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

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Soria, Spain, 42004
    • Faculty of Health Sciences, University of Valladolid Soria Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

Postmenopausal women aged 60-75 years with a history of ductal carcinoma in situ, lobular carcinoma in situ, or stage I-III breast cancer diagnosed 5 years or more previously; not currently receiving chemotherapy, radiotherapy, or endocrine therapy; and with an Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

Exclusion Criteria:

Women who had exercised regularly for at least 20 minutes per session and at least twice per week during the 3 months before the study; stage IV breast cancer or systemic recurrence; previous malignancies of any type other than breast cancer, basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; known autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis; decompensated liver cirrhosis; severe kidney disease; use of adjuvant hormonal therapy, oral estrogen or progesterone replacement therapy, or luteinizing hormone-releasing hormone agonists currently or within the previous 60 days; less than 6 months since completion of 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 defined as a Barthel Index <100 or Lawton-Brody score <8; uncontrolled hypertension (>180/100 mmHg); uncontrolled atrial or ventricular arrhythmias, dissecting aortic aneurysm, severe aortic stenosis, or acute endocarditis/pericarditis; acute thromboembolic disease; moderate or severe chronic obstructive pulmonary disease (COPD) with BODE index C or D; recent bone fracture within the previous month; any other medical condition considered by the treating physician to preclude participation in physical activity; neoadjuvant chemotherapy or radiotherapy; concomitant use of beta-blockers; less than 6 months since completion of radiotherapy; concomitant use of postmenopausal hormone replacement therapy; use of any type of oral melatonin supplement within the previous 30 days; acute or chronic heart failure with New York Heart Association (NYHA) class >II; uncontrolled orthostatic hypotension; recent acute myocardial infarction (3-6 months) or unstable angina; acute or chronic respiratory failure; diabetes mellitus with acute decompensation or uncontrolled hypoglycemia; history of diagnosed dementia; and shift work or 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; Participants received one capsule containing 6 mg of melatonin once daily for 10 weeks, in addition to the concurrent exercise-training program.	Dietary supplement: Melatonin 6 mg; One capsule containing 6 mg of melatonin was administered once daily for 10 weeks. Melatonin (Nutrifoods® Laboratories, Barcelona, Spain) was prepared by the Magistral Formulation Laboratory of a pharmacy (Soria, Spain), in accordance with the requirements of the Royal Spanish Pharmacopoeia (Ministry of Health, Government of Spain). Melatonin had a technical data sheet certifying its composition and purity (Reference No. DIE-134).
Placebo Comparator: Placebo supplementation group; Participants received one matched placebo capsule once daily for 10 weeks, in addition to the same concurrent exercise-training program.	Other: Placebo; One matched placebo capsule containing 100 mg of maltodextrin was administered once daily for 10 weeks. The placebo capsule was identical in appearance to the melatonin capsule to maintain participant blinding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma irisin concentration	Plasma irisin concentration was measured using an enzyme-linked immunosorbent assay (ELISA).	Baseline and after 10 weeks (Day 70)
Plasma sestrin-2 concentration	Plasma sestrin-2 concentration was measured using an enzyme-linked immunosorbent assay (ELISA).	Baseline and after 10 weeks (Day 70)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biological antioxidant potential (BAP)	Biological antioxidant potential (BAP) was measured to assess plasma antioxidant capacity.	Baseline and after 10 weeks (Day 70)
Plasma reactive oxygen metabolite concentration (d-ROMs)	Plasma reactive oxygen metabolites (d-ROMs), reflecting circulating hydroperoxide levels and oxidant status, were measured using the FREE Carpe Diem analytical system.	Baseline and after 10 weeks (Day 70)
World Health Organization Quality of Life-BREF (WHOQOL-BREF) domain scores	Quality of life was assessed using the World Health Organization Quality of Life-BREF (WHOQOL-BREF), covering four domains: physical health, psychological health, social relationships, and environment. Domain scores range from 4 to 20, with higher scores indicating better quality of life.	Baseline and after 10 weeks (Day 70)
Plasma creatine kinase (CK) activity	Plasma creatine kinase (CK) activity was measured as a biomarker of muscle damage using an automated clinical chemistry analyzer (Hitachi 917).	Baseline and after 10 weeks (Day 70)
Plasma lactate dehydrogenase (LDH) activity	Plasma lactate dehydrogenase (LDH) activity was measured as a biomarker of muscle damage using an automated clinical chemistry analyzer (Hitachi 917).	Baseline and after 10 weeks (Day 70)
Blood cortisol concentration	Blood cortisol concentration was measured using an enzyme-linked fluorescence assay (ELFA) on a MiniVIDAS® multiparametric immunoanalyzer. Results were expressed in µg/dL.	Baseline and after 10 weeks (Day 70)
Blood total testosterone concentration	Blood total testosterone concentration was measured using an enzyme-linked immunosorbent assay (ELISA). Results were expressed in ng/mL.	Baseline and after 10 weeks (Day 70)
Plasma estradiol concentration	Plasma estradiol concentration was measured using an enzyme-linked immunosorbent assay (ELISA).	Baseline and after 10 weeks (Day 70)
Body mass index (BMI)	Body mass index (BMI) was calculated from body mass and height and expressed in kg/m².	Baseline and after 10 weeks (Day 70)
Fat mass percentage	Fat mass was assessed by bioelectrical impedance analysis using a Tanita BC-730 analyzer and expressed as a percentage of body mass (%)	Baseline and after 10 weeks (Day 70)
Short Physical Performance Battery (SPPB) total score	Physical performance was assessed using the Short Physical Performance Battery (SPPB), comprising balance, 4-meter gait speed, and five-repetition chair-stand tests. The total score ranges from 0 to 12 points, with higher scores indicating better physical performance.	Baseline and after 10 weeks (Day 70)
Hand-grip strength	Handgrip strength was measured as an indicator of upper-limb muscular strength and expressed in kilograms (kg).	Baseline and after 10 weeks (Day 70)
Rating of Perceived Exertion using the Borg Category Ratio-10 (CR-10) scale	Perceived exertion was assessed using the Borg Category Ratio-10 (CR-10) scale, ranging from 0 (no exertion) to 10 (maximal exertion). Higher scores indicate greater perceived exertion.	Baseline and after 10 weeks (Day 70)

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Celorrio San Miguel AM, Cacharro LM, Santamaria G, Garrosa M, Celorrio San Miguel M, Roche E, Garrosa E, Fernandez-Lazaro D. Adjuvant melatonin therapy during exercise prescription in breast cancer survivors on physical and anthropometric parameters, quality of life, and hormonal response. A randomized controlled trial. Front Sports Act Living. 2025 Jun 23;7:1594733. doi: 10.3389/fspor.2025.1594733. eCollection 2025.

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2024
• Primary Completion (Actual): May 5, 2025
• Study Completion (Actual): May 5, 2025

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Actual): September 30, 2026
• Last Update Submitted That Met QC Criteria: September 25, 2026
• Last Verified: September 1, 2026

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: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Tryptamines; 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