In 2022, 2.3 million women were diagnosed with breast cancer (BC) and 670,000 died worldwide from the disease. BC affects women of all ages globally after puberty, with its incidence increasing with age (1). Scientific advances in the last decades have improved our understanding of BC biology, leading to the development of new drugs, the identification of prognostic factors, and personalized therapies, thereby optimizing treatment protocols. These advancements have collectively contributed to an increase in average overall survival rates (2).

However, survival presents a dual challenge for breast cancer survivors (BCS): they must work to restore their psychosocial and physical well-being while managing symptoms and treatment side effects. The disease itself, along with adjuvant chemotherapy and radiotherapy, is associated with serious complications such as muscle wasting and weakness (3). These adverse effects stem not only from the therapies (chemotherapy and radiotherapy), but also from physical inactivity, which is common among cancer patients and exacerbates the decline in physical function, aerobic capacity, and quality of life (QoL) (4, 5). Therefore, although BCS are now living longer, disease burden and treatment-related toxicities continue to impair their QoL and overall well-being.

Approximately 50% of BC cases are diagnosed in women aged up to 65 years, and over 30% in women aged 70 or older (6). With increasing life expectancy, projections indicate that by 2035, 60% of new BC cases will be diagnosed in patients aged 70 and older (7). BC in women over 70 presents specific clinical and biological characteristics that require tailored diagnostic and therapeutic approaches (8). Moreover, treating BC in older patients remains challenging, as older women are less likely to receive standard treatment for the disease (9). This clinical challenge underscores the need of pharmacological adjuvant treatment strategies to help manage this patient group by modulating BC and reducing treatment side effects (10). Among these strategies, therapeutic physical exercise (PE) and nutritional interventions, particularly nutritional supplementation, have shown promising results (11).

PE plays a key role in mitigating many of the adverse effects of BC therapy, enhancing physical performance, and reducing fatigue in BCS (4, 5). PE may help reduce chronic inflammation and stimulate the proliferation and differentiation of muscle stem cells (satellite cells) as part of the adaptive response to exercise, helping in recovery from muscle wasting and weakness (12). Additionally, PE supports mental and social well-being in BCS, alleviating symptoms associated with the disease or its treatment (13). However, single exercise sessions are unlikely to produce significant adaptive changes; instead structured PE programs over extended periods of time are required (11).

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized by the pineal gland and other tissues or organs such as the retina, gastrointestinal tract and skin (14–16). Endogenous melatonin is synthesized from tryptophan, which is converted into serotonin before undergoing acetylation and methylation to form melatonin (17). Melatonin plays a fundamental role in regulating circadian rhythm (18, 19) and contributes to various gastrointestinal functions such as mucosal protection and gastrin release (15, 20). Moreover, melatonin exhibits anti-inflammatory (21), antioxidant (22, 23), and immunoregulatory (24) properties, acting as an antitumor agent (25, 26) and free radical scavenger (27, 28).

In cancer treatment, melatonin provides several benefits, including mitigating the toxic effects of chemotherapy (29) and radiotherapy (30). Specifically in BC, melatonin has been associated with inhibiting cell division and stimulating cell necrosis (31). Additionally, melatonin has demonstrated antiestrogenic properties (32, 33), due to its ability to reduce steroid production in the gonads; decreasing the synthesis of enzymes involved in the conversion of androgens to estrogens and binding directly to estrogen receptors (34, 35). Likewise, the role of melatonin in cancer extends to improving the QoL of patients with this pathology (36), particularly by addressing one of the main consequences of chemotherapy and radiotherapy: circadian rhythm disruption (37). Supplementing with exogenous melatonin can help reduce treatment-related side effects, including fatigue and sleep disturbances, thereby optimizing overall treatment outcomes (38).

Since cancer is strongly associated with aging, demographic trends suggests that the incidence of epithelial neoplasms will increase in the coming decades (1). BC is currently the leading cause of cancer-related death among women, with age being the primary risk factor for its development (39). Furthermore, the biological and clinical changes associated to aging influence cancer progression and treatment (9). Since most BC treatment and prevention guidelines for older adults are based on studies conducted on younger populations, research specifically targeting older adults would be highly beneficial (40). PE and appropriate nutritional supplementation are fundamental to both individual and community health. Therefore, this study aims to examine the effects of a 10-week melatonin supplementation combined with a PE program, on physical and anthropometric parameters, QoL, and hormonal response in elderly female BCS.

The study participants were Spanish women aged 60–75. Table 1 presents the participants' baseline characteristics. The body mass index was within the normal weight range (20–25 kg/m²) in the MEL group and slightly overweight (>25 kg/m²) in the CG group, although the differences were not significant. Smoking habits are one of the most determining variables in the development of breast cancer. There was only one smoker in both groups, while the rest of the participants were equally distributed between women who had quit smoking (non-smoker) and those who had never smoked (never smoker). In this regard, both groups were quite homogeneous. Regarding allergies, both groups also presented homogeneity, with the majority being women without allergies (70%–80%). This ensured that they could adhere to the physical activity plan without experiencing respiratory problems during the exercises. In fact, 20% of the women who reported having allergies did not experience any allergic crises during the intervention protocol, maintaining proper respiratory function. Regarding other vital signs, both groups had slightly elevated blood pressure values (144.22/86.22 mmHg in CG and 146.29/77.71 mmHg in MEL) and a resting heart rate in accordance with their age range (60–100 beats per min). Temperature data indicated that they did not suffer from any infections causing fever at the time of recruitment, and their oxygen saturation was within the correct range (95%–98%) for their age group. All these values ensured that the participants could successfully complete the physical activity protocol and that the results obtained were comparable between the two groups (MEL and CG), as well as within the same group between the beginning (T1) and end (T2) of the study (Table 1).

All patients (n = 20) underwent surgery. The most common procedure was lumpectomy with sentinel lymph node removal (CG = 4; MEL = 3). Seven BCS received radiotherapy (3 in MEL, 4 in CG), 8 underwent chemotherapy (5 in MEL, 3 in CG), and 2 received both treatments (1 in MEL, 1 in CG). Five participants received hormone therapy (3 in MEL, 2 in CG). The predominant stage in Stage I–III BC was stage I in the CG (n = 5) and stage II in the MEL group (n = 5) (Table 2).

Table 3 presents the main anthropometric characteristics of participants. In the CG, average body mass slightly decreased at T2 (p > 0.05), likely due to a reduction in fat mass. Conversely, MEL showed an increase in body mass at the end of intervention (T2), despite a decrease in fat mass. However, no significant differences were found when comparing MEL vs. CG at either time point (T1 or T2). Furthermore, no significant differences (p > 0.05) were observed between T1 vs. T2 within either group (MEL or CG).

Table 4 presents the SPPB index values, which showed no significant differences (p > 0.05) between groups or across time points. Both groups exhibited a decrease in RPE when comparing T1 vs. T2. This change over time was statistically significant (p = 0.018), with moderate effect size (η²p = 0.347) and a statistical power of 0.642. These results suggest similar reduction in perceived fatigue at T2 in both groups.

Table 5 presents the results of the four domains of the WHOQOL-BREF questionnaire and the total score obtained. Physical health scores did not significantly increase (p > 0.05) in the CG, nor were any significant changes observed in MEL (p > 0.05). The CG maintained a constant score in the psychological health domain, while MEL showed a decrease, though not significantly (p > 0.05). In the social relationship's domain, both groups exhibited a decrease in average scores, with no significant differences (p > 0.05) between them. Similarly, the environment domain remained relatively constant in CG but decreased in MEL, although this difference was not significant (p > 0.05). Regarding the total score, an increase (indicating improvement) was observed in CG, while a decrease was noticed in MEL. However, these differences were not statistically significant (p = 0.183).

Table 6 presents the hormonal response data, based on testosterone and cortisol levels. No significant (p > 0.05) differences were observed in hormonal patterns within either group or between the two groups.

Blinding index ranged from 1 (none of the subjects knew to which group they were assigned) to 0 (all subjects knew to which group they were assigned). Values above 0.5 indicated that the blinding was successful (47). The blinding index at T2 was 0.86, with five participants stating that they knew which group they belonged to, although only three BCS were correct. This suggested that the blinding process was successful (Results not reported in table).

This study investigated the effects of 10 weeks of melatonin supplementation combined with a PE program on body composition, physical condition, HRQoL, and hormonal responses in BCS. After the 10-week intervention, all measured parameters were modified in both MEL and CG. However, no significant differences (p > 0.05) were found between the groups, suggesting that the observed changes were likely due to the PE program. While previous research has highlighted the potential benefits of melatonin in managing certain aspects of BC (31, 62), the results of the present report indicate that melatonin supplementation has not a clear effect on the parameters examined in this study. No adverse effects related to the PE program or melatonin supplementation were reported. The only notable observation was an increase in BMI in the MEL group at the end of intervention, likely due to an increase in muscle mass. The results obtained in the different tests, suggest that melatonin does not appear to affect the measured parameters. Additionally, the hormonal pattern observed suggests that the stress associated to exercise remained constant through the study, with no influence of melatonin.

BC is a prevalent disease among older women, with approximately one-third of diagnoses occurring in women aged 60 and over (63). In addition, women in this age group have a 1 in 15 chance of developing additional tumors. With the projected growth of the aging population, these figures are expected to rise in the coming years (64). Treating BC in older women presents a therapeutic challenge, as BC-related mortality increases with age (9). Given the variability in symptoms presentation across different BC stages, this study focused on women aged 60–75 years with a history of BC stages I, II, and III. Demonstrating a positive response to the combined melatonin and PE intervention in this population could enhance the clinical applicability of the findings. Although survival was not an outcome assessed in this study, long-term survival analysis between the 2 groups could offer valuable insights into survival rates for BCS, potentially impacting clinical practice. Importantly, melatonin supplementation (6 mg/day) was well-tolerated, consistent with reports indicating that doses of up to 20 mg/day are generally safe (65, 66). Melatonin has also demonstrated protective effects against toxicity associated with oncologic treatments (29), mitigating adverse effects such as thrombocytopenia, neurotoxicity, or cardiotoxicity, among others (65, 66).

Our study found no significant differences in anthropometric parameters between MEL and CG. This may be due to the melatonin dosage, which seems to be insufficient to induce changes in body composition. However, studies in young obese and diabetic Zucker rats (an experimental model of metabolic syndrome) have shown that melatonin treatment (10 mg/kg/day) reduced white adipose tissue by promoting a partial conversion to brown fat, which allows fatty acid oxidation through thermogenic mechanisms (67). This effect of melatonin does not seem to be operative in humans. Consistent with this, melatonin supplementation did not reverse side effects such as weight loss or appetite changes associated with chemotherapy and radiotherapy in patients with advanced lung, gastrointestinal, or brain tumors (62). Furthermore, other clinical trials using melatonin dosages of 3 mg for 14 days in head and neck cancer (68), 6 mg for 3 months in BC patients (49), and 20 mg for 6 weeks in patients with various cancer types (69) did not assess body composition, making it challenging to determine the optimal dosage and duration for modulating anthropometric changes.

In the present study, as mentioned above, MEL and CG experienced a decrease in fat mass, but only MEL showed a non-significant increase (p > 0.05) in body mass at T2. A plausible explanation is that MEL experienced an increase in muscle mass, which would account for the observed rise in BMI at the end of the 10-week intervention. This increase in muscle mass is likely due to the melatonin-plus-exercise program. The combined aerobic and resistance exercise program implemented in this study is expected to improve both cardiovascular and muscle metabolism through muscle protein synthesis (70). This type of exercise program can help maintain muscle mass during weight loss, contributing to improved physical function and reduced frailty (71). Additionally, this exercise protocol could lower the risk of future cancer recurrence associated with overweight, as excess fat mass has been linked to increased estrogen production, which may promote the development and growth of hormone receptor-positive BC cells (72, 73).

For BCS, PE is widely recommended and has been associated with improvements in physical function (4), QoL (4) and increased survival (5). Physical parameters were evaluated using the SPPB index (59), which showed no significant differences (p > 0.05) between groups or across measurement times. This lack of significance is likely due to participants were non-frail (SPPB ≥10) before the study and remaining in this state at the end, suggesting a low likelihood of major health events such as hospital admission or exacerbation of chronic conditions. Moreover, patients enrolled in clinical trials are often highly selected for their robust physical health, making them potentially unrepresentative of the general geriatric population (74). Additionally, a recent study by Celorrio et al. (75) reported no direct relationship between melatonin supplementation and physical performance. The effects of melatonin on physical status could depend on factors like the type and duration of supplementation, or the type and duration of exercise, which may influence melatonin's impact on physical parameters (75).

The RPE CR-10 scale is used to assess effort and fatigue during physical activity (76). In this study, both groups recorded a significant decrease (p < 0.05) in RPE CR-10 values from T1 to T2, displaying significant (p = 0.018) trends over the course of the study. Melatonin supplementation (20 mg weekly) in phase IV cancer patients from a palliative care unit (77) or early-stage BC patients during and two weeks post-radiotherapy (78) did not improve fatigue, insomnia, or tiredness. However, a study by Dieli-Conwright et al. (79) found that a 16-week concurrent exercise program (aerobic and strength training) significantly reduced fatigue in BC patients. Similarly, our participants indirectly demonstrated reduced fatigue, as they were able to significantly increase exercise intensity. In this regard, elastic band exercises were progressively adjusted based on the RPE scale to reach a level of 10 (80), without inducing fatigue. These findings support the incorporation of exercise routines, which are associated with favorable survival trends, across various cancer populations (4). Given the clinical characteristics of the sample, acute physical exercise also increases oxidative stress (81). In this context, MEL reported lower RPE-CR-10 values, likely due to melatonin's antioxidant, anti-inflammatory, and circadian rhythm-regulating properties (82). However, these last points need further investigation. Lower RPE in BCS is associated with various clinical and HRQoL implications, including higher treatment adherence, lower risk of complications, and improved HRQoL. Fatigue, a common side effect, can limit physical activity, social participation, cognitive function, negatively impacting HRQoL, and the well-being of patients (83). RPE allows for prescribing individual exercise values (56) adjusted to FITT for each BCS, ensuring the absence of side effects or withdrawals from the study due to PE.

Although participants showed improvements in SPPB, RPE, and body composition, no changes were observed in the total score or dimensions (physical and psychological health, social relationships, and environment) of HRQoL, as measured by the WHOQOL-BREF questionnaire (60). This may be due to several factors, such as the impact of the disease on survivors (e.g., depression, low self-esteem, changes in physical conditions, loneliness, among others) at different stages (84). These factors can have long-term effects across all four HRQoL dimensions, often associated with disease progression or oncologic treatments received (85). In addition, our results might be influenced by the study's duration, the supplementation protocol, or the training protocol. It is possible that a 10-week intervention is too short to elicit measurable changes in HRQoL. Consistent with our findings, Seely et al. (86) also reported no QoL benefit in non-small cell lung cancer (NSCLC) patients receiving 20 mg of melatonin over two years. Similarly, the meta-analysis conducted by Fan et al. (87), which included 19 randomized controlled trials involving 2,101 cancer patients receiving melatonin supplementation, found no improvement in HRQoL. However, a systematic review by Fernández-Lázaro et al. (4) reported that PE programs significantly improved QoL compared to controls (no exercise). QoL has been evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires [Core-30 (QLQ-C30), Lung Cancer-13 (QLQ-LC13)] modules, the Functional Assessment of Cancer Therapy (FACT), and the Short Form-36 Health Survey (SF-36) (86). To our knowledge, this is the first study to use the WHOQOL-BREF questionnaire in a trial involving melatonin supplementation (60) and PE, although this HRQoL test is commonly applied in cancer-related research (88).

In healthy humans, melatonin and cortisol circadian rhythms display opposite phases: melatonin peaks at night when cortisol levels are low, and vice versa during the day (89). In contrast, abnormalities in the diurnal cortisol rhythm are common in cancer patients and have been associated with poorer survival in BC patients (37). Furthermore, cancer patients undergoing mixed treatments (chemotherapy and radiotherapy) or post-treatment often exhibit elevated cortisol levels, which can negatively affect QoL due to both the physical and emotional impact of the disease (90). In our study, cortisol levels increased slightly in both MEL and CG, suggesting that melatonin supplementation does not affect the MT1 melatonin receptor in the adrenal gland or inhibit adrenocorticotropic hormone (ACTH)-stimulated cortisol production (91). It remains unclear whether a higher dose or longer duration of treatment would have influenced daytime cortisol production. Studies on melatonin supplementation show no conclusive effects on plasma cortisol levels, with mixed findings indicating that melatonin either increases (92, 93), decreases (91, 94), or has no effect (95, 96). The high cortisol levels observed in our BCS, at T1 and T2 could be influenced by threat minimization and problem-focused coping strategies, which serve as mediating factors in adapting to BC (90). This triggers activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to cortisol secretion (91). When stress is persistent and uncontrollable, HPA axis activity decreases. However, when BCS stress has some controllable elements, such as fight-flight responses to BC, the HPA axis may be activated (97). The HPA axis plays an instrumental role in providing metabolic support, mobilizing energy to address cancer management and implications of oncological treatment (97). Cortisol is also released in response to physical and psychological stress, with significant increases following exercise due to training adaptations (98). Cortisol levels are generally highest in the morning, when blood was collected in this study, and lowest around midnight (89). All these factors may contribute to the observed increases in plasma cortisol levels. High cortisol concentrations are linked to chronic inflammation, which raises the risk of cellular epigenetic alterations (99). This explains why persistent chronic inflammation itself constitutes a risk factor for certain cancers (100), through activation of the NF-kB and STAT3 signaling pathways associated with tumor growth (101). Additionally, stress induces both indirect mechanisms (e.g., immune system inhibition) and direct mechanisms (e.g., binding of stress signaling molecules to cell receptors) that can promote cancer progression (102, 103). However, an increased cortisol response may help coping with stress during the daytime (104). Future studies should include more frequent, multi-day cortisol monitoring to better understand melatonin's true effects on cortisol.

Finally, testosterone levels tended to decrease substantially, though not significantly (p > 0.05), in both groups from T1 to T2, with no significant (p > 0.05) differences between-groups. The testosterone/cortisol ratio also decreased, but without significant differences (p > 0.05). The evidence regarding whether melatonin supplementation reduces testosterone levels is conflicting in animal models (105, 106), whereas studies in humans suggest no effect (75, 107). The notable decreases in testosterone observed in our study could be attributed to the continuous PE program. Testosterone levels are influence by exercise duration and intensity, which may disrupt the hypothalamic-pituitary-gonadal axis, leading to suppressed testosterone secretion (108). Testosterone plays an essential role in the physical and mental health, as well as in QoL of women, including BCS. The hormone is generally protective against BC by reducing tissue proliferation. However, testosterone can also be converted to estradiol (E2), which may increase BC risk due to stimulation of cell proliferation (109).

While exercise is beneficial, it can also exacerbate fatigue, increasing the perception of exertion, particularly in this population with significant impairment due to BC and BC treatments. This would directly affect the physical condition and QoL of BCS. Melatonin may help mitigate these adverse effects, providing a protective role against exercise-induced fatigue. Although the effects were not statistically significant, the qualitative differences in parameter responses between the MEL and CG groups could support the success of our intervention. Higher doses of melatonin or extended periods of exercise and supplementation may be required to achieve significant effects. However, our study uses three times the dose authorized by the Spanish Agency for Medicines and Health Products. Additionally, our structured exercise program was carefully tailored to the condition of our patients. It is also important to consider that some patients may be non-responders. Several factors could explain this lack of response, including underlying diseases, interactions with other medications, or individual variability in melatonin response. Furthermore, the dose or timing of administration may not be optimal for BCS, who are older adults. Age could influence the effect of melatonin through multiple mechanisms, including alterations in melatonin receptors, age-related hormonal changes, underlying health conditions, and the use of certain concomitant medications.

A 10-week supplementation of 6 mg/day of melatonin combined with a PE program did not influence anthropometric measure, physical parameters, HRQoL, and hormonal response compared to the placebo-supplemented group, which also participated in the PE program. These results further support the lack of a clear effect of melatonin in this context, suggesting that the observed modifications are likely due to the PE program itself. However, differences in biomarker responses between the MEL and CG groups may indicate some success of our melatonin supplementation protocol. These findings suggest a novel therapeutic strategy that could enhance health outcomes and QoL for individuals with BCS. Further research is needed to validate these results and explore the broader implications of this combined intervention.