Ketone Monoester for Hormonal Imbalance After Resistance Training

Overseen By Tyler A. Churchward-Venne, Ph.D.

Age: 18 - 65

Sex: Male

Trial Phase: Academic

Sponsor: McGill University

Must not be taking: Corticosteroids, Hormone replacement therapy

Disqualifiers: Diabetes, Cardiovascular, Endocrine, Immune, others

Compensation: Varies

Number of Visits: 17

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to assess how a ketone supplement affects hormones such as testosterone and growth hormone following resistance exercise. The researchers compare ketone monoester supplements, specifically (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate, to a placebo (flavored water) to determine if ketones alter the hormonal response post-exercise. The trial targets healthy young men who exercise regularly and maintain stable habits. Participants should not have major health issues like diabetes or heart disease and should not have engaged in regular weightlifting in the past year. As an unphased trial, this study allows participants to contribute to foundational research that could enhance the understanding of exercise and hormone interactions.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the ketone supplement (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate is generally safe for people. Studies have found it can safely increase blood ketone levels. Some individuals might experience mild stomach issues, such as an upset stomach, but these are usually not serious. Overall, the treatment is well-tolerated and does not pose significant health risks. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for hormonal imbalance after resistance training focus on hormone replacement or lifestyle adjustments. However, the ketone monoester supplement, (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate, offers a fresh approach. This treatment uses a ketone monoester to potentially regulate hormone levels by providing an alternative energy source that might influence metabolic pathways differently from traditional methods. Researchers are excited because this could offer a quicker, more targeted way to address hormonal imbalances without directly altering hormone levels through medication. Plus, its use as a nutritional supplement means it could be more accessible and have fewer side effects compared to hormonal therapies.

What evidence suggests that ketone monoester might be an effective treatment for hormonal imbalance after resistance training?

This trial will compare the effects of a ketone monoester supplement, (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate, with a placebo drink. Research has shown that ketone supplements can quickly raise blood ketone levels without dietary changes. Studies have found that these supplements can affect hormone levels in the blood at rest. Ketone bodies, such as β-hydroxybutyrate (β-HB), naturally occur during fasting or a high-fat, low-carb diet and might influence hormones related to muscle growth. However, the effects of these ketone supplements on hormones after exercise remain under investigation. Early findings suggest they might aid in hormone regulation, but further research is needed to understand their effects after resistance training. ^{1 3 6 7 8}

Who Is on the Research Team?

Tyler Churchward-Venne, PhD

Principal Investigator

Department of Kinesiology and Physical Education, McGill University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

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

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

Ingesting a ketone monoester after exercise significantly increases postexercise erythropoietin (EPO) concentrations, with peak levels reaching 9.0 IU·L-1 compared to 7.5 IU·L-1 in the control group, indicating a potential benefit for enhancing red blood cell production.

This study, involving nine healthy men in a crossover design, is the first to show that ketone monoester ingestion can also lower serum glucose levels, suggesting a dual effect that could influence athletic performance and recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men. Evans, E., Walhin, JP., Hengist, A., et al.[2023]

In a study involving type 2 diabetic rats, 8 weeks of regular resistance training significantly increased muscle levels of sex steroid hormones, including DHT, which contributed to muscle growth and improved blood sugar control.

Blocking DHT synthesis with a 5α-reductase inhibitor during resistance training reduced the benefits on muscle mass and glucose metabolism, highlighting the importance of DHT in the positive effects of exercise on diabetes management.

NCBI (Pubmed)

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. Horii, N., Sato, K., Mesaki, N., et al.[2018]

The natural ketone body d-β-hydroxybutyrate (βHB) can potentially improve metabolic function and help manage chronic diseases like diabetes and Alzheimer's, and a new ingestible βHB monoester allows for rapid elevation of blood ketone levels without the downsides of traditional high-fat diets.

The βHB monoester has been shown to be safe for human consumption in studies involving athletes and healthy volunteers, and it may have specific applications in treating various conditions, including neurodegenerative diseases and heart failure, although further research is needed to fully understand its limitations and potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why a d-β-hydroxybutyrate monoester? Soto-Mota, A., Norwitz, NG., Clarke, K.[2020]

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]

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate effectively elevates blood ketone levels in healthy volunteers, reaching maximum plasma concentrations of 3.30 mM for β-hydroxybutyrate within 1-2 hours after ingestion.

This ketone monoester was generally well-tolerated over a 5-day period, although some gastrointestinal side effects were noted at higher doses, indicating it is a safe alternative to traditional ketogenic diets for enhancing physical and cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

HMB supplementation during resistance training shows small but significant strength gains in previously untrained individuals, with an average increase in lower-body strength of about 9.9%.

In trained lifters, HMB does not provide meaningful strength improvements, and its effects on body composition are negligible, indicating that HMB may be more beneficial for those new to resistance training.

NCBI (Pubmed)

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. Rowlands, DS., Thomson, JS.[2016]

The study involving 20 moderately active young adults found that a ketone monoester supplement significantly increased blood β-hydroxybutyrate levels but did not improve muscle recovery or reduce soreness after eccentric exercise compared to a carbohydrate supplement.

Both the ketone and carbohydrate groups experienced similar declines in muscle performance and soreness post-exercise, indicating that the ketone supplement does not provide additional benefits for recovery in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone Monoester Supplementation Does Not Expedite the Recovery of Indices of Muscle Damage After Eccentric Exercise. Martin-Arrowsmith, PW., Lov, J., Dai, J., et al.[2020]

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]

Resistance exercise training (RT) for 12 weeks significantly increased sex hormone-binding globulin (SHBG) levels and decreased free androgen index (FAI) and cortisol in overweight/obese young men, indicating a positive hormonal response to exercise.

Participants in the RT group also experienced improvements in body composition, including increased lean body mass and reduced fat mass, alongside better glucose and insulin responses, suggesting that RT can enhance metabolic health without requiring weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resistance training increases SHBG in overweight/obese, young men. Roberts, CK., Croymans, DM., Aziz, N., et al.[2021]

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]

In a study involving 14 healthy young adults, both ketone monoester (KME) and ketone monoester/salt (KMES) formulations significantly increased circulating R-beta-hydroxybutyrate (R-βHB) levels in a dose-dependent manner, with KME10 reaching a peak concentration of 2.4 mM after 15 minutes.

Both formulations were well-tolerated, but KMES was slightly more acceptable due to a better taste, while KME was associated with a more frequent decrease in appetite, indicating that user experience may vary between different ketone products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. Bolyard, ML., Graziano, CM., Fontaine, KR., et al.[2023]

The study developed a sensitive liquid chromatography-tandem mass spectrometry assay to measure 1,5alpha-androsten-3beta,17beta-diol (1AD) and its analogues in plasma and urine, achieving high accuracy and precision in quantification.

Despite the intended effects of 1AD as a testosterone mimic, the study found that 1AD and its analogues were not detectable in plasma or urine, suggesting limited bioavailability or metabolism in the body.

NCBI (Pubmed)

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. Reilly, CA., Crouch, DJ.[2019]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT06683547

The Impact of Ketone Monoester Intake on Post-exercise ... This study investigates how orally ingested exogenous ketone monoester supplements affect circulating hormone concentrations in healthy young adult males ...

2. withpower.com withpower.com/trial/ketone-monoester-for-hormonal-imbalance-after-resistance-training-f5e65

Ketone Monoester for Hormonal Imbalance After ... This study investigates how orally ingested exogenous ketone monoester supplements affect circulating hormone concentrations in healthy young adult males ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9734240/

Exogenous Ketone Supplements in Athletic Contexts The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by ...

4. frontiersin.org frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.793987/full

Ketone Ester Supplementation in Healthy Volunteers by MRS In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine ...

5. clinicaltrial.be clinicaltrial.be/en/details/458376?per_page=20&only_recruiting=0&only_eligible=0&only_active=0

The Impact of Ketone Monoester Intake on Post-exercise ... Ketone monoester supplement: (R)-3-hydroxybutyl (R)-3-hydroxybutyrate dosed based on participants' body weight (0.36g/kg body weight). The ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3810007/

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R) These results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels.

7. mdpi.com mdpi.com/2072-6643/14/20/4426

Toxicity Investigations of (R)-3-Hydroxybutyrate Glycerides ... Ketones have been shown to have beneficial effects on human health. To be used by humans, TCN006 must be determined safe in appropriately designed safety ...

8. researchgate.net researchgate.net/publication/336774484_Safety_and_tolerability_of_sustained_exogenous_ketosis_using_ketone_monoester_drinks_for_28_days_in_healthy_adults

Safety and tolerability of sustained exogenous ketosis ... Here we report results for 24 healthy adults, aged 18-70 years, who drank 25 ml (26.8 g) of the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, ...