Ketone Monoester for Hormonal Imbalance After Resistance Training

Recruiting in Palo Alto (17 mi)

Overseen by Tyler Churchward-Venne, PhD

Age: 18 - 65

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: McGill University

Must not be taking: Corticosteroids, Hormone replacement therapy

Disqualifiers: Diabetes, Cardiovascular, Endocrine, Immune, others

Trial Summary

What is the purpose of this trial?

This study investigates how orally ingested exogenous ketone monoester supplements affect circulating hormone concentrations in healthy young adult males after a single session of resistance exercise. Resistance exercise is known to stimulate an acute increase in the circulating concentration of various hormones that are involved in the regulation of muscle mass, including testosterone, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Recently, there has been growing interest in how nutritional supplements impact these natural hormone responses at rest. One such intervention is the oral ingestion of exogenous ketone body supplements. Ketone bodies (i.e., β-hydroxybutyrate (β-HB), acetoacetate (AcAc), and acetone) are naturally occurring compounds that are normally produced by the body during prolonged fasting/starvation, or in response to a "ketogenic" diet (a diet very high in fat and very low in carbohydrates). These ketone body supplements taken in the form of a ketone monoester can quickly raise blood ketone levels without needing to change your diet. Recent research has shown that the ingestion of exogenous ketone supplements or following a 'ketogenic diet' can alter the concentration of certain hormones measured in blood samples at rest. However, the effects of ketone monoester intake on the exercise-induced elevation in circulating hormones is yet to be explored. Therefore, the purpose of this study is to examine how elevated β-HB, induced via the ingestion of the ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate, affects blood concentrations of various anabolic hormones, during post-exercise recovery in healthy young adult males, compared to a placebo drink (flavoured water).

Will I have to stop taking my current medications?

The trial requires that you have maintained stable use of your current medications and supplements for the last 3 months and continue to do so throughout the study, as long as they are not excluded by the trial's criteria.

What evidence supports the effectiveness of the drug (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate for hormonal imbalance after resistance training?

The research suggests that resistance training can increase levels of certain hormones like testosterone, which are important for muscle growth and energy. While the specific drug (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate isn't directly studied, similar treatments that affect hormone levels have shown benefits in muscle growth and energy regulation. ^{1 2 3 4 5}

Is (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate safe for humans?

Research shows that (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate, a ketone monoester, is generally safe for humans, with some mild stomach-related side effects reported at high doses. It is well-tolerated when used to raise blood ketone levels. ^{6 7 8 9 10}

How does the drug (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate differ from other treatments for hormonal imbalance after resistance training?

This drug is unique because it elevates blood ketone levels quickly and safely without the need for a ketogenic diet, which can be inconvenient. It also increases post-exercise erythropoietin (a hormone that stimulates red blood cell production) levels, which is not a common effect of other treatments for hormonal imbalance after resistance training. ^{6 7 11 12 13}

Research Team

Tyler Churchward-Venne, PhD

Principal Investigator

Department of Kinesiology and Physical Education, McGill University

Eligibility Criteria

This trial is for healthy young adult males interested in how a ketone monoester supplement might affect their hormone levels after resistance exercise. Participants should be regularly involved in resistance training and not currently taking any hormonal supplements.

Inclusion Criteria

Willing and able to agree to the requirements and restrictions of this study, be willing to give voluntary consent, be able to understand and read the questionnaires, and carry out all study-related procedures

BMI >18.5 and <30.0 kg/m2

Recreationally active (at least 150 minutes of activity/week)

Exclusion Criteria

Individuals with metabolic disorders including Type I or Type II diabetes

I have a history of blood clots or heart disease.

I have an injury to my knee, such as an ACL tear.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

10-RM Testing

Participants' 10-repetition maximum (10-RM) will be determined for each exercise machine used

1 visit

1 visit (in-person)

Experimental Trial Phase 1

Participants perform a lower-body resistance exercise session and receive either the ketone monoester or placebo drink

1 visit

1 visit (in-person)

Washout Period

A minimum 7-day washout period between experimental trial phases

7 days

Experimental Trial Phase 2

Participants perform a second lower-body resistance exercise session with the alternate treatment (ketone monoester or placebo)

1 visit

1 visit (in-person)

Follow-up

Participants are monitored for changes in hormone concentrations post-exercise

4 hours

13 timepoints for blood sampling

Treatment Details

Interventions

• (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (Ketone Supplement)

Trial Overview The study is testing the impact of a ketone monoester drink on post-exercise hormone levels, like testosterone and growth hormone, compared to a placebo. It aims to see if this supplement can alter the body's natural hormonal response to resistance training.

Participant Groups

Group I: Ketone Monoester (KET) Active Control 2 Interventions

Ketone monoester supplement: (R)-3-hydroxybutyl (R)-3-hydroxybutyrate dosed based on participants' body weight (0.36g/kg body weight). The nutritional beverage will be consumed twice: 30 minutes prior to the exercise workout (t = -60 min) and immediately following the completion of the exercise protocol (t = 0 min).

Group II: Placebo drink Placebo Group 2 Interventions

Flavoured water. Participants will consume this beverage twice: 30 minutes prior to the exercise workout (t = -60 min) and immediately following the completion of the exercise protocol (t = 0 min).

Who Is Running the Clinical Trial?

McGill University

Lead Sponsor

Trials

421

Recruited

1,017,000+

Philippe Drouet

McGill University

Chief Executive Officer since 2021

Master of Science and Bachelor in Chemical Engineering from McGill University

Marianne Mancini

McGill University

Chief Medical Officer

BS in Nutritional Sciences from McGill University

Findings from Research

Resistance exercise triggers a significant acute hormonal response, particularly in anabolic hormones like testosterone and growth hormone, which are crucial for muscle growth and remodeling, rather than relying solely on chronic hormonal changes.

High-volume, moderate to high-intensity resistance training with short rest intervals is most effective for maximizing acute hormonal elevations, which are essential for optimizing muscle adaptation and performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormonal responses and adaptations to resistance exercise and training. Kraemer, WJ., Ratamess, NA.[2022]

The study found that 11-ketotestosterone (KT) can be detected in urine for over 20 hours after a single oral dose, indicating a significant window for potential misuse in sports.

A new method using carbon isotope ratio mass spectrometry was developed to confirm the presence of KT and its metabolites, providing a reliable way to detect this substance in athletes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of mass spectrometry-based methods for the detection of 11-ketotestosterone and 11-ketodihydrotestosterone. Piper, T., Thevis, M.[2023]

In a study involving 20 resistance-trained men, ingesting 1g of β-hydroxy-β-methylbutyrate free acid (HMB-FA) before heavy resistance exercise significantly increased growth hormone (GH) levels compared to a placebo, indicating enhanced endocrine response.

The results suggest that HMB-FA supplementation prior to exercise not only boosts GH but also elevates insulin-like growth factor (IGF-1) levels, supporting its potential anabolic benefits for muscle growth and recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of β-Hydroxy-β-methylbutyrate Free Acid Ingestion and Resistance Exercise on the Acute Endocrine Response. Townsend, JR., Hoffman, JR., Gonzalez, AM., et al.[2020]

In a study involving 37 untrained collegiate males over 8 weeks of resistance training, supplementation with beta-hydroxy-beta-methylbutyrate (HMB) at doses of 36 and 76 mg/kg/day showed no adverse effects on liver or kidney function, indicating its safety during exercise.

The group receiving 38 mg/kg/day of HMB experienced a significant increase in basophils, a type of white blood cell, compared to the other groups, suggesting a potential immune response, but overall blood and urine health markers remained stable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-hydroxy-beta-methylbutyrate ingestion, part II: effects on hematology, hepatic and renal function. Gallagher, PM., Carrithers, JA., Godard, MP., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Increased Muscular 5α-Dihydrotestosterone in Response to Resistance Training Relates to Skeletal Muscle Mass and Glucose Metabolism in Type 2 Diabetic Rats. [2018]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Hormonal responses and adaptations to resistance exercise and training. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Analysis of the nutritional supplement 1AD, its metabolites, and related endogenous hormones in biological matrices using liquid chromatography-tandem mass spectrometry. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Resistance training increases SHBG in overweight/obese, young men. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Development of mass spectrometry-based methods for the detection of 11-ketotestosterone and 11-ketodihydrotestosterone. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]

7. Egypt pubmed.ncbi.nlm.nih.gov

Effects of β-Hydroxy-β-methylbutyrate Free Acid Ingestion and Resistance Exercise on the Acute Endocrine Response. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Beta-hydroxy-beta-methylbutyrate ingestion, part II: effects on hematology, hepatic and renal function. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Effects of beta-hydroxy-beta-methylbutyrate supplementation during resistance training on strength, body composition, and muscle damage in trained and untrained young men: a meta-analysis. [2016]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Why a d-β-hydroxybutyrate monoester? [2020]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Ketone Monoester Supplementation Does Not Expedite the Recovery of Indices of Muscle Damage After Eccentric Exercise. [2020]