REFUEL PCOS Study 1 (REFUEL-PCOS)

April 15, 2024 updated by: Royal College of Surgeons, Ireland

The RolE oF Androgen Excess in MUscle Energy MetaboLism in Women With PolyCystic Ovary Syndrome (The REFUEL PCOS) Study 1

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 the investigators 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, the investigators want to investigate the effects of androgens on muscle energy metabolism. The investigators 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.

Study Overview

Status

Recruiting

Conditions

Detailed Description

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).

The investigators hypothesise that androgen-mediated disturbances in skeletal muscle energy balance play a major role in the pathogenesis of metabolic disease in women with PCOS. The investigators propose to test this using cross-sectional and interventional approaches utilising state-of-the-art metabolic phenotyping tools.

Study Type

Observational

Enrollment (Estimated)

40

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Ireland
      • Dublin, Ireland
        • Recruiting
        • Royal Collage Of Surgeons
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

This study aims to recruit women with PCOS who have a BMI between 20 and 40kg/m2 with clinical or biochemical evidence of androgen excess. Their matched controls will have no clinical features of possible polycystic ovary syndrome (absence of clinical features of androgen excess and ovulatory dysfunction).

Description

Inclusion Criteria:

-

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

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 20.0-40kg/m2
  • Age range 18-50 years
  • Ability to provide informed consent

For participants with PCOS, a diagnosis of PCOS should be established on the basis of the Androgen Excess and PCOS (AE-PCOS) Society guidelines:

  • Androgen excess (clinical and/or biochemical evidence)
  • Chronic oligo-/anovulation (clinical and/or biochemical evidence)
  • Clinical and/or biochemical exclusion of other conditions that could explain the above manifestation (e.g. congenital adrenal hyperplasia, Cushing's syndrome, Prolactinoma, adrenal and gonadal tumours)

Exclusion Criteria:

  • The participant may not enter the study if ANY of the following apply:

    • A confirmed diagnosis of diabetes
    • Current or recent (<3-months) use of weight loss medications
    • Current or recent use of oral contraceptive pill or hormone replacement therapy (within last 3-months)
    • Blood haemoglobin <11.0g/dL
    • History of alcoholism or a greater than recommended alcohol intake (recommendations > 21 units on average per week for men and > 14 units on average per week for women)
    • Haemorrhagic disorders
    • Treatment with anticoagulant agents
    • Other co-morbidities that in the view of the investigators may affect data collection
    • Any medical condition in the opinion of the investigator that might impact upon safety or validity of the results
    • Pregnancy or breastfeeding at the time of planned recruitment
    • A diagnosis of PCOS according to Rotterdam criteria where the patient does not have clinical or biochemical evidence of androgen excess
    • History of significant renal (eGFR<30) or hepatic impairment (AST or ALT >two-fold above ULN; pre-existing bilirubinaemia >1.2 ULN)
    • Any other significant disease or disorder that, in the opinion of the Investigator, may either put the participant at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.
    • Participants who have participated in another research study involving an investigational medicinal product in the 12 weeks preceding the planned recruitment
    • Glucocorticoid use via any route within the last six months
    • Current intake of drugs known to impact upon steroid or metabolic function or intake of such drugs during the six months preceding the planned recruitment
    • Use of oral or transdermal hormonal contraception in the three months preceding the planned recruitment
    • Use of contraceptive implants in the twelve months preceding the planned recruitment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Women with PCOS

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
Women without PCOS (controls)

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To delineate the relationship between androgen excess and skeletal muscle energy metabolism in women
Time Frame: 2.5 years
Baseline differences in the skeletal muscle proteome and differentially regulated pathways relating to mitochondrial function in hyperandrogenic women with PCOS compared to healthy controls
2.5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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
2.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Royal College of Surgeons, Ireland

Collaborators

University of Liverpool
University of Birmingham

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2023

Primary Completion (Estimated)

October 1, 2025

Study Completion (Estimated)

October 1, 2025

Study Registration Dates

First Submitted

July 25, 2023

First Submitted That Met QC Criteria

July 25, 2023

First Posted (Actual)

August 2, 2023

Study Record Updates

Last Update Posted (Actual)

April 17, 2024

Last Update Submitted That Met QC Criteria

April 15, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • REC 22/28

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan 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 Sharing Time Frame

6 months following publication

IPD Sharing 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 Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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