Exploring the Efficacy of Melatonin in Alleviating Menopausal Symptoms in Breast Cancer Survivors: A Randomized, Double-Blind, Placebo-Controlled Study

Authors: Parinaz Sattari, Melika Shakourifar, Khatereh Jafarian, Erfan Naghsh, Alireza Sadeghi, Mehran Sharifi, Azadeh Moghaddas

Abstract

Background:

Patients with hormone-positive breast cancer (BC) who are receiving antihormone medications suffer from complications, including hot flashes, decreased libido, and mood changes due to artificial menopause. Considering the positive effects of melatonin administration on ameliorating hot flashes and depression in postmenopausal women, we aimed to examine the effects of melatonin supplementation on menopausal-related complications in BC patients who were receiving antihormone medications.

Materials and Methods:

This study was a randomized, placebo-controlled clinical trial conducted in the hematology-oncology clinic of Omid hospital, Isfahan, Iran, during 1-year patients’ recruitment. Adult patients with BC who were being treated with selective estrogen receptor modulator family drugs or aromatase inhibitors while they were complaining of menopausal complications were included. Melatonin (3 mg) or an identical placebo was administered twice a day orally. Several questionnaires, including the Menopause Rating Scale, the Menopause*-*specific Quality of Life-Intervention and the Female Sexual Function Index, were applied for the evaluation of comparison items.

Results:

Sixty patients fulfilled the requirements to complete the four-week treatment. There were no significant differences in patients’ baseline clinical characteristics. Supplementation by melatonin was associated with a significant decrease in frequency and severity of hot flashes, and the mean score of menopausal symptoms. The quality of life and sexual function were enhanced by a four-week melatonin treatment.

Conclusion:

Considering the effect of melatonin on menopausal complications and quality of life during menopause and sexual function scores in people undergoing BC antihormone treatment, melatonin can be considered a potential candidate to include in the treatment regimen of BC patients.

INTRODUCTION

Breast cancer (BC) is the most commonly diagnosed cancer among women worldwide,[1] and it has been noted that one out of every eight to ten women will eventually develop BC in their lifetime. Importantly, it is the second deadliest cancer among women due to its high prevalence.[2] In recent years, the global incidence of BC has increased, and the utmost increase was seen in developing countries.[3] Several strategies have been used to treat BC, including chemotherapy, surgery, radiation, and hormone therapy.[4]

The role of estrogen and its active metabolites in BC has been evidenced.[56] Estrogen binds to its receptor (ER), which leads to the proliferation of estrogen-sensitive epithelial tissues and increases the potential of genetic errors and tumor tissue formation.[7] As two-thirds of BC cases are estrogen receptor-positive (ER-positive),[8] hormone therapy can be a beneficial approach for treatment. The patients with ER-positive tumors usually undergo treatment with endocrine therapies, including the selective ER modulator (SERM) like tamoxifen or aromatase inhibitors (AIs) like letrozole.[9]

Antihormone treatments of BC are often accompanied by long-term morbidity and side effects such as hot flashes, vaginal bleeding, menstrual cramps, mood disorders, depression, and gastrointestinal disorders, which can negatively impact patient’s quality of life.[1011] Various drug categories, such as serotonin reuptake inhibitors, including sertraline, paroxetine, and anticonvulsant drugs, including gabapentin and pregabalin, have been used to mitigate those symptoms.[1213] However, most of these medications have noticeable nervous system side effects, including mental disturbance, cognitive changes, and impaired concentration.[1415] Thus, searching for such alternative treatments to reduce the vasomotor symptoms with fewer side effects is ongoing.[1617]

Melatonin is an endogenous hormone synthesized by the pineal gland and is known as the sleep cycle regulator in the body.[1819] Melatonin is available as an over-the-counter supplement. Extensive evaluations in humans have shown that it does not seem to have any significant side effects across a wide range of doses and periods of use.[20] Melatonin may have effects on reducing cancer therapy side effects, especially in BC.[2122] Melatonin may mitigate these side effects, including hot flashes, vaginal dryness, and loss of libido, due to its nontoxic antioxidant effects.[23] Melatonin selectively counteracts the effects of estrogen on breast tissue and regulates the local synthesis of estrogens from androgens. This capability positions melatonin as a promising treatment for patients with ER-positive breast cancer.[23] Additionally, these benefits indicate that melatonin could serve as an adjunct therapy to alleviate various side effects associated with anticancer drugs.[2425]

Research has shown that melatonin can effectively address postmenopausal symptoms, including hot flashes, mood swings, and sleep disturbances, by influencing other tissues like the brain or other parts of the central nervous system (CNS).[2223]

On the other hand, while melatonin has been shown to inhibit estrogen biosynthesis and receptor activity—particularly within breast tissue—[26] its effects appear to be tissue-specific, which may explain its dual role in both cancer treatment and menopausal symptom relief. In BC patients receiving antiestrogen therapy, melatonin may enhance therapeutic outcomes by limiting estrogen-driven tumor growth. Simultaneously, melatonin’s activity in the brain and CNS has been linked to improvements in sleep quality, mood regulation, and thermoregulatory balance, potentially mitigating common menopausal symptoms.[26]

Insomnia is a common complaint among postmenopausal women, often caused by various factors, one of which is the reduction in melatonin secretion.[27] Supplementing with melatonin has been shown to effectively enhance sleep quality in postmenopausal women.[27] This effect may be partly due to melatonin’s alleviating impact on sleep disorders associated with fibromyalgia syndrome, which is characterized by tenderness, sensitivity, and muscle weakness.[28]

Research indicates that melatonin’s psychopharmacological effects are partly due to its ability to enhance central gamma-aminobutyric acid (GABA) ergic transmission by modulating GABA receptor activity.[29] Similar to gabapentin, a well-known drug that operates through the GABA pathway, melatonin has shown beneficial effects on hot flashes.[30] Hence, melatonin’s potential efficacy in alleviating hot flashes, a common menopausal complaint, is plausible. In a clinical trial, women with severe climacteric symptoms at baseline were treated with 3 mg of melatonin and exhibited significant improvement in vasomotor symptoms.[31] The findings regarding the effects of melatonin on alleviating hot flashes are controversial and need further elucidation.

Melatonin has shown promising effects on attenuating vasomotor symptoms in women in menopausal age.[32] Given that the symptoms experienced by hormone-positive BC patients on antiestrogen drugs resemble those of menopause, we aimed to investigate the effects of melatonin supplementation on reducing vasomotor symptoms and improving the menopausal-associated quality of life and sexual function in those patients.

MATERIALS AND METHODS

Participants and trial design

This study was a randomized, double-blinded placebo-controlled clinical trial performed over 12 months, from March 2020 to March 2021. Patients were recruited to the study from the outpatient clinic of the hematology-oncology Center of Omid Hospital (affiliated to Isfahan University of Medical Sciences), Isfahan, Iran. Omid hospital is a 200-bed referral tertiary hospital specialized in the treatment of hematology-oncology patients. The study protocol has been approved by the Isfahan University of Medical Sciences ethics committee (ID IR.MUI.RESEARCH.REC.1398.724), and the trial was submitted in the Iranian Clinical Trial Registry Center (IRCT20180722040556N3) available at www.irct.ir.

We included all adult female patients (18 years and older) with ER-positive BC of any stage (I–III) who had a treatment history involving either SERM family drugs (such as tamoxifen) or AIs (both steroidal and nonsteroidal agents). Eligible patients had to meet the primary criterion of having completed all courses of chemotherapy and radiotherapy and currently receiving hormonal therapy. Additionally, they needed to have reported menopausal complications, particularly hot flashes occurring at least four times a week over the past month.

The exclusion criteria included a history of other malignancies, psychiatric disorders (such as depression, bipolar disorder, psychosis), use of anticonvulsant medications for active seizures, and other medications that affect the CNS, including antipsychotics, hypnotics, antidepressants, and antianxiety drugs. Patients on propranolol (due to its CNS impact), warfarin (due to high interaction risks), and supplements containing soy or vitamin E (due to their effect on menopausal symptoms) were also excluded. Additionally, patients with liver or kidney failure, autoimmune diseases, and those with a history of smoking or chronic alcohol consumption were excluded. All patients who met the inclusion criteria signed a written informed consent form.

Concealing and randomization

The randomization of samples was performed based on the blocked randomization method. Information such as the number of treatment groups (A for melatonin group and B for placebo), block size (a multiple of the number of groups that were selected in this study), and total patients (the sample size of 75 people) was entered into the internet-based software machines to assigned specific codes to each patient to receive melatonin or placebo. Blocking was commonly used to balance the number of samples assigned to each group studied when the sample size was limited. After completing the sample size allocation, the code of each patient was opened and matched with the software output. The data collector, the investigators, and the statistician were not informed of randomization during patient recruitment to keep the study blinded. The melatonin group received 3 mg of the drug twice a day orally, and the placebo group received an identical tablet with the same shape and packaging containing lactose, cellulose microcrystalline, and magnesium stearate. Both melatonin supplement and placebo were produced by Razak^®^ Pharmaceutical Company, Tehran, Iran.

Melatonin or an identical placebo was administered as recruited patients were informed about the study’s investigative method. They were then followed up for one week without taking any supplements or a placebo and asked to complete questionnaires by the end of that week. From the second week of follow-up, patients received either melatonin or placebo supplements at a dose of 3 mg twice daily for four weeks.

Questionnaires

Following patient recruitment, at the baseline and at the conclusion of the four-week treatment period, all questionnaires—such as the Menopausal Rating Scale (MRS),[33] the Menopause-Specific Quality of Life Intervention (MENQOL),[34] and the Female Sexual Function Index (FSFI)[35]—were completed by the enrolled patients.

In this study, the primary goal was to determine vasomotor and psychological changes in patients receiving hormone therapy measured by several questionnaires, including the MRS, MENQOL, and FSFI.

The MRS questionnaire consists of 11 questions regarding patients’ psychomotor symptoms, which may have been experienced in the previous week due to hormone therapy. The questionnaire was rated from 0 (having no symptoms) to 4 (having very severe symptoms).[33]

The MENQOL is a self-administered questionnaire and has 29 items in a Likert-scale format. Each item assesses the impact of one of four menopausal symptoms domains, as experienced over the last vasomotor (items 1–3), psychosocial (items 4–10), physical (items 11–26), and sexual (items 27–29). A national version of the questionnaire was prepared and validated by specialists, including two psychologists, one literature expert, two oncologists, and ten general practitioners. Then, a forward-backwards translation method was employed for translating the questionnaire, and the same questionnaire was given to 30 matched patients within two weeks. Finally, the reliability of the questionnaire with an intraclass correlation coefficient was assessed.[34]

The FSFI questionnaire is a self-reported scale consisting of six different aspects of female sexual function, including desire, arousal, lubrication, orgasm, satisfaction, and pain in the previous month. This scale has been translated and validated in many countries and is widely applied for clinical and research studies. The reliability and validity of the FSFI questionnaire were assessed and confirmed in the Ghassami et al.[35] study.

Patients were also asked to evaluate and write the frequency, severity, and location of hot flashes using the Daily Menopause Diary Index.[35] In the menopause diary index, patients recorded the number of hot flashes per day and the severity of hot flashes rated from 0 (lowest Intensity) to 4 (maximum intensity) in each week of follow-up. Then, the enrolled patients were asked to deliver the filled forms to the investigators for statistical analysis after four weeks of treatment.

The study’s primary endpoint was defined as a total four-point score decrease in MRS and MENQOL questionnaire and a total four-point increase in FSFI score.

Patients’ adherence and adverse drug reaction

At the start of the trial, participants were trained on the correct way to take the provided pills. They were instructed to retain the medication packaging and return it to the investigators at the end of the study. Adherence was monitored through the pill count method. Additionally, participants were asked to maintain a daily diary, noting the time they took their medication and any side effects experienced. During each follow-up visit, pill count data were recorded, and regular feedback on adherence was provided to participants. Those who did not consume at least 80% of the total cumulative doses of melatonin or placebo were considered noncompliant and excluded from the study. Any reported adverse drug reactions were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4 during the four-week follow-up period.[3637]

STATISTICAL APPROACH

Sample size calculation

The following equation has been used to determine the number of experimental samples in this research and to investigate the changes of a specific parameter that is used in two different modes.[38]

In this equation, N indicates the number of patients, z1 is the reliability coefficient (95%), z2 is the power factor (80%), p1 and p2 are the probability of beta power in the first and second groups (50%), and d is called the study error.

Due to difficulties in reaching the optimal sample size and based on the inclusion criteria and subjects who dropped out in addition to missing data, the authors had to terminate the study with fewer samples, adopting a pilot study design (see flow diagram).

Statistical analysis

Per-protocol analysis was considered for comparison of the data of those patients who completed the treatment originally allocated. In the data analysis stage, the Kolmogorov–Smirnov test was used to evaluate the normality of data distribution in both melatonin and placebo groups (patients’ demographic and clinical characteristics). Also, in order to evaluate the homogeneity of the distribution parameters in two groups, a paired t-test and Chi-square test were applied. The differences between the two groups were assessed by a paired t-test, analysis of variance with repeated observations and Fisher’s exact test. For measuring the internal consistency of the considered questionnaires, Cronbach’s Alpha reliability tests were used. In this study, the Statistical Package for Social Sciences version 20 software was used and P value less than 0.05 was considered significant.

RESULTS

During one year, a total of 85 eligible volunteers were recruited in the study [Figure 1]. Of those, ten patients were excluded due to either refusing to participate in the study or being noneligible due to the following not having drug adherence, disease progression, data missing, and death [Figure 1].

After that, subjects were randomly divided into melatonin (41 patients) or the placebo group (34 patients). Seven patients from melatonin and eight from the placebo group dropped out of the study due to unwillingness to complete the course of treatment. Eventually, 34 and 26 patients completed the study in the melatonin and placebo group, respectively (Figure 2 for study process).

Clinical and demographic characteristics of patients are shown in Table 1. There were no significant differences in the baseline characteristics regarding age, menopausal status, underlying diseases, pathological type of cancer, and previous treatment regimens between the two groups. The mean age was 50 ± 8.7 years in the placebo group and 50.2 ± 8.6 years in the melatonin group (P = 0.79). In addition, the mean score of daily hot flashes in terms of severity and frequency was not significantly different at the baseline [Table 1].

Using the self-reported Daily Menopause Diary Index, the severity and frequency of daily hot flashes decreased over the course of treatment, and this decrease was significant in the melatonin group when compared to the placebo group (P < 0.001) [Table 2]. Also, the mean of hot flashes severity and frequency scores after four weeks of treatment were significantly lower in the melatonin group than the placebo (severity: P < 0.001 and P = 0.001).

Before melatonin treatment, MRS, MENQOL, and FSFI mean scores were not significantly different between the two groups. In contrast, after the melatonin treatment, the mean scores of MRS and MENQOL in the melatonin group were significantly lower than the placebo group (P < 0.001), and the mean score of FSFI was significantly higher in the melatonin group than those of the placebo (P = 0.001, Table 3).

There was a significant difference among all the included items in the MRS questionnaire, including vasomotor, psychosocial, physical, and sexual scores between melatonin and placebo group after four weeks of treatment. However, in the FSFI questionnaire, the difference was insignificant in the sexual satisfaction items [Table 3]. Of note, the differences were significant between the two groups in other items such as desire, arousal, lubrication, orgasm, and pain.

The analysis based on CTCAE version 4 revealed no unforeseen adverse effects during the four-week administration of 6 mg of melatonin per day in both the intervention and placebo groups. However, it is worth noting that three cases of mild to moderate excessive daytime sleepiness were reported in the melatonin group. Despite this, the difference between the two groups was not statistically significant (P value < 0.18).

DISCUSSION

This study aimed to assess the effects of melatonin on reducing vasomotor symptoms in female patients undergoing hormone therapy. Administration of 3 mg of melatonin twice daily for four weeks resulted in a significant decrease in the frequency and severity of hot flashes compared to the placebo group. Additionally, the mean scores of menopausal symptoms, quality of life, and sexual function improved with the four-week melatonin administration in BC patients receiving hormone therapy.

The beneficial effects of melatonin administration on general mood improvement, treatment of depression, and weight reduction have been reported.[2038] For instance, Chen et al.[20] investigated the effects of melatonin supplementation on sleep, mood, and hot flashes in postmenopausal BC survivors who had completed active cancer treatment. Their study found that 52% of participants reported poor sleep before starting melatonin therapy. After four months of oral melatonin treatment, sleep quality significantly improved, although there was no notable change in depression or hot flash frequency. While our study also explored the effects of melatonin on menopausal complications, Chen et al.’s[20] study focused on sleep quality with less emphasis on menopausal symptoms, whereas our study specifically highlights the positive impact of melatonin on hot flashes, menopausal symptoms, and overall quality of life in a shorter treatment duration. In contrast to the study by Chen et al.,[20] our research demonstrates a significant reduction in the frequency and severity of hot flashes and menopausal symptoms, as well as improvements in quality of life and sexual function following melatonin treatment. Our findings suggest that melatonin could be included in the treatment regimen for BC patients due to its beneficial effects on menopausal complications and overall quality of life.

Similarly, in another randomized clinical trial by Palmer et al.,[39] treatment with 20 mg of melatonin for ten days before and during the first cycle of adjuvant chemotherapy for BC patients showed a neuroprotective effect against hormone therapy side effects on cognitive function, sleep quality, and depressive symptoms. Researchers assessed cognitive performance using various tests and examined the effects of melatonin on cognition, depressive symptoms, sleep quality, and serum levels of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin kinase B (TrkB). Results showed that melatonin improved executive function, episodic memory, recognition, and verbal fluency. Baseline levels of TrkB and BDNF were negatively correlated with cognitive performance. After treatment, changes in TrkB and BDNF were inversely associated with depressive symptoms and sleep quality. In contrast to our study, the study focuses on cognitive impairment, depressive symptoms, and sleep quality in the context of chemotherapy for BC.

The current study results showed a significant improvement in sleep and psychosocial quality of life assessed by MRS and MENQOL questionnaires. By its lipophilic nature, Melatonin can cross cell membranes, act on the inner surface of cells, and communicate with the nucleus. In addition to nuclear receptors, melatonin can bind to other important intracellular molecules, such as calmodulin, calreticulin, or tubulin. Therefore, it causes rearrangement of cytoskeletal components.[40] In addition, melatonin can relieve sleep problems caused by fibromyalgia syndrome (a syndrome associated with tenderness sensitivity and muscle weakness).[27] Those mechanisms can partly explain the beneficial effects of melatonin on improving sleep disorders.

The effects of melatonin extend beyond psychological issues. Abdali et al.[41] investigated the effects of melatonin on climacteric symptoms in menopausal women. They demonstrated that treatment with 3 mg melatonin at bedtime for three months led to significant improvement in climacteric symptoms in four psychological, somatic, vasomotor, and sexual. The climacteric symptoms score decreased from 35.73 ± 11.6 to 17.09 ± 10.22 during the three-month study period and regardless of time. Our study found a significant improvement in the total score for vasomotor, psychosocial, physical, and sexual domains evaluated by the MENQOL and daily menopause diary index questionnaires, which shows consistency with the Abdali et al.[41] study.

Many BC patients are still sexually active and undergo treatment protocols involving antiestrogen drugs, such as AIs or long-term selective ER blockers. These treatments inhibit all sex hormones in a woman’s body, which can lead to numerous psychomotor and psychosomatic issues, including psychological problems, mood swings, and sexual dysfunction. Although conclusive evidence for the regulation of sex hormones by melatonin is lacking, and the precise mechanism of interaction between melatonin and sex hormones is not well understood,[41] significant improvements in sexual function—including desire, arousal, lubrication, orgasm, and pain—were observed in the studies conducted by Parandavar et al.[31] and our research.

Based on these results and the results of our study, 3 mg or more is the appropriate dose for improving sexual function in women. There is also evidence of the increasing impact of melatonin on mammals’ sexual function through the central serotonergic system.[42434445] It is likely that melatonin reduces the arousal threshold by modulating central 5-hydroxy tryptaminergic receptors, thereby enhancing sexual function in mammals.[46]

In a 24-h cycle, increasing the melatonin level is accompanied by a decrease in the core body temperature and the cortisol level. On the other hand, when melatonin decreases, the core body temperature and the cortisol level increase. Exogenous utilization of melatonin could change the body temperature and the sleeping time and improve the endogenous melatonin levels. Elevation of core body temperature occurs before most hot flashes and can be considered a triggering mechanism.[47] It may partly explain the beneficial effects of melatonin on vasomotor symptoms, especially hot flashes. In addition, the immediate vasodilatory effects of melatonin lead to heat dissipation via the skin, which may increase sleep propensity.[48]

In addition, melatonin may help alleviate side effects such as hot flashes, vaginal dryness, and loss of libido due to its nontoxic antioxidant properties. Its ability to specifically counteract the effects of estrogen on breast tissue and regulate the local synthesis of estrogens from androgens makes melatonin a promising treatment for ER-positive BC patients. These potential benefits suggest that melatonin could be used as an adjunct therapy to reduce various side effects caused by anticancer drugs. Furthermore, research indicates that melatonin can effectively alleviate postmenopausal symptoms, such as hot flashes, mood swings, and sleep disturbances, by acting on other tissues like CNS.[2223]

To our knowledge, this study is the first to demonstrate that a 3 mg twice-daily dose of melatonin, administered over four weeks, can effectively and safely improve the frequency and severity of hot flashes, as well as enhance sexual function and quality of life in BC patients receiving antihormonal therapy. Furthermore, we observed beneficial effects of melatonin in a relatively short duration, particularly regarding hot flashes, sexual function, and overall quality of life. The primary limitations of this study were the small sample size, which introduced uncertainty and resulted in wide confidence intervals, and the short follow-up period. To fully elucidate melatonin’s mechanistic and therapeutic potential, future randomized, placebo-controlled clinical trials should incorporate larger sample sizes along with stratified dosing regimens, ideally ranging from low (1–3 mg) to high (10–20 mg) doses. These studies should span extended follow-up periods—preferably 6–12 months—to capture both acute and long-term effects. Investigating melatonin’s tissue-specific actions, especially its neuromodulatory and thermoregulatory effects in menopausal women undergoing antiestrogen therapy, remains crucial. Integrating biomarkers, sleep architecture analysis, and patient-reported outcome measures will further strengthen the evidence base and clarify its role in managing menopausal symptoms without undermining oncologic safety.

CONCLUSION

Our study demonstrated that melatonin supplementation can effectively improve hot flashes, menopausal scores, quality of life, and sexual function (excluding satisfaction) in BC patients receiving antihormonal treatment. Given these positive effects on menopausal parameters, quality of life, and sexual function, melatonin may have a potential role in the treatment regimen for BC patients.

Authors’ contributions

Conceptualization was done by P.S., K.J., and A.M; data curation was done by A.S., P.S, and M.S.; formal analysis was done by P.S., K.J., M.S., and A.M.; funding acquisition was done by A.M.; investigation was done by P.S., K.J., A.S., and A.M.; methodology was done by P.S., M.S., and A.M.; project administration was done by P.S., K.J., A.S., and A.M.; resources were provided by A.M.; supervision was done by A.M.; validation was done by M.S. and A.M.; visualization was done by P.S; writing—original draft was done by P.S, E.N., and A.M.; writing—review and editing was done by K.J., and A.M., A.S., E.N., and P.S. All authors have read and agreed to the published version of the manuscript.

Ethics approval and consent to participate

The protocol of the study has been approved by the Isfahan University of Medical Sciences ethics committee (ID IR.MUI.RESEARCH.REC.1398.724) and also the trial was submitted in Iranian Clinical Trial Registry Center (IRCT20180722040556N3).

Availability of data and material

Not applicable.

Code availability

Not applicable.

Consent to participate

The consent form was signed by all participants.

Consent for publication

Not applicable.

Conflicts of interest

There are no conflicts of interest.