REFUEL PCOS Study 1

Phase

N/A

Condition

Polycystic Ovarian Syndrome

Reproductive Health

Treatment

N/A

Clinical Study ID

NCT05973175

REC 22/28

Ages 18-50
Female
Accepts Healthy Volunteers

Study Summary

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.

Eligibility Criteria

Inclusion

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 onclinical 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 clinicalfeatures 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 theAndrogen 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 abovemanifestation (e.g. congenital adrenal hyperplasia, Cushing's syndrome, Prolactinoma,adrenal and gonadal tumours)

Exclusion

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 averageper week for women)
Haemorrhagic disorders
Treatment with anticoagulant agents
Other co-morbidities that in the view of the investigators may affect datacollection
Any medical condition in the opinion of the investigator that might impact uponsafety 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 nothave 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 theInvestigator, may either put the participant at risk because of participation inthe study, or may influence the result of the study, or the participant's abilityto participate in the study.
Participants who have participated in another research study involving aninvestigational medicinal product in the 12 weeks preceding the plannedrecruitment
Glucocorticoid use via any route within the last six months
Current intake of drugs known to impact upon steroid or metabolic function orintake of such drugs during the six months preceding the planned recruitment
Use of oral or transdermal hormonal contraception in the three months precedingthe planned recruitment
Use of contraceptive implants in the twelve months preceding the plannedrecruitment

Study Design

August 01, 2023

October 01, 2025

Study 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.

Connect with a study center

Royal Collage Of Surgeons
Dublin,
Ireland
Active - Recruiting

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