xml: <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/NCT05973175</url>
    </required_header>
    <id_info>
      <org_study_id>REC 22/28</org_study_id>
      <nct_id>NCT05973175</nct_id>
    </id_info>
    <brief_title>REFUEL PCOS Study 1</brief_title>
    <acronym>REFUEL-PCOS</acronym>
    <official_title>The RolE oF Androgen Excess in MUscle Energy MetaboLism in Women With PolyCystic Ovary Syndrome (The REFUEL PCOS) Study 1</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Royal College of Surgeons, Ireland</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>University of Birmingham</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>University of Liverpool</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Royal College of Surgeons, Ireland</source>
    <oversight_info>
      <has_dmc>Yes</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>
        Polycystic Ovary Syndrome (PCOS) affects 10% of all women, and it usually co-exists with high&#xD;
        levels of male pattern hormones (also termed androgens). Women with PCOS are at increased&#xD;
        risk of metabolic complications such as diabetes, non-alcoholic fatty liver disease, high&#xD;
        blood pressure and heart disease. However, very little is understood about how androgen&#xD;
        excess results in increased metabolic complications observed in women with PCOS.&#xD;
  &#xD;
        The main aims of the REFUEL PCOS study are to compare markers of energy metabolism in women&#xD;
        with PCOS to those without PCOS. This will allow us to better understand metabolic risk by&#xD;
        examining the relationship between androgen excess and energy metabolism. Skeletal muscle is&#xD;
        an important site of energy metabolism, and emerging theories are that androgen excess&#xD;
        impairs skeletal muscle energy balance and increases the risk of complications. Based on&#xD;
        these emerging theories, we want to investigate the effects of androgens on muscle energy&#xD;
        metabolism. We will also examine whether certain blood and urine result patterns can help&#xD;
        identify differences in muscles energy metabolism and which women are at the highest risk of&#xD;
        metabolic complications. This research will give insight into the metabolic risk associated&#xD;
        with PCOS and treat and, where possible, prevent the development of metabolic disease in&#xD;
        affected women.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Polycystic ovary syndrome (PCOS) is a lifelong metabolic disorder, affecting 10-13% of all&#xD;
        women, and is associated with a major healthcare and economic burden, estimated at $8 billion&#xD;
        annually the US in 2020 (1, 2). Traditionally considered a reproductive disorder only, it is&#xD;
        now increasingly clear that PCOS is associated with severe metabolic health consequences&#xD;
        across the entire life course of women (3, 4). There is a two-fold increased risk of type 2&#xD;
        diabetes mellitus (T2DM) and nonalcoholic fatty liver disease, as well as emerging evidence&#xD;
        of increased incidence of cardiovascular disease (CVD) (5-7). There are no disease-specific&#xD;
        therapies to mitigate or treat metabolic risk in women with PCOS. This is consistently&#xD;
        highlighted as the priority concern amongst PCOS patient advocacy groups.&#xD;
  &#xD;
        Androgen excess is a cardinal feature of PCOS and circulating androgen burden is closely&#xD;
        correlated with metabolic complications (5, 8-12). In women with PCOS, the risk of developing&#xD;
        metabolic dysfunction is above that conferred by simple obesity, suggesting that androgen&#xD;
        excess is a key player; however, a distinct mechanistic role for androgens in this process&#xD;
        remains to be elucidated (13, 14). Androgen excess is associated with metabolically&#xD;
        deleterious visceral fat accumulation and circulating testosterone levels correlate directly&#xD;
        with the risk of T2DM and NAFLD. Muscle is a critical metabolic target tissue that plays a&#xD;
        central role in energy metabolism through processes such as glucose uptake and oxidation, as&#xD;
        well as oxidation of fatty acids to generate ATP in the mitochondria (15). Recent mechanistic&#xD;
        data have shown that androgen excess is associated with changes in the transcriptional&#xD;
        profile of skeletal muscle genes linked with metabolism and energy balance (15-17).&#xD;
        Therefore, skeletal muscle is likely to represent an important site of crosstalk between&#xD;
        androgen excess, disturbances in energy metabolism and risk of metabolic disease in PCOS.&#xD;
  &#xD;
        Defective skeletal muscle glucose uptake is a key early step in the pathogenesis of insulin&#xD;
        resistance in PCOS, and an early predictor of progression to overt type 2 diabetes mellitus.&#xD;
        Impaired mitochondrial oxidation of free fatty acids in skeletal muscle, as well as other&#xD;
        disturbances in skeletal muscle mitochondrial function such as oxidative phosphorylation, are&#xD;
        increasingly implicated in the pathogenesis of metabolic disease such as T2DM (18-20).&#xD;
        Abnormalities in skeletal muscle mitochondrial function have also been identified in small&#xD;
        scale studies in women with PCOS, and were associated with impaired fatty acid oxidation,&#xD;
        weight gain and an increased risk of diabetes (21, 22).&#xD;
  &#xD;
        I hypothesise that androgen-mediated disturbances in skeletal muscle energy balance play a&#xD;
        major role in the pathogenesis of metabolic disease in women with PCOS. I propose to test&#xD;
        this using cross-sectional and interventional approaches utilising state-of-the-art metabolic&#xD;
        phenotyping tools.&#xD;
  &#xD;
        16. REFERENCES&#xD;
  &#xD;
          1. Skiba MA, Islam RM, Bell RJ, Davis SR. Understanding variation in prevalence estimates&#xD;
             of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update.&#xD;
             2018;24(6):694-709.&#xD;
  &#xD;
          2. Riestenberg C, Jagasia A, Markovic D, Buyalos RP, Azziz R. Health Care-Related Economic&#xD;
             Burden of Polycystic Ovary Syndrome in the United States: Pregnancy-Related and&#xD;
             Long-Term Health Consequences. J Clin Endocrinol Metab. 2021.&#xD;
  &#xD;
          3. Schiffer L, Arlt W, O'Reilly MW. Understanding the Role of Androgen Action in Female&#xD;
             Adipose Tissue. Frontiers of hormone research. 2019;53:33-49.&#xD;
  &#xD;
          4. Nanba AT, Rege J, Ren J, Auchus RJ, Rainey WE, Turcu AF. 11-Oxygenated C19 Steroids Do&#xD;
             Not Decline With Age in Women. J Clin Endocrinol Metab. 2019;104(7):2615-22.&#xD;
  &#xD;
          5. Kumarendran B, O'Reilly MW, Manolopoulos KN, Toulis KA, Gokhale KM, Sitch AJ, et al.&#xD;
             Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver&#xD;
             disease in women: A longitudinal study based on a United Kingdom primary care database.&#xD;
             PLoS Med. 2018;15(3):e1002542.&#xD;
  &#xD;
          6. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis&#xD;
             and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice&#xD;
             guideline. J Clin Endocrinol Metab. 2013;98(12):4565-92.&#xD;
  &#xD;
          7. Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, et al. Cardiometabolic&#xD;
             aspects of the polycystic ovary syndrome. Endocr Rev. 2012;33(5):812-41.&#xD;
  &#xD;
          8. Kempegowda P, Melson E, Manolopoulos KN, Arlt W, O'Reilly MW. Implicating androgen&#xD;
             excess in propagating metabolic disease in polycystic ovary syndrome. Ther Adv&#xD;
             Endocrinol Metab. 2020;11:2042018820934319.&#xD;
  &#xD;
          9. Subramanian A, Anand A, Adderley NJ, Okoth K, Toulis KA, Gokhale K, et al. Increased&#xD;
             COVID-19 infections in women with polycystic ovary syndrome: a population-based study.&#xD;
             Eur J Endocrinol. 2021;184(5):637-45.&#xD;
  &#xD;
         10. Barry JA, Kuczmierczyk AR, Hardiman PJ. Reporting the rates of depression in polycystic&#xD;
             ovary syndrome (PCOS). J Sex Med. 2014;11(7):1882-3.&#xD;
  &#xD;
         11. Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in&#xD;
             women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod&#xD;
             Update. 2014;20(5):748-58.&#xD;
  &#xD;
         12. O'Reilly MW, Kempegowda P, Jenkinson C, Taylor AE, Quanson JL, Storbeck KH, et al.&#xD;
             11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome. J&#xD;
             Clin Endocrinol Metab. 2017;102(3):840-8.&#xD;
  &#xD;
         13. Escobar-Morreale HF, Alvarez-Blasco F, Botella-Carretero JI, Luque-Ramirez M. The&#xD;
             striking similarities in the metabolic associations of female androgen excess and male&#xD;
             androgen deficiency. Hum Reprod. 2014;29(10):2083-91.&#xD;
  &#xD;
         14. O'Reilly MW, House PJ, Tomlinson JW. Understanding androgen action in adipose tissue. J&#xD;
             Steroid Biochem Mol Biol. 2014;143:277-84.&#xD;
  &#xD;
         15. Nilsson E, Benrick A, Kokosar M, Krook A, Lindgren E, Kallman T, et al. Transcriptional&#xD;
             and Epigenetic Changes Influencing Skeletal Muscle Metabolism in Women With Polycystic&#xD;
             Ovary Syndrome. J Clin Endocrinol Metab. 2018;103(12):4465-77.&#xD;
  &#xD;
         16. Insenser M, Montes-Nieto R, Martinez-Garcia MA, Escobar-Morreale HF. A nontargeted study&#xD;
             of muscle proteome in severely obese women with androgen excess compared with severely&#xD;
             obese men and nonhyperandrogenic women. Eur J Endocrinol. 2016;174(3):389-98.&#xD;
  &#xD;
         17. Pasquali R, Casimirri F, Labate AM, Tortelli O, Pascal G, Anconetani B, et al. Body&#xD;
             weight, fat distribution and the menopausal status in women. The VMH Collaborative&#xD;
             Group. Int J Obes Relat Metab Disord. 1994;18(9):614-21.&#xD;
  &#xD;
         18. Hojlund K, Mogensen M, Sahlin K, Beck-Nielsen H. Mitochondrial dysfunction in type 2&#xD;
             diabetes and obesity. Endocrinol Metab Clin North Am. 2008;37(3):713-31, x.&#xD;
  &#xD;
         19. Montgomery MK, Turner N. Mitochondrial dysfunction and insulin resistance: an update.&#xD;
             Endocr Connect. 2015;4(1):R1-R15.&#xD;
  &#xD;
         20. Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and&#xD;
             type 2 diabetes mellitus. Nat Rev Endocrinol. 2011;8(2):92-103.&#xD;
  &#xD;
         21. Skov V, Glintborg D, Knudsen S, Jensen T, Kruse TA, Tan Q, et al. Reduced expression of&#xD;
             nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle&#xD;
             of insulin-resistant women with polycystic ovary syndrome. Diabetes. 2007;56(9):2349-55.&#xD;
  &#xD;
         22. Hutchison SK, Teede HJ, Rachon D, Harrison CL, Strauss BJ, Stepto NK. Effect of exercise&#xD;
             training on insulin sensitivity, mitochondria and computed tomography muscle attenuation&#xD;
             in overweight women with and without polycystic ovary syndrome. Diabetologia.&#xD;
             2012;55(5):1424-34.&#xD;
  &#xD;
         23. O'Reilly MW, Kempegowda P, Walsh M, Taylor AE, Manolopoulos KN, Allwood JW, et al.&#xD;
             AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic&#xD;
             Ovary Syndrome. J Clin Endocrinol Metab. 2017;102(9):3327-39.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 1, 2023</start_date>
    <completion_date type="Anticipated">October 1, 2025</completion_date>
    <primary_completion_date type="Anticipated">October 1, 2025</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Case-Control</observational_model>
      <time_perspective>Cross-Sectional</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>To delineate the relationship between androgen excess and skeletal muscle energy metabolism in women</measure>
      <time_frame>2.5 years</time_frame>
      <description>Baseline differences in the skeletal muscle proteome and differentially regulated pathways relating to mitochondrial function in hyperandrogenic women with PCOS compared to healthy controls</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Proteomic profiling of skeletal muscle biopsies will be integrated with serum steroid and non-targeted metabolome data to delineate the relationship between androgens and skeletal muscle energy metabolism in women</measure>
      <time_frame>2.5 years</time_frame>
      <description>Differences in the non-targeted serum metabolome at baseline between women with PCOS and controls and Identification of differentially regulated pathways to facilitate targeted pathway analysis in future studies</description>
    </secondary_outcome>
    <number_of_groups>2</number_of_groups>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Polycystic Ovary Syndrome</condition>
    <arm_group>
      <arm_group_label>Women with PCOS</arm_group_label>
      <description>The following inclusion criteria need to be met for the PCOS Study participants:&#xD;
  Women with a confirmed diagnosis polycystic ovary syndrome with androgen excess on clinical or biochemical grounds&#xD;
  BMI 20-40kg/m2&#xD;
  Age range 18-50 years&#xD;
  Ability to provide informed consent</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Women without PCOS (controls)</arm_group_label>
      <description>The following inclusion criteria need to be met for the control Study participants:&#xD;
  No clinical features of possible polycystic ovary syndrome (absence of clinical features of androgen excess and ovulatory dysfunction).&#xD;
  BMI 20-40kg/m2&#xD;
  Age range 18-50 years&#xD;
  Ability to provide informed consent</description>
    </arm_group>
    <biospec_retention>Samples Without DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        Routine blood (cholesterol profile, HbA1C, LFTs, FBC, Renal profile) will be sent to the&#xD;
        laboratory in the Beaumont Hospital for processing on the same day of sampling. Samples for&#xD;
        steroid nontargeted metabolomics and muscle biopsy specimens will be stored in a -80C freezer&#xD;
        in the research laboratory in the CRC building until analysis. Serum samples for targeted&#xD;
        nontargeted metabolomics will be measured and analysed at the University of Birmingham by&#xD;
        LC-MS/MS. Muscle biopsy specimens will undergo proteomic sequencing at the University College&#xD;
        Dublin and metabolomic analysis at the University of Liverpool.&#xD;
  &#xD;
        The blood volume that will be collected is approximately 350ml. The amount collected for&#xD;
        skeletal muscle tissue biopsies will be similar to half a grain of rice for each biopsies.&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          This study aims to recruit women with PCOS who have a BMI between 20 and 40kg/m2 with&#xD;
          clinical or biochemical evidence of androgen excess. Their matched controls will have no&#xD;
          clinical features of possible polycystic ovary syndrome (absence of clinical features of&#xD;
          androgen excess and ovulatory dysfunction).&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          -&#xD;
  &#xD;
          The following inclusion criteria need to be met for the PCOS Study participants:&#xD;
  &#xD;
            -  Women with a confirmed diagnosis polycystic ovary syndrome with androgen excess on&#xD;
               clinical or biochemical grounds&#xD;
  &#xD;
            -  BMI 20-40kg/m2&#xD;
  &#xD;
            -  Age range 18-50 years&#xD;
  &#xD;
            -  Ability to provide informed consent&#xD;
  &#xD;
          The following inclusion criteria need to be met for the control Study participants:&#xD;
  &#xD;
            -  No clinical features of possible polycystic ovary syndrome (absence of clinical&#xD;
               features of androgen excess and ovulatory dysfunction).&#xD;
  &#xD;
            -  BMI 20.0-40kg/m2&#xD;
  &#xD;
            -  Age range 18-50 years&#xD;
  &#xD;
            -  Ability to provide informed consent&#xD;
  &#xD;
          For participants with PCOS, a diagnosis of PCOS should be established on the basis of the&#xD;
          Androgen Excess and PCOS (AE-PCOS) Society guidelines:&#xD;
  &#xD;
            -  Androgen excess (clinical and/or biochemical evidence)&#xD;
  &#xD;
            -  Chronic oligo-/anovulation (clinical and/or biochemical evidence)&#xD;
  &#xD;
            -  Clinical and/or biochemical exclusion of other conditions that could explain the above&#xD;
               manifestation (e.g. congenital adrenal hyperplasia, Cushing's syndrome, Prolactinoma,&#xD;
               adrenal and gonadal tumours)&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  The participant may not enter the study if ANY of the following apply:&#xD;
  &#xD;
                 -  A confirmed diagnosis of diabetes&#xD;
  &#xD;
                 -  Current or recent (&lt;3-months) use of weight loss medications&#xD;
  &#xD;
                 -  Current or recent use of oral contraceptive pill or hormone replacement therapy&#xD;
                    (within last 3-months)&#xD;
  &#xD;
                 -  Blood haemoglobin &lt;11.0g/dL&#xD;
  &#xD;
                 -  History of alcoholism or a greater than recommended alcohol intake&#xD;
                    (recommendations &gt; 21 units on average per week for men and &gt; 14 units on average&#xD;
                    per week for women)&#xD;
  &#xD;
                 -  Haemorrhagic disorders&#xD;
  &#xD;
                 -  Treatment with anticoagulant agents&#xD;
  &#xD;
                 -  Other co-morbidities that in the view of the investigators may affect data&#xD;
                    collection&#xD;
  &#xD;
                 -  Any medical condition in the opinion of the investigator that might impact upon&#xD;
                    safety or validity of the results&#xD;
  &#xD;
                 -  Pregnancy or breastfeeding at the time of planned recruitment&#xD;
  &#xD;
                 -  A diagnosis of PCOS according to Rotterdam criteria where the patient does not&#xD;
                    have clinical or biochemical evidence of androgen excess&#xD;
  &#xD;
                 -  History of significant renal (eGFR&lt;30) or hepatic impairment (AST or ALT&#xD;
                    &gt;two-fold above ULN; pre-existing bilirubinaemia &gt;1.2 ULN)&#xD;
  &#xD;
                 -  Any other significant disease or disorder that, in the opinion of the&#xD;
                    Investigator, may either put the participant at risk because of participation in&#xD;
                    the study, or may influence the result of the study, or the participant's ability&#xD;
                    to participate in the study.&#xD;
  &#xD;
                 -  Participants who have participated in another research study involving an&#xD;
                    investigational medicinal product in the 12 weeks preceding the planned&#xD;
                    recruitment&#xD;
  &#xD;
                 -  Glucocorticoid use via any route within the last six months&#xD;
  &#xD;
                 -  Current intake of drugs known to impact upon steroid or metabolic function or&#xD;
                    intake of such drugs during the six months preceding the planned recruitment&#xD;
  &#xD;
                 -  Use of oral or transdermal hormonal contraception in the three months preceding&#xD;
                    the planned recruitment&#xD;
  &#xD;
                 -  Use of contraceptive implants in the twelve months preceding the planned&#xD;
                    recruitment&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <gender_based>Yes</gender_based>
      <gender_description>Studying a female reproductive condition</gender_description>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>50 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>Royal Collage Of Surgeons</name>
        <address>
          <city>Dublin</city>
          <country>Ireland</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Ireland</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 25, 2023</study_first_submitted>
    <study_first_submitted_qc>July 25, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 2, 2023</study_first_posted>
    <last_update_submitted>July 25, 2023</last_update_submitted>
    <last_update_submitted_qc>July 25, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 2, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Polycystic Ovary Syndrome</mesh_term>
      <mesh_term>Syndrome</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Clinical data (anthropomorphic and medical history) and data from in vivo phenotyping will be pseudonymised and uploaded to Redcap with biomaterial samples (urine, serum, muscle biopsy) stored in a bio-repository within the RCSI clinical research centre as per ethical approval. To ensure due process and aid sharing of the data the study will be registered online at (https://clinicaltrials.gov). Data will be shared upon request in keeping with Wellcome policy and as per REC guidance at the time of request post-publication of results.</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_time_frame>6 months following publication</ipd_time_frame>
      <ipd_access_criteria>To ensure due process and aid sharing of the data the study will be registered online at (https://clinicaltrials.gov). Data will be shared upon request in keeping with Wellcome policy and as per REC guidance at the time of request post-publication of results.</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05973175
  org study id: REC 22/28
  nct id: NCT05973175
  lead sponsor: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Polycystic Ovary Syndrome (PCOS) affects 10% of all women, and it usually co-exists with high
        levels of male pattern hormones (also termed androgens). Women with PCOS are at increased
        risk of metabolic complications such as diabetes, non-alcoholic fatty liver disease, high
        blood pressure and heart disease. However, very little is understood about how androgen
        excess results in increased metabolic complications observed in women with PCOS.
  
        The main aims of the REFUEL PCOS study are to compare markers of energy metabolism in women
        with PCOS to those without PCOS. This will allow us to better understand metabolic risk by
        examining the relationship between androgen excess and energy metabolism. Skeletal muscle is
        an important site of energy metabolism, and emerging theories are that androgen excess
        impairs skeletal muscle energy balance and increases the risk of complications. Based on
        these emerging theories, we want to investigate the effects of androgens on muscle energy
        metabolism. We will also examine whether certain blood and urine result patterns can help
        identify differences in muscles energy metabolism and which women are at the highest risk of
        metabolic complications. This research will give insight into the metabolic risk associated
        with PCOS and treat and, where possible, prevent the development of metabolic disease in
        affected women.
  Polycystic ovary syndrome (PCOS) is a lifelong metabolic disorder, affecting 10-13% of all
        women, and is associated with a major healthcare and economic burden, estimated at $8 billion
        annually the US in 2020 (1, 2). Traditionally considered a reproductive disorder only, it is
        now increasingly clear that PCOS is associated with severe metabolic health consequences
        across the entire life course of women (3, 4). There is a two-fold increased risk of type 2
        diabetes mellitus (T2DM) and nonalcoholic fatty liver disease, as well as emerging evidence
        of increased incidence of cardiovascular disease (CVD) (5-7). There are no disease-specific
        therapies to mitigate or treat metabolic risk in women with PCOS. This is consistently
        highlighted as the priority concern amongst PCOS patient advocacy groups.
  
        Androgen excess is a cardinal feature of PCOS and circulating androgen burden is closely
        correlated with metabolic complications (5, 8-12). In women with PCOS, the risk of developing
        metabolic dysfunction is above that conferred by simple obesity, suggesting that androgen
        excess is a key player; however, a distinct mechanistic role for androgens in this process
        remains to be elucidated (13, 14). Androgen excess is associated with metabolically
        deleterious visceral fat accumulation and circulating testosterone levels correlate directly
        with the risk of T2DM and NAFLD. Muscle is a critical metabolic target tissue that plays a
        central role in energy metabolism through processes such as glucose uptake and oxidation, as
        well as oxidation of fatty acids to generate ATP in the mitochondria (15). Recent mechanistic
        data have shown that androgen excess is associated with changes in the transcriptional
        profile of skeletal muscle genes linked with metabolism and energy balance (15-17).
        Therefore, skeletal muscle is likely to represent an important site of crosstalk between
        androgen excess, disturbances in energy metabolism and risk of metabolic disease in PCOS.
  
        Defective skeletal muscle glucose uptake is a key early step in the pathogenesis of insulin
        resistance in PCOS, and an early predictor of progression to overt type 2 diabetes mellitus.
        Impaired mitochondrial oxidation of free fatty acids in skeletal muscle, as well as other
        disturbances in skeletal muscle mitochondrial function such as oxidative phosphorylation, are
        increasingly implicated in the pathogenesis of metabolic disease such as T2DM (18-20).
        Abnormalities in skeletal muscle mitochondrial function have also been identified in small
        scale studies in women with PCOS, and were associated with impaired fatty acid oxidation,
        weight gain and an increased risk of diabetes (21, 22).
  
        I hypothesise that androgen-mediated disturbances in skeletal muscle energy balance play a
        major role in the pathogenesis of metabolic disease in women with PCOS. I propose to test
        this using cross-sectional and interventional approaches utilising state-of-the-art metabolic
        phenotyping tools.
  
        16. REFERENCES
  
          1. Skiba MA, Islam RM, Bell RJ, Davis SR. Understanding variation in prevalence estimates
             of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update.
             2018;24(6):694-709.
  
          2. Riestenberg C, Jagasia A, Markovic D, Buyalos RP, Azziz R. Health Care-Related Economic
             Burden of Polycystic Ovary Syndrome in the United States: Pregnancy-Related and
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  observational model: Case-Control
  time perspective: Cross-Sectional
  measure: To delineate the relationship between androgen excess and skeletal muscle energy metabolism in women
  time frame: 2.5 years
  description: Baseline differences in the skeletal muscle proteome and differentially regulated pathways relating to mitochondrial function in hyperandrogenic women with PCOS compared to healthy controls
  measure: Proteomic profiling of skeletal muscle biopsies will be integrated with serum steroid and non-targeted metabolome data to delineate the relationship between androgens and skeletal muscle energy metabolism in women
  time frame: 2.5 years
  description: Differences in the non-targeted serum metabolome at baseline between women with PCOS and controls and Identification of differentially regulated pathways to facilitate targeted pathway analysis in future studies
  arm group label: Women with PCOS
  description: The following inclusion criteria need to be met for the PCOS Study participants:
  Women with a confirmed diagnosis polycystic ovary syndrome with androgen excess on clinical or biochemical grounds
  BMI 20-40kg/m2
  Age range 18-50 years
  Ability to provide informed consent
  arm group label: Women without PCOS (controls)
  description: The following inclusion criteria need to be met for the control Study participants:
  No clinical features of possible polycystic ovary syndrome (absence of clinical features of androgen excess and ovulatory dysfunction).
  BMI 20-40kg/m2
  Age range 18-50 years
  Ability to provide informed consent
  Routine blood (cholesterol profile, HbA1C, LFTs, FBC, Renal profile) will be sent to the
        laboratory in the Beaumont Hospital for processing on the same day of sampling. Samples for
        steroid nontargeted metabolomics and muscle biopsy specimens will be stored in a -80C freezer
        in the research laboratory in the CRC building until analysis. Serum samples for targeted
        nontargeted metabolomics will be measured and analysed at the University of Birmingham by
        LC-MS/MS. Muscle biopsy specimens will undergo proteomic sequencing at the University College
        Dublin and metabolomic analysis at the University of Liverpool.
  
        The blood volume that will be collected is approximately 350ml. The amount collected for
        skeletal muscle tissue biopsies will be similar to half a grain of rice for each biopsies.
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: Female
  gender based: Yes
  gender description: Studying a female reproductive condition
  minimum age: 18 Years
  maximum age: 50 Years
  healthy volunteers: Accepts Healthy Volunteers
  facility: 
  country: Ireland
  responsible party type: Sponsor
  mesh term: Polycystic Ovary Syndrome
  mesh term: Syndrome
  sharing ipd: Yes
  ipd description: Clinical data (anthropomorphic and medical history) and data from in vivo phenotyping will be pseudonymised and uploaded to Redcap with biomaterial samples (urine, serum, muscle biopsy) stored in a bio-repository within the RCSI clinical research centre as per ethical approval. To ensure due process and aid sharing of the data the study will be registered online at (https://clinicaltrials.gov). Data will be shared upon request in keeping with Wellcome policy and as per REC guidance at the time of request post-publication of results.
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd time frame: 6 months following publication
  ipd access criteria: To ensure due process and aid sharing of the data the study will be registered online at (https://clinicaltrials.gov). Data will be shared upon request in keeping with Wellcome policy and as per REC guidance at the time of request post-publication of results.