Exogenous Ketone Supplementation in Females With Polycystic Ovary Syndrome

Study Overview
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Brief Summary
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Polycystic ovary syndrome (PCOS) affects 1 in 5 females of reproductive age. Commonly characterized as a disorder of infertility, PCOS is often accompanied by 3 potent cardiovascular disease (CVD) risk factors: insulin resistance, endothelial dysfunction, and elevated blood pressure. Accordingly, PCOS is associated with the development of CVD, the second leading cause of death in females in Canada. However, effective treatments to improve cardiovascular health in PCOS are lacking. Exogenous ketone monoester (KME) ingestion has been shown to improves outcomes associated with insulin resistance, endothelial function, and blood pressure regulation in healthy individuals and individuals predisposed to CVD. Therefore, oral ketone supplements offer a practical and effective strategy for improving cardiovascular health; however, this treatment has yet to be evaluated in PCOS. Therefore, the overall goal of this project is to employ KME ingestion to improve markers of cardiovascular health in females with PCOS. On two different days, participants will consume either a beverage containing a ketone supplement or a beverage containing a placebo supplement. The objectives are to compare responses between KME and placebo ingestion, and examine all outcomes related to cardiovascular health in females with PCOS in comparison with female controls of similar age and body mass index. The effects of KME ingestion will be quantified on: 1) glycemic control during an oral glucose tolerance test; 2) endothelial function using the flow-mediated dilation test; 3) blood pressure and acute blood pressure regulation; and 4) hemodynamic responses to acute exercise.

Official Title
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Exogenous Ketone Supplementation to Improve Cardiovascular Disease Risk Factors in Females With Polycystic Ovary Syndrome

Conditions
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PCOS

Intervention / Treatment
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* Dietary Supplement: Ketone
* Dietary Supplement: Water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All female participants will report female sex assigned at birth All participants will be aged 18 to 40 PCOS diagnosis Exclusion Criteria: Current smokers or a prolonged history of smoking Presence or history of overt cardiometabolic disease (e.g., stage 2 hypertension, diabetes, heart disease), neurologic disease, or endocrinopathy (with the exception of PCOS) Current pregnancy or currently breastfeeding Current use of medications which may affect our outcomes of interest (e.g., anti-hypertensives, anti-androgens, metformin)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketone<br>- Ketone monoester supplement in the form of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate based on participants' body weight (0.45ml/kg body weight) ingested with water and vanilla-flavored stevia in a total volume of 100 ml. | Dietary Supplement: Ketone<br>* - Ketone monoester supplement in the form of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate based on participants' body weight (0.45ml/kg body weight) ingested with water and vanilla-flavored stevia in a total volume of 100 ml.<br>|
| Placebo Comparator: Placebo<br>100 ml water combined with 10ml bitter flavor and vanilla-flavored stevia | Dietary Supplement: Water<br>* 100 ml water combined with 10ml bitter flavor and vanilla-flavored stevia<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycemic responses to a 2-hr oral glucose tolerance test | - Glucose is calculated by the area under the curve using the trapezoid method. | 0-2.5 hours in the post-prandial period | 
| Flow mediated dilation (FMD) | - Endothelial function is assessed using the standard FMD; quantified as the percent increase in diameter from rest to peak diameter observed during reactive hyperemia (%FMD). The % change in diameter reflects the ability of the vessel to dilate in response to sheer stress induced by the flow following the release of occlusion. This reflects the function of the endothelium, or release of nitric oxide. | 30 minutes | 
| Systolic Blood Pressure (SBP) | - SBP, measured in mmHg | 2 hours | 
| Diastolic Blood Pressure (DBP) | - DBP, measured in mmHg | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin area under the curve | - Insulin area under the curve during oral glucose tolerance test | 0-2.5 hours in the post-prandial period | 
| C-peptide | - C-peptide area under the curve during oral glucose tolerance test | 0-2.5 hours in the post-prandial period | 
| Glucagon-like peptide-1 (GLP-1) | - GLP-1 area under the curve during oral glucose tolerance test. | 0-2.5 hours in the post-prandial period | 
| Glucose-dependent insulinotropic polypeptide (GIP) | - GIP area under the curve during oral glucose tolerance test. | 0-2.5 hours in the post-prandial period | 
| Triglycerides | - Triglycerides area under the curve during oral glucose tolerance test | 0-2.5 hours in the post-prandial period | 
| Insulinogenic index | - (Insulin at 30 min - fasting insulin)/ (plasma glucose at 30 min- fasting plasma glucose). | 0-2.5 hours in the post-prandial period | 
| Arterial artery blood flow | - Calculated as the product of mean blood flow velocity (cm/sec) and cross-sectional area (2Πr2) x 60 sec/min. | 0-2.5 hours in the post-prandial period | 
| Shear rate and low-flow mediated vasoconstriction to the FMD | - Shear rate calculated as area under the curve from cuff deflation to the time of peak dilation using the trapezoidal rule, as well as low flow-mediated vasoconstriction during forearm occlusion, which provides an index of the endothelial contribution to resting vascular tone and which predicts cardiovascular disease risk. | 30 minutes | 
| Muscle sympathetic nerve activity (MSNA) | - Measured using microneurography, and expressed in burst/min or bursts/100 heart beats | 2 hours | 
| Neurovascular transduction | - Assessed by the MSNA signal (recorded in both raw and filtered/rectified/integrated formats for subsequent analyses) and arterial blood flow extracted on a beat-by-beat basis and processed using custom transduction software. | 2 hours | 
| Vascular resistance | - Calculated as mean arterial pressure divided by Finometer-derived cardiac output | 2 hours | 
| Capillary blood Beta-OHB concentrations | - Measures in mmol/L | 0-2.5 hours in the post-prandial period | 
| Serum testosterone | - Measured in pg/ml. | 5 minutes | 
| Serum sex hormone binding globulin | - Measured in pg/ml. | 5 minutes | 
| Serum estradiol | - Measured in pg/ml. | 5 minutes | 
| Serum Progesterone | - Measured in pg/ml. | 5 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polycystic ovary syndrome, Ketone monoester ingestion, Insulin resistance, Endothelial function, Blood pressure, Oral glucose tolerance test, Flow mediated dilation, Handgrip exercise, Neurovascular transduction, Cold pressor test