This study employed a correlational research design using a cross-sectional study approach. The objective was to assess between dexamethasone therapy and sleep quality, insomnia, and melatonin levels in patients with brain tumors. The study was conducted at RSSA, East Java, Indonesia. The research was carried out over a 3-month period, from November 2024 to January 2025, involving outpatients at RSSA. The sampling technique used in this study was purposive sampling. The study population consisted of all patients who had been diagnosed with brain tumor and were receiving outpatient care at the hospital during the study period. The population in this study was divided into two groups, namely the group with dexamethasone therapy and the dexamethasone-free group. This study was approved by the Ethics Committee General Hospital Dr. Saiful Anwar with approval number 400/303/K.3/102.7/2024.

The inclusion criteria for participants with dexamethasone therapy:

1) Individuals diagnosed with brain tumor, including both newly diagnosed patients and those undergoing routine follow-up.

2) Currently receiving dexamethasone therapy.

3) Total assessment of Glasgow Coma Scale 15.

4) Willing to voluntarily participate in this study.

The inclusion criteria for participants with dexamethasone therapy:

1) Individuals diagnosed with brain tumor, including both newly diagnosed patients and those undergoing routine follow-up.

2) Patients who have been off dexamethasone therapy for more than 72 hours.

3) Total assessment of Glasgow Coma Scale 15.

4) Willing to voluntarily participate in this study.

The exclusion criteria for respondents were as follows:

1) There are confounding factors in the patient (obstructive sleep apneu, restless leg syndrome, cardiovascular and pulmonary disorders, alcoholism, mood disorders).

2) Not willing to participate in the study.

This study examined three variables:

1) Sleep quality: The Pittsburgh Sleep Quality Index (PSQI) is a 19-item test that evaluates the quality of sleep during the previous month. It generates seven component scores, which range from 0 to 3, with higher scores denoting lower quality sleep. Sleep disruptions, the use of sleep aids, subjective sleep quality, sleep onset delay, length, and efficiency [(% of time spent sleeping/time spent in bed)×100], as well as dysfunction during the day, are among the components. The sum of the component scores yields a global score between 0 and 21, where a score of more than 5 denotes poor sleep quality.

2) Severity of insomnia: The Insomnia Severity Index (ISI) has been verified in cancer populations and is a commonly used screening tool for insomnia. The ISI has a total score range of 0 to 28, where higher scores indicate more severe insomnia. The cut-off scores for the ISI are as follows: 0–7 (no clinically significant symptoms of insomnia), 8–14 (subthreshold scores), 15–21 (moderately severe clinical insomnia), and 22–28 (severe clinical insomnia).

3) Melatonin level: Plasma melatonin was drawn from a venous blood sample. Blood sampling was done once, in morning time at 11.00–12.00 am. Samples were stored at -20°C in Saiful Anwar Hospital Laboratory

Primary data were collected from brain tumor patients at the neurology outpatient clinic of RSSA who met the inclusion and exclusion criteria and provided informed consent. Patients underwent anamnesis and physical examination to obtain primary data. Data collection was carried out by a team of four neurology residents who had received appropriate training and were deemed competent. The collected data were subsequently analyzed using SPSS version 26 (IBM Corp.).

We used SPSS version 26 (IBM Corp.) to do all of the statistical analyses. We showed categorical data as frequencies and percentages. For continuous data, we used medians with interquartile ranges because the data were not normally distributed.

We used the chi-square test to see if there was a link between dexamethasone therapy and sleep quality as measured by the PSQI. The Kolmogorov–Smirnov test was used to look at the link between dexamethasone therapy and the severity of insomnia, as measured by the ISI. At the same time, the Mann– Whitney U test, which does not assume a normal distribution, was used to look at the link between dexamethasone therapy and melatonin levels.

Also, we looked at possible confounding variables, such as the type and location of the tumor, to see if they were related to PSQI and ISI scores. We also looked at these comparisons using the right bivariate statistical tests, which depend on the data distribution and measurement scale. For all analyses, a p-value of less than 0.05 was thought to be statistically significant.

There were 66 hospitalized patients with brain tumors who had lab tests done at RSSA in Malang as part of this study. Most of the people who took part were between the ages of 18 and 65, with an average age of 48.1 years. This age distribution is important for clinical reasons because sleep problems are more common in adults, especially those with neurological conditions, because of the complicated ways that biological, psychological, and environmental factors interact [5,6]. Also, it is well known that as people get older, their ability to heal while they sleep decreases. This could make the side effects of corticosteroid therapy, such as dexamethasone [7], worse.

There were a little more men than women among the patients. Some studies suggest that men and women see and report sleep problems differently, but in neuro-oncological settings, the effects of dexamethasone are mostly affected by the dose and length of time it is taken, not by biological factors related to sex [8,9]. Epidemiological data consistently show that males are at a greater risk for most malignant primary brain tumors, including gliomas and glioblastomas, across all age groups and geographic regions [10,11]. For example, glioblastoma, which is the most common and aggressive type of primary brain tumor, has a ratio of about 1.6:1 in favor of males [11]. In addition to being affected more often, male patients often have worse responses to treatment and shorter overall survival rates than female patients [10,11]. There are many reasons why brain tumors are more common in men than in women, and we don’t fully understand them yet. Genetic and hormonal differences are very important. Recent genomic studies have found risk loci for different types of brain tumors that are specific to each sex. Some genomic regions are more dangerous for males, while others are more dangerous for females [12]. Molecular studies also show that glioblastoma cells in men may be more likely to turn cancerous because they have higher levels of tumor suppressor proteins that are turned off, like Retinoblastoma protein (RB), than glioblastoma cells in women. Some people think that the protective effects of estrogen might be why women with glioblastoma do better in the clinic [11].

There are some exceptions, like meningiomas, which are more common in women and are often linked to hormones. However, these tumors are usually not cancerous and don’t add much to the overall burden of brain tumor-related illness and death [10]. On the other hand, men are more likely to get malignant brain tumors, which are the main cause of brain tumor-related deaths [11]. These biological differences show how important it is to think about sex as an important factor in both research and clinical practice in order to come up with more personalized and effective treatment plans [10].

The brain tumors in the people in this study were a mix of primary intracranial neoplasms and metastatic lesions. We looked at tumor type and location as possible confounding variables, but we didn’t find any significant links between them and sleep problems as measured by PSQI and ISI. This means that these factors didn’t act as confounders in this group [13].

Dexamethasone therapy, either orally or through an IV, was given to most of the patients in this study. The doses and lengths of time were based on each patient’s specific condition. In neuro-oncology, dexamethasone is commonly used to lower vasogenic edema and intracranial pressure [9]. Corticosteroids are also known to impair sleep [14]. Glucocorticoids are thought to disrupt sleep by activating the orexin system and reducing the sensitivity of GABAergic neurons to sleep-promoting signals.

The subjects were fairly evenly split between the dexamethasone and non-dexamethasone groups. This supports the use of PSQI, ISI, and melatonin levels as objective measures of sleep disturbance in comparative studies [8]. The fact that the participants had similar clinical characteristics and functional status also helped to reduce systematic bias when looking at how dexamethasone affected sleep quality.

The characteristics of the subjects in this study are similar to those of neuro-oncology patients who are treated in tertiary care settings, where the clinical complexity is high. The differences in age, sex, tumor types, and treatment methods make it possible to look at the link between using dexamethasone, sleep problems, and melatonin regulation [15]. However, when looking at these results, you should keep in mind the limitations of psychosocial factors, the quality of the hospital’s sleep environment, and the patient’s mood [16].

One of the main findings of the study is that there is a strong link between dexamethasone treatment and worse sleep quality in brain tumor patients, as shown by higher PSQI scores. Patients who took dexamethasone had much higher PSQI scores than those who did not, which suggests that the glucocorticoid medication changed the way their sleep worked in a way that was clinically significant [8].

The PSQI is a reliable and widely used tool for measuring how well someone slept in the last month. There are seven parts to it: sleep quality as seen by the person, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medications, and daytime dysfunction. A total PSQI score of more than 5 means that the person has a clinically significant sleep problem [17]. The average PSQI score in the dexamethasone group was over 10, while the average score in the non-dexamethasone group was much lower. This shows that there were statistically and clinically significant differences in sleep quality.

Dexamethasone and other glucocorticoids are known to mess with sleep regulation in a number of neuroendocrine ways. Dexamethasone is a strong agonist of glucocorticoid receptors. It suppresses the hypothalamic-pituitary-adrenal (HPA) axis and increases circadian cortisol activity, which helps people stay awake. Cortisol levels are highest in the early morning and lowest at night when the body is in a normal state. This helps people fall asleep and stay asleep. But this rhythm is messed up in people who are taking dexamethasone. High levels of exogenous cortisol at night make it harder to fall asleep, make sleep less effective, and lower slow-wave sleep [6,18].

It’s not just in your head that this sleep disruption is happening. Previous studies have shown that corticosteroids shorten total sleep time and change the distribution of sleep stages, especially by cutting down on slow-wave sleep, which is important for restoring cognitive function and regulating the immune system [15,19]. These effects are made worse by increased sympathetic activity and psychological stress, which are common in people with serious illnesses like brain tumors. In neuro-oncology, long-term use of corticosteroids is linked to more complaints of insomnia, irritability, and mood changes, all of which make life much worse [9,16].

Dexamethasone changes the orexin and GABAergic systems, which affects sleep-wake regulation in addition to the HPA axis. Glucocorticoids make neurons in the lateral hypothalamus that make orexin more active, which makes people more awake. At the same time, glucocorticoids block the effects of gamma-aminobutyric acid (GABA), which is the main neurotransmitter that stops things from happening and keeps sleep going [14,20]. Because of this dual mechanism, sleep starts later, is broken up, and doesn’t help you feel better, even though you get enough sleep.

It is important to remember that sleep problems in brain tumor patients taking dexamethasone are not only caused by the drug itself. Headaches, focal neurological deficits, anxiety, and invasive medical procedures are some of the clinical factors that can make it hard to sleep. Even so, the big difference in PSQI scores between the dexamethasone and non-dexamethasone groups shows how important glucocorticoids are for making sleep worse, no matter how sick you are [8]. Sleep problems that aren’t treated could have big effects on how diseases progress and how well treatments work. Poor sleep can mess up your immune system, make you forget things, change your mood, and raise your risk of delirium, especially if you’re in the hospital [15]. In neuro-oncology, the quality of sleep can affect how well patients follow their treatment, how quickly they recover after surgery, and even the quality of care they receive at the end of their lives. So, keeping an eye on sleep with tools like the PSQI should be a key part of clinical evaluation, especially for patients who are getting dexamethasone therapy for a medium to long time [17].

Some ways to lessen sleep problems caused by dexamethasone are to give the dose earlier in the day (for example, only in the morning and afternoon), gradually lower the dose when it is safe to do so, and use behavioral therapies like Cognitive Behavioral Therapy for Insomnia (CBT-I). CBT-I has been shown to work in raising PSQI scores in a variety of groups, such as people with cancer and neurological disorders [15,21]. Teaching patients about sleep hygiene and making the sleep environment better may help with sleep problems caused by treatment [7].

PSQI is a good way to learn about sleep quality, but it is still a subjective measure. Still, it is a useful and dependable tool in clinical settings, especially when access to more advanced sleep tests may be limited. Combining objective tests like actigraphy or polysomnography may help future research get a better picture of how dexamethasone affects sleep architecture [22].

This study backs up what has been found in other countries and adds to what we know from an Indonesian clinical setting, especially when it comes to how to care for brain tumor patients at a tertiary referral center. Dexamethasone therapy is still very important in many neuro-oncology cases, but these results show that we need to take a multidisciplinary approach that looks at more than just neurological symptoms and cerebral edema. It should also look at patient-centered outcomes like sleep and quality of life [23].

In conclusion, this study’s strong link between dexamethasone therapy and higher PSQI scores shows how important sleep is for full neuro-oncological care. Intervening quickly for sleep problems could help people stick to their treatment, speed up their neurocognitive recovery, and improve their long-term functional prognosis.

People with chronic medical conditions, such as neuro-oncological diseases, often have insomnia. The ISI showed a strong link between giving people dexamethasone and making their insomnia worse. Patients who took dexamethasone had higher ISI scores, which suggests a strong link between using systemic glucocorticoids and having insomnia symptoms. This finding is in line with what other studies have found: corticosteroid-induced circadian disruption and sleep architecture disturbances are major causes of insomnia in people with cancer [8,24].

The ISI is a widely accepted self-report tool that measures the severity of insomnia over the past week in seven areas: trouble falling asleep, staying asleep, waking up too early, being satisfied with sleep, daytime dysfunction, being aware of sleep problems by others, and being upset about sleep problems [25]. People who used dexamethasone had ISI scores that ranged from moderate to severe insomnia. Most of the people who didn’t use dexamethasone had mild or no insomnia. These results show how dexamethasone affects sleep regulation and back up the idea that systemic corticosteroids play a big role in the development of insomnia.

Dexamethasone causes insomnia in a number of different ways. Dexamethasone is a strong synthetic glucocorticoid that activates the HPA axis, keeping cortisol levels high in the blood, especially at night. Normally, cortisol levels drop in the evening to help people fall asleep. However, giving dexamethasone from outside the body changes this pattern, making it take longer to fall asleep and waking up more often at night [6,26]. Previous research has shown that changing dosing schedules or using tapering protocols can lessen these effects without affecting the effectiveness of the treatment [24].

Corticosteroids also have an effect on important neurotransmitter systems that help control sleep and wakefulness. Glucocorticoids boost orexinergic signaling, which helps keep you awake, and block GABA transmission, which is very important for starting and keeping sleep [14,27]. This dual action causes a state of hyperarousal, which is a sign of chronic insomnia [28]. Our results support this mechanism because patients in the dexamethasone group said they had a lot of trouble starting and staying asleep, which were the biggest factors that affected their ISI scores.

It is important to put these results in the bigger picture of neuro-oncology. People with brain tumors often have mental health problems, such as anxiety, existential fear, and mood swings caused by brain damage [13,29]. These psychosocial factors may make the insomnia caused by drugs worse. Our study also shows that sleep assessment tools are not all equally sensitive. For example, both the PSQI and ISI showed significant sleep problems, but the ISI was better at showing how insomnia affected people’s mental and physical health. Chen et al. [30] found that the ISI was better at finding therapeutic changes after CBT-I intervention than the PSQI. This supports what we have seen.

Untreated insomnia can have very serious effects on health. It makes people more tired, makes it harder for them to think clearly, makes them less likely to stick to their treatment plan, and can even lead to mood disorders, all of which lower the quality of life for cancer patients [31]. Because of this, finding and treating insomnia should be a key part of full neuro-oncological care. Care plans should include evidence-based treatments like CBT-I, teaching patients about good sleep hygiene, and careful use of drugs like GABA agonists or exogenous melatonin [31,32].

The production of melatonin occurs mainly at night, with the pineal gland being the principal source of melatonin secretion. It is the hormone that regulates the circadian rhythm. The suprachiasmatic nucleus (SCN) in the hypothalamus is in charge of this rhythm. It maintains synchronization of the body’s natural physiological processes with the cycle of light and darkness outside. Melatonin plays a vital role in initiating and sustaining sleep. Its serum level is often used as an objective biomarker to seek out circadian-related sleep issues, even in patients on glucocorticoid therapy such as with dexamethasone [33]. We assessed melatonin levels as a means to evaluate whether sleep disturbances in patients with brain tumors who were treated with dexamethasone were connected to the medication. In the dexamethasone group, the average melatonin level was slightly elevated. However, those differences were not statistically significant and there was no strong correlation to sleep measures such as the PSQI and the ISI.

You need to think about how the study’s sample was chosen when you look at this finding. We only took blood samples for melatonin testing once during the day (11:00–12:00) because of logistical issues. It is well known, though, that melatonin levels follow a circadian pattern, with the highest levels happening at night between 02:00 and 04:00 [21,33]. Daytime sampling, when melatonin levels are naturally low, probably doesn’t pick up on important circadian changes and might hide possible differences between groups. This methodological limitation is in line with what Cai et al. [34] found in animal models: dexamethasone changes melatonin rhythms in a time-dependent way. This shows that hormonal assessments need to be chronobiologically aligned.

Lee-Chiong [6] also said that melatonin levels during the day don’t vary much from person to person and mostly show basal secretion instead of peak circadian amplitude. Because of this, daytime measurements are less affected by circadian disruptions, which makes it more likely that they will miss melatonin’s role in sleep disturbance or give it too little credit [33].

However, the slightly higher levels of melatonin seen in the dexamethasone group may be a sign of a neuroendocrine compensatory response. Glucocorticoids are known to lower melatonin production by changing the SCN [14]. However, long-term sleep problems may cause enzymes that are important for melatonin production (AANAT, HIOMT) to work harder as a way for the body to adapt [6,34]. But higher levels of melatonin don’t always mean better sleep. In neuro-oncological patients getting dexamethasone therapy, increased activity in the HPA axis and decreased sensitivity of melatonin receptors (MT1, MT2) may make melatonin less effective [35]. Also, dexamethasone-induced hyperarousal, which happens when the orexin system is turned on and GABA is blocked, may make melatonin less effective at promoting sleep [14].

The hospital environment may have affected how melatonin functions. Continuous artificial illumination, nocturnal noise, and other medical activities disrupt the natural cycles of light and dark, which can affect melatonin secretion. Batchelor et al. [13] report that neuro-oncology inpatients frequently experience circadian rhythm disorders, particularly when in intensive care, in the absence of windows, and in enclosed cubicles devoid of natural light. Mangini et al. [36] discovered that non-circadian hospital lighting delays the onset of DLMO, thereby exacerbating sleep disorders. The rhythms of melatonin may still exist, but due to environmental factors, they do not align with sleep and wake cycles due to a state of environmental desynchronization [37].

Tumor location and other anatomical factors may also be important. Tumors that affect the hypothalamus or SCN can stop the pineal gland from getting rhythmic signals. Kamara et al. [38] found that children with hypothalamic tumors had DLMO that was very different from normal or not present at all. This suggests that circadian signaling was disrupted in their bodies. The results of this study suggest that measuring serum melatonin levels at one point during the day is not a good way to represent circadian dynamics. Researchers should think about taking samples at night between 2:00 and 4:00 am when melatonin levels are highest [33].

Alternative methods like salivary melatonin or urinary 6-sulfatoxymelatonin (aMT6s) are less invasive and can give more accurate results over time [36]. As previously stated, sleep problems within the context of neuro-oncological patients receiving dexamethasone treatment are most likely due to sleep issues that are more complex than mere lack of sleep hormone production. Such issues include but are not limited to: psychological and neurophysiological dysregulation of the body’s systems such as the HPA axis, hyperarousal, mood changes, and an imbalance of neurohormones. In more simpler terms, it suggests that something more is going on in the body than just crazy levels of hormones running wild. Jiang et al. [35] also reiterated this point in their research by noting that even when melatonin is present in normal or higher concentrations, receptor downregulation and impairment of signaling pathways can render melatonin’s actions ineffective.

The same author and their colleagues also described their findings along the lines of an over-simplified assumption that because sleep disturbances exist there is an overproduction of melatonin and/or cortisol within neuro-oncological patients. Finally, using subjective tools to capture participants’ data (e.g., PSQI, ISI), along with hormonal measurements (melatonin, cortisol) and behavior monitoring would present the most effective way to address sleep problems using the multidimensional approach system as advanced by Jiang et al. [35]. Integrative sleep assessment as proposed by Duclos et al. [37] was overviewed in light of the importance of assessing sleep as a separate value from level of melatonin produced in the body.

As with any study, this one has its limitations. To begin, considering that melatonin levels typically peak between 2:00 am and 4:00 am, the measurement taken during mid-morning (11:00–12:00 [UTC+7]) would capture only a single snapshot of the participants’ daily rhythms [7]. It is likely that participants sampled during the daytime resulted in each group averaging their values, leading to obscured meaningful differences between groups. Furthermore, the use of cross-sectional data in the study limits the ability to determine the relationship between changes in melatonin concentration, sleep abnormalities, and the use of dexamethasone. In order to determine whether the impacts are transient or enduring, the study requires longitudinal data. In addition, the PSQI and ISI scores were not attributed to the proper cause due to the lack of utilizing standardized instruments, like the Hospital Anxiety and Depression Scale, for evaluating anxiety and depression which impact the sleep quality. Also, the classification and independent examination of the tumor locations was not done, which adds anatomic bias particular to the hypothalamus or SCN regions. Other than the numerous biases, the confounding effects of dexamethasone could result from a multitude of external factors that independently disrupt circadian rhythms and sleep in the hospital environment, such as fluorescent lights.

In conclusion, the purpose of this study was to assess the effects of dexamethasone therapy on sleep disorders in patients with brain tumors, evaluating them using the PSQI, ISI, and melatonin levels at RSSA, Malang. The cross-sectional study involving 66 participants showed that the use of dexamethasone was significantly correlated with low sleep quality and higher insomnia severity, apparent through increased PSQI and ISI scores. On the other hand, no significant correlation was found between the use of dexamethasone and serum melatonin levels. These results demonstrate the need to proactively manage sleep disorders as a clinical issue in neuro-oncology patients treated with corticosteroids. In addition, these results highlight the need for a holistic as well as interdisciplinary strategies in evaluating and managing sleep issues in this patient group.