calderon FJ, Peinado AB. Influence of the Menstrual Cycle on Blood Markers of Muscle Damage and Inflammation Following Eccentric Exercise. Int J Environ Res Public Health. 2020 Mar 2;17(5):1618. doi: 10.3390/ijerph17051618.
PMID: 32131554
responsible party type: Principal Investigator
investigator affiliation: Universidad Politecnica de Madrid
investigator full name: ANA BELEN PEINADO LOZANO
investigator title: Associate Professor
mesh term: Anemia, Iron-Deficiency
mesh term: Iron Deficiencies
mesh term: Metabolic Diseases
mesh term: Iron Metabolism Disorders
mesh term: Inflammation
sharing ipd: No