Exogenous Ketone Supplementation in Females With Polycystic Ovary Syndrome

Sponsor

McGill University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06155708

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
PCOS	Dietary Supplement: Ketone Dietary Supplement: Water	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jan 1, 2024

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

Dec 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketone - 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 - 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.
Placebo Comparator: Placebo 100 ml water combined with 10ml bitter flavor and vanilla-flavored stevia	Dietary Supplement: Water 100 ml water combined with 10ml bitter flavor and vanilla-flavored stevia

Arm

Intervention/Treatment

Experimental: Ketone

- 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

Placebo Comparator: Placebo

100 ml water combined with 10ml bitter flavor and vanilla-flavored stevia

Dietary Supplement: Water

100 ml water combined with 10ml bitter flavor and vanilla-flavored stevia

Outcome Measures

Primary Outcome Measures

Glycemic responses to a 2-hr oral glucose tolerance test [0-2.5 hours in the post-prandial period]
- Glucose is calculated by the area under the curve using the trapezoid method.
Flow mediated dilation (FMD) [30 minutes]
- 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.
Systolic Blood Pressure (SBP) [2 hours]
- SBP, measured in mmHg
Diastolic Blood Pressure (DBP) [2 hours]
- DBP, measured in mmHg
Isometric handgrip exercise [15 minutes]
- While measuring beat-by beat blood pressure, we ask the participant to perform an isometric forearm handgrip exercise protocol (3-min) at 40% of maximal voluntary contraction, followed immediately by 1-min post-exercise circulatory occlusion to isolate the hemodynamic consequences of the muscle metaboreflex.

Secondary Outcome Measures

Insulin area under the curve [0-2.5 hours in the post-prandial period]
- Insulin area under the curve during oral glucose tolerance test
C-peptide [0-2.5 hours in the post-prandial period]
- C-peptide area under the curve during oral glucose tolerance test
Glucagon-like peptide-1 (GLP-1) [0-2.5 hours in the post-prandial period]
- GLP-1 area under the curve during oral glucose tolerance test.
Glucose-dependent insulinotropic polypeptide (GIP) [0-2.5 hours in the post-prandial period]
- GIP area under the curve during oral glucose tolerance test.
Triglycerides [0-2.5 hours in the post-prandial period]
- Triglycerides area under the curve during oral glucose tolerance test
Insulinogenic index [0-2.5 hours in the post-prandial period]
- (Insulin at 30 min - fasting insulin)/ (plasma glucose at 30 min- fasting plasma glucose).
Arterial artery blood flow [0-2.5 hours in the post-prandial period]
- Calculated as the product of mean blood flow velocity (cm/sec) and cross-sectional area (2Πr2) x 60 sec/min.
Shear rate and low-flow mediated vasoconstriction to the FMD [30 minutes]
- 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.
Muscle sympathetic nerve activity (MSNA) [2 hours]
- Measured using microneurography, and expressed in burst/min or bursts/100 heart beats
Neurovascular transduction [2 hours]
- 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.
Vascular resistance [2 hours]
- Calculated as mean arterial pressure divided by Finometer-derived cardiac output
Cold pressor test reactivity [2 hours]
- To examine blood pressure regulation during a pressor stimulus, we will use a cold pressor test, involving placing the participant's hand in ice cold water (~4ºC) for 3-min. This increases the sympathetic nervous system activity
Capillary blood Beta-OHB concentrations [0-2.5 hours in the post-prandial period]
- Measures in mmol/L
Serum testosterone [5 minutes]
- Measured in pg/ml.
Serum sex hormone binding globulin [5 minutes]
- Measured in pg/ml.
Serum estradiol [5 minutes]
- Measured in pg/ml.
Serum Progesterone [5 minutes]
- Measured in pg/ml.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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)