Melatonin Supplementation and Exercise Program in Breast Cancer Women (MEXBSO)

Impact of Melatonin Supplementation Plus Exercise Program in Women Who Have Suffered from Breast Cancer in the Province of Soria, Spain

Introduction: Breast cancer (BC) remains the leading cause of cancer in women with nearly 1.4 million new cases worldwide annually and 27.000 in Spain. Increasingly effective oncology therapies, however, have numerous adverse effects such as muscle degeneration, fatigue, decreased physical function and aerobic capacity, and deteriorating quality of life. In this sense, physical activity (PA) seems to be an interesting non-pharmacological strategy to alleviate these serious complications and with potential benefits for women with BC. Melatonin (N-acetyl-5 methoxytryptamine) is an indolic compound present with pleiotropic bioactions that regulates the circadian rhythm, antioxidant, anti-inflammatory, immunostimulant, cardioprotective, antidiabetic, antiobesity, neuroprotective, and antiaging actions. Furthermore, in recent years, many studies have described the key role of melatonin in preventing and developing cancer. The general anticarcinogenic mechanisms include epigenetic control, cell proliferation modulation, cell cycle regulation, apoptosis induction, and telomerase inhibition. Melatonin also exerts antiestrogenic activity, which is particularly significant in hormone-dependent tumors, regulating the expression and transactivation of the estrogen receptor, and modulating the enzymes involved in the local synthesis of estrogens. Despite all the mentioned properties, the use of melatonin in daily clinical practice is very limited, and additional studies are needed to better establish the role of this hormone in oncological clinical applications against different types of cancer.

Objective: To analyze the effect of supplementation with 4 g/day of melatonin for 10 weeks on muscle damage (CK and LDH), hormonal responses (estradiol, testosterone, cortisol and testosterone/cortisol ratio), antioxidant capacity (BAP and d-ROMs), Exerkins (Irisin and Sestrin 2), physical performance (handgrip strength, RPE and SPPB), anthropometry (body mass, BMI and fat mass) and WHOQOL-BREF (physical and psychological health, social relationships and environment) in women over 60 years of age who have suffered breast cancer and who follow a physical training program.

Methods: A total of 20 female volunteers between 60 and 73 years old (age: 65.5±4.52 years, BMI: 25.83±2.67 and body fat percentage: 33.73±5.54) who followed a physical activity adapted to their age and abilities are the members. of this study. The volunteers were divided into two groups: placebo (CG; n = 10) and supplemented with 5 g/day of melatonin (GI; n = 10). Differtent test were performed muscle damage (CK, and LDH), hormonal responses (estradiol, testosterone, cortisol, and testosterone/cortisol ratio), antioxidant capacity (BAP and d-ROMs), Exerkins (Irisin and Sestrin 2), physical performance (Hand-grip strength, RPE and SPPB), anthropometrics (Body mass, BMI and fat mass), and WHOQOL-BREF (physical and psychological health, social relationships and environment) were analyzed at the beginning (T1) and at the end of the 10 weeks of intervention (T2).

Study Overview

• Status: Recruiting
• Conditions: Older Adults; Female Breast Cancer; Exercise Trainning Progrmam
• Intervention / Treatment: Dietary supplement: Melatonin 6 mg; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Diego Fernández Lázaro, Professor; PhD; Phone Number: +34 658073375; Email: diego.fernandez.lazaro@uva.es
• Study Contact Backup: Name: Cesar Ignacio Fernández Lázaro, Professor; PhD; Phone Number: +34 975129185; Email: fernandezlazaro@usal.es

Study Locations

• Spain
  • Soria, Spain, 42004
    • Recruiting
    • Faculty of Health Sciences, University of Valladolid Soria Campus
    • Contact: Diego Fernández Lázaro, Vice Dean; Phone Number: 658073375; Email: diego.fernandez.lazaro@uva.es

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Study participants were women with a history of ductal carcinoma in situ, lobular carcinoma in situ, or stage 1 to 3 breast cancer (5 years or more since diagnosis), not currently receiving chemotherapy or hormone therapy, postmenopausal, and Eastern Cooperative Oncology Group (ECOG) score ≤ 1

Exclusion Criteria:

• women who had exercised regularly for at least 20 minutes once and at least twice a week in the 3 months before the study
• Stage IV breast cancer or systemic recurrences
• Known autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis.
• Severe kidney disease
• Use of adjuvant hormonal therapy, oral estrogen or progesterone replacement therapy, luteinizing hormone-releasing hormone agonists currently or within the past 60 days
• 6-month ≥ post-chemotherapy
• Concomitant use of sleeping pills every night at bedtime
• Concomitant use of black cohosh, flaxseed, or soy in pill or supplement form
• Functional limitation using the Barthel scale (less than 100 = maximum score) and the Lawton-Brody scale (less than 8 = maximum value).
• Uncontrolled hypertension (>180/100 mm Hg).
• Uncontrolled atrial or ventricular arrhythmias, dissecting aortic aneurysm, severe aortic stenosis, acute endocarditis/pericarditis
• Acute thromboembolic disease.
• Moderate/severe chronic obstructive pulmonary disease (COPD) with Bodex index C or D Recent bone fracture (last month).
• Any other circumstance that your doctor considers prevents physical activity.
• Neoadjuvant chemotherapy or radiotherapy
• Concomitant use of beta-blockers
• 6-month ≥ post-radiotherapy
• Concomitant use of postmenopausal hormone replacement therapy
• Use of any type of oral melatonin supplement in the past 30 days
• Acute/chronic heart failure with NYHA (New York Heart Association) score >II
• Uncontrolled orthostatic hypotension
• Recent acute myocardial infarction (3 to 6 months) or unstable angina.
• Acute/chronic respiratory failure.
• Diabetes mellitus with acute decompensation or uncontrolled hypoglycemia
• History of dementia (suspected by the GP environment and diagnosed).
• Shift-work and night-work

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melatonin supplementation group; 2 capsules distributed in a single daily oral intake at 9 p.m. or 30 minutes before bedtime, whichever came first, for 10 weeks.	Dietary supplement: Melatonin 6 mg; wo capsules per day; Each capsule includes 3mg Melatonin Nutrifoods® Laboratories, Barcelona, Spain) by the Magistral Formulation Laboratory of a Pharmacy (Soria, Spain), following the rules of the Royal Spanish Pharmacopoeia (Ministry of Health, Government of Spain). Melatonin has a technical data sheet that guarantees its composition and purity (Reference No.: DIE-134).
Placebo Comparator: Placebo supplementation group; 2 capsules distributed in a single daily oral intake at 9 p.m. or 30 minutes before bedtime, whichever came first, for 10 weeks.	Other: Placebo; Two capsules per day; Each capsule includes 100-mg maltodextrin capsules were used as a placebo to match the color and texture of the Melatonin tablets to ensure blinding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Irisin	Exerkin secreted primarily by skeletal muscle in response to exercise	first day of study and after 60 days of supplementation (end of study)
Sestrin-2	Exerkin a highly conserved stress-responsive protein, can be triggered by various noxious stimuli, such as hypoxia, DNA damage, oxidative stress, endoplasmic reticulum (ER) stress, and inflammation.	first day of study and after 60 days of supplementation (end of study)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BAP	biological antioxidant potential (BAP) test to estimate antioxidant capacity by measuring the blood concentration of antioxidants	first day of study and after 60 days of supplementation (end of study)
d-ROMs	diacron reactive oxygen metabolites (d-ROMs) pro-oxidant state of a biological sample, measures hydroperoxides	first day of study and after 60 days of supplementation (end of study)
World Health Organization Quality of Life - BREF (WHOQOL-BREF)	a self-report questionnaire which assesses 4 domains of quality of life (QOL): physical health, psychological health, social relationships, and environment	first day of study and after 60 days of supplementation (end of study)
Creatine kinase (CK)	CK is an enzyme expressed by various tissues and cell types; markers of muscle damage	first day of study and after 60 days of supplementation (end of study)
Lactate dehydrogenase (LDH)	LDH is a catalytic enzyme found in many tissues of the body;markers of muscle damage	first day of study and after 60 days of supplementation (end of study)
Cortisol	catabolic hormone released in response to stress	first day of study and after 60 days of supplementation (end of study)
Testosterone	anabolic hormone	first day of study and after 60 days of supplementation (end of study)
Estradiol	female sex hormone of the estrogen group.	first day of study and after 60 days of supplementation (end of study)
BMI	Body Mass Index (BMI) anthropometric parameter which is the relationship between a person's body mass and their height	first day of study and after 60 days of supplementation (end of study)
Fat Mass	Anthropometric parameter fat mass allows the estimation of overweight or obesity in humans	first day of study and after 60 days of supplementation (end of study)
Short Physical Performance Battery (SPPB)	Test evaluates three aspects of mobility measures balance, the second gait speed, and the third leg strength	first day of study and after 60 days of supplementation (end of study)
Hand-grip strength	Grip strength is a measure of muscular strength or the maximum force/tension generated by one's forearm muscles	first day of study and after 60 days of supplementation (end of study)
RPE-Borg 10	RPE stands for Rating of Perceived Exertion.	first day of study and after 60 days of supplementation (end of study)

Collaborators and Investigators

• Sponsor: University of Valladolid
• Collaborators: Ministerio de Ciencia e Innovación, Spain; Sanidad de Castilla y León; Fundación General Universidad de Valladolid

Study record dates

Study Major Dates

• Study Start (Estimated): January 15, 2025
• Primary Completion (Estimated): December 20, 2025
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: August 22, 2024
• First Submitted That Met QC Criteria: November 18, 2024
• First Posted (Estimated): November 20, 2024

Study Record Updates

• Last Update Posted (Estimated): November 20, 2024
• Last Update Submitted That Met QC Criteria: November 18, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Melatonin; quality of life; physical performance; antioxidant capacity; health biomarkers; Brear Cancer; anthropometrics parameters; Exerkins
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antioxidants; Protective Agents; Melatonin
• Other Study ID Numbers: 2024.08.12

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.: Yes