The Effects of 17β-estradiol on Skeletal Muscle

NCT03069781 | Withdrawn Early Phase 1

• 1 other identifier: REB-2919
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The maintenance of skeletal muscle mass and function is critical for healthy aging. Muscle loss with disuse, termed muscle disuse muscle atrophy, leads to impaired functional capacity, the onset of insulin resistance, as well as a heightened risk for morbidity and mortality. With advancing age there is a chronic wasting of muscle. This is especially true in women, where rapid rates of decline in muscle mass and greater anabolic resistance are experienced around the time of menopause, despite higher protein synthesis rates. As women have a longer life expectancy, they are particularly venerable to age-related frailty and morbidity. Skeletal muscle protein turnover serves to maintain the optimal function of proteins and also provides plasticity of the tissue during altered demands such as during increased loading or unloading of the muscle. Reduced periods of physical activity also have a similar, albeit milder, impact on skeletal muscle and most, people will likely experience multiple bouts of skeletal muscle disuse during their lifetime from which some, particularly older adult women, will fail to fully recover. Thus, muscle disuse atrophy is a significant and continuing problem as reclamation of lost muscle mass, strength/function, and potentially metabolic health (particularly insulin-induced glucose disposal), following disuse is oftentimes incomplete and may be further exacerbated after menopause. Previous evidence has demonstrated that in the loss of muscle mass is less pronounced in post-menopausal women when receiving hormone replacement therapy. Skeletal muscle has estrogen-β-receptors on the cell membrane, in the cytoplasm and on the nuclear membrane, and therefore a direct mechanistic link between low estrogen levels and a decrease MPS. Interestingly, despite higher rates of protein synthesis, older women still lose muscle mass with advancing age. It has been suggested that the negative muscle protein balance is due to an enhanced rate of MPB. Insulin is a potent inhibitor of MPB and estrogen has been shown to enhance insulin sensitivity in skeletal muscle. However, to our knowledge, no study has examined the efficacy of estrogen supplementation to attenuate the losses of skeletal muscle mass and function during a period of disuse. The findings of this investigation may yield critical data for those who wish to combat skeletal muscle disuse atrophy, particularly after menopause.

Conditions

Muscle Atrophy

Keywords

estrogen

Outcome Measures

Primary Outcomes (1)

• Muscle protein synthesis and breakdown rates

  Myofibrillar protein will be extracted from the muscle biopsies. Myofibrillar protein-bound 2H-alanine enrichments will be determined by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) by Metabolic Solutions, Nashua, NH as described previously (16). The saliva and plasma samples will be analyzed for 2H enrichments by cavity ring-down spectroscopy by Metabolic Solutions. Fractional synthetic rates of muscle protein synthesis will be calculated by dividing the increment in muscle protein-bound enrichment between two muscle biopsies over time by the average enrichment in total body water/plasma.

  Prior to immobilization (-3-0 d) and over the 7 days of immobilization (0-7 d).

Secondary Outcomes (2)

• Muscle size

  At t=0 and after 7 days of immobilization.

• Muscle strength

  At t=0 and after 7 days of immobilization.

Study Arms (2)

17β-estradiol

EXPERIMENTAL

1mg/day for 3-days and 3mg/day for 7-days of 17β-estradiol (Estrace, Acerus Pharmaceuticals Corporation, Mississauga, ON, Canada). 7 Day Breg Knee Brace unilateral immobilization.

Drug: 17β-estradiol

Placebo

PLACEBO COMPARATOR

400 mg/day for 10-days of Polycose (Abbott Laboratories, St. Laurent, QC, Canada).7 Day Breg Knee Brace unilateral immobilization.

Drug: Polycose

Interventions

17β-estradiol DRUG

1mg/day for 3-days and 3mg/day for 7-days of Estrance

Also known as: Estrance

17β-estradiol

Polycose DRUG

400 mg/day for 10-days of Polycose (Abbott Laboratories, St. Laurent, QC, Canada)

Also known as: Enteral Nutrition Formulas

Placebo

Eligibility Criteria

• Age: 18 Years - 30 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Generally healthy, non-smoking as assessed by questionnaire
• Willing and able to provide informed consent
• BMI between 22 and 29 kg/m2

You may not qualify if:

• Any concurrent medical, orthopedic, or psychiatric condition that, in the opinion of the Investigators, would compromise the ability to comply with the study requirements
• Significant orthopedic, cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would preclude oral 17β-estradiol supplementation
• Current illnesses which could interfere with the study (e.g. prolonged severe diarrhea, regurgitation, difficulty swallowing)
• Excessive alcohol consumption (\>21 units/week)
• History of bleeding diathesis, platelet or coagulation disorders, or antiplatelet/anticoagulation therapy
• Personal or family history of clotting disorder or deep vein thrombosis
• Concomitant use of corticosteroids, testosterone replacement therapy (ingestion, injection, or transdermal), or any anabolic steroid

Sponsors & Collaborators

• McMaster University: lead

Study Sites (1)

McMaster Univeristy

Hamilton, Ontario, Canada

Location

MeSH Terms

Conditions

Muscular Atrophy

Interventions

Estradiol; Glucans

Condition Hierarchy (Ancestors)

Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Biopolymers; Polymers; Macromolecular Substances; Polysaccharides; Carbohydrates

Study Officials

• Stuart Phillips, PhD

  McMaster University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Both forms of supplementation (estrogen and placebo) will be packaged and administered in identical fashion.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Parallel-group, double-blinded, randomized controlled trial.

Study Record Dates

• First Submitted: February 27, 2017
• First Posted: March 3, 2017
• Study Start: May 1, 2017
• Primary Completion: May 1, 2018
• Study Completion: August 14, 2018
• Last Updated: August 16, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)