Exogenous Ketone Supplementation in Females with Polycystic Ovary Syndrome

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

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.

Study Overview

• Status: Recruiting
• Conditions: PCOS
• Intervention / Treatment: Dietary supplement: Ketone; Dietary supplement: Water

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Charlotte Usselman, Ph.D; Phone Number: 5143962140; Email: charlotte.usselman@mcgill.ca

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H2W 1S4
      • Recruiting
      • Cardiovascular Health and Autonomic Research Laboratory
      • Contact: Charlotte Usselman, Ph.D; Email: charlotte.usselman@mcgill.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: McGill University
• Investigators: Principal Investigator: Charlotte Usselman, Ph.D, McGill University

Study record dates

Study Major Dates

• Study Start (Estimated): January 20, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: October 18, 2023
• First Submitted That Met QC Criteria: December 1, 2023
• First Posted (Actual): December 4, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 20, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Insulin resistance; Endothelial function; Blood pressure; Polycystic ovary syndrome; Oral glucose tolerance test; Flow mediated dilation; Cold pressor test; Handgrip exercise; Ketone monoester ingestion; Neurovascular transduction
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Ovarian Cysts; Cysts; Polycystic Ovary Syndrome
• Other Study ID Numbers: 2024-9710

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No