Review

Volume 15, Number 3, August 2025, pages 69-80

Craniopharyngiomas, Alterations of Melatonin Secretion and Their Implications: A Systematic Review

Craniopharyngiomas (CPs) are rare, locally aggressive neoplasms of the pituitary region originating from embryonic residues of Rathke’s pouch [1]. Their incidence is approximately 0.13 cases per 100,000 person-years, with 30-50% occurring in individuals < 18 years: in this age group, CPs represent 5-11% of intracranial tumors, making them the most common central nervous system (CNS) neoplasm [2-4].

Based on histological features, we classify CPs into two subtypes that differ in microscopy, epidemiology, and molecular characteristics [5].

Adamantinomatous craniopharyngioma (ACP) is predominantly cystic, has a double incidence peak (5 - 15 years and 45 - 60 years), and harbors somatic mutations in CTNNB1, which encodes β-catenin [4, 6].

In contrast, papillary craniopharyngioma (PCP) is usually solid, commonly affects older adults (50 - 60 years), and involves BRAF-V600E mutations [4, 7].

Because they grow along the sellar and suprasellar regions [8], the tumor and its treatment often damage the pituitary axis [9, 10]. This can lead to severe complications, such as panhypopituitarism and hypothalamic disease, which impact quality of life (QoL) and drive various comorbidities, including appetite dysregulation and hypothalamic obesity, thirst dysregulation and diabetes insipidus, body temperature alteration, and sleep disorders [11-13].

Several factors contribute to these manifestations, like hormone deficiencies, altered leptin and hypocretin signaling, and damage to the suprachiasmatic nucleus (SCN), the biological pacemaker regulating circadian rhythms like melatonin secretion and sleep-wake cycles [14-16].

Melatonin, or N-acetyl-5-methoxytryptamine, is a pineal indolamine derived from L-tryptophan [17]. Its complete biochemical synthesis is shown in Figure 1. Historically known for sleep regulation, recent research has stressed its positive effects on oxidative stress, inflammation, metabolism, and cancer [18-20]. Its release strongly depends on light/dark cycle information conveyed from the eye to the SCN by intrinsically photosensitive retinal ganglion cells (ipRGCs) via the retinohypothalamic tract [21-23]. These cells, under dim light conditions, use melanopsin, an excitable photopigment, to photoisomerize the 11-cis-retinal into all-trans-retinal, thereby activating the phospholipase C (PLCB4) pathway and depolarizing [24-26]. The resulting action potential causes the release of glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP), stimulating the SCN neurons to activate the superior cervical ganglia cells of the sympathetic system [27, 28]. At this point, norepinephrine and neuropeptide-Y (NPY) released by their endings induce pinealocytes to increase melatonin levels [29].

Click for large image

Figure 1. Melatonin synthesis in humans.

Although several authors point out that hypothalamic damage in CNS tumor survivors alters circadian rhythms [30-32], we lack research focusing on CP patients. Some studies indicate that patients undergoing surgery and/or radiotherapy have a higher prevalence of impaired melatonin release and sleep disorders than the general population [33-37]. However, the findings are inconsistent: while some report reduced melatonin levels, others describe peak irregularities, probably due to methodological heterogeneity. Furthermore, the implications concerning sleep, metabolism, and overall well-being are unclear, as well as melatonin’s role as a relevant biomarker or therapeutic target.

Consequently, this study aims to systematically review the available findings on melatonin secretion in CP patients, focusing on alterations in melatonin levels and their possible implications. Moreover, we want to evaluate the risk of bias and the consistency of results to estimate the certainty of current evidence. Finally, we highlight the need for future studies assessing melatonin as a potential marker and supplement for CP-related hypothalamic disease.

We formulated a research question using the PICO framework [38], where the population (P) included adult and pediatric patients with CP; the intervention (I) involved the assessment of melatonin secretion patterns; the comparison (C) group consisted of healthy controls; and the outcome (O) focused on alterations in melatonin secretion and their implications.

A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement and checklist [39]. No language or publication year restrictions were placed to include all relevant studies.

The following inclusion and exclusion criteria were applied to select studies.

Inclusion criteria were: 1) Evaluation of melatonin secretion in CP patients; 2) Involvement of adult or pediatric patients with CP; 3) Validated methods to assess melatonin levels (e.g., plasma, saliva, urine); 4) Full-text articles published in peer-reviewed journals.

Exclusion criteria were: 1) Review articles, editorials, letters, and conference abstracts without sufficient data; 2) Studies not addressing patients with CP; 3) Studies not measuring melatonin secretion; 4) Articles without available full text.

The following electronic databases were systematically searched between January 17 and 18, 2025: PubMed/MEDLINE, using the query (“Craniopharyngioma” (Mesh) OR craniopharyngioma) AND (“Melatonin” (Mesh) OR melatonin); Embase, with the query (“craniopharyngioma”/exp OR craniopharyngioma) AND (“melatonin”/exp OR melatonin); and Scopus, Web of Science Core Collection, and Cochrane Library using the query “craniopharyngioma” AND “melatonin”.

Results from all databases were imported into Zotero for duplicate removal [40].

Four reviewers independently selected studies in four steps: 1) Titles and abstracts screening: studies not assessing melatonin secretion in CP patients were excluded; 2) Full-text retrieval: articles were downloaded as PDFs and saved in a desktop folder; 3) Eligibility assessment: studies were assessed based on eligibility criteria, focusing on methods and results; 4) Resolution of discrepancies: disagreements between reviewers were solved through discussion.

The four reviewers collected data independently, each assigned one of the included articles.

Their initials are provided in Table 1 for transparency.

Click to view

Table 1. Melatonin Secretion Evaluation

Extracted data included: population characteristics (e.g., age); methods used for melatonin level assessment; melatoninergic system features (e.g., plasma and salivary melatonin levels (pg/mL), dim light melatonin onset (DLMO, clock time)); and associations between melatonin secretion alterations and clinical features, which include: 1) Body mass index (BMI, kg/m²); 2) Sleep/wake cycle characteristics (sleep onset latency (SOL, min), sleep quality (Pittsburgh Sleep Quality Index), total sleep time (min), nighttime sleep duration (min), sleep efficiency (%), and disorders like excessive daytime sleepiness (Epworth Sleepiness Scale (ESS))); 3) Physical activity (activity counts per minute).

Data were entered into an Excel form, and a final collaborative review was conducted to ensure completeness.

The risk of bias in included studies was evaluated using the Risk of Bias in Non-randomized Studies - of Interventions, Version 2 (ROBINS-I V2) tool [41].

Seven domains were examined: 1) Confounding factors; 2) Classification of interventions; 3) Selection of participants; 4) Deviations from intended interventions; 5) Missing data; 6) Measurement of the outcome; and 7) Selection of the reported result.

Given the heterogeneity in methodologies, populations, and outcomes among the studies, a meta-analysis was unfeasible. Instead, the results were synthesized narratively to provide an overview of the key findings.

Microsoft PowerPoint was used to create figures, while Microsoft Word was used to create tables.

We used ChatGPT (OpenAI, version February 2025, based on the GPT-4) to assist with language refinement and improve the clarity of the manuscript [42]. Specifically, ChatGPT was employed to revise linguistic accuracy and provide suggestions for improving fluency in all sections. The authors verified all scientific content to ensure accuracy and reliability.

The search yielded 99 records. After importing them into Zotero for duplicate removal, 24 articles remained.

After screening titles and abstracts,14 records were excluded: four were additional duplicates [43-46] and 10 were irrelevant [47-56]. Next, five studies were excluded because the full text was unavailable [57-61]. Five articles were assessed for eligibility, and one was excluded as it lacked specific data from CP patients [37].

Ultimately, four studies met the criteria for this systematic review [33-36].

The complete PRISMA flowchart of the selection process is presented in Figure 2.

Click for large image

Figure 2. PRISMA flowchart. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; CP: craniopharyngioma.

The included studies vary in their methodologies, populations, and outcomes.

All studies involved patients with CP. Two focused on pediatric patients [34, 36], one included patients aged 18 - 70 [35], and another covered patients aged 6 - 33 [33].

Three studies measured salivary melatonin using enzyme-linked immunosorbent assay (ELISA) [36] or radioimmunoassay (RIA) [33, 35], and one assessed plasma melatonin with no specified test [34].

Muller et al [33] examined median salivary melatonin in the morning (6:00 am - 8:00 am), midday (11:00 am - 2:00 pm), evening (6:00 pm - 9:00 pm), and night (11:00 pm - 12:00 am). Lipton’s study [34] evaluated 24-h and nighttime mean plasma melatonin. Pickering’s paper [35] focused on the 24-h median salivary melatonin collecting samples at 12:00 pm, 4:00 pm, 8:00 pm, 10:00 pm, 12:00 am, 4:00 am, 8:00 am, and 12:00 pm. Kamara et al [36] assessed the DLMO, which is the point when melatonin levels rise in response to dim light conditions.

Furthermore, they explored associations between melatonin secretion and clinical features.

The key findings are summarized in Table 1 and described in detail below.

Muller et al [33] found that nighttime salivary melatonin levels were markedly lower in patients with BMI > 4 standard deviation (SD) compared to obese controls (P < 0.0001) but did not significantly differ between non-obese CP patients and healthy controls. Similarly, Lipton’s data [34] show reduced 24-h and nocturnal plasma melatonin compared to historical controls, with an undetectable nighttime peak. Pickering’s research [35] highlights a lower area under the curve (AUC) for salivary melatonin in CP patients than in healthy controls (P = 0.04), indicating reduced secretion.

In conclusion, Kamara et al [36] reported that 47.2% of participants had an invalid DLMO: of these, 19 had elevated initial melatonin levels, two remained below the threshold, and four displayed irregular secretion patterns.

Three out of the four studies explored associations between melatonin alterations and clinical features.

Muller et al [33] observed that higher BMI was associated with increased morning melatonin (P = 0.004) and reduced nighttime concentrations (P < 0.001), along with a negative correlation to ESS scores (r: -0.42, P = 0.001 and r: -0.31, P = 0.02, respectively).

Pickering’s study [35] confirmed a negative correlation between midnight melatonin concentrations, ESS scores (r: -0.49, P = 0.08), and sleep quality (r: -0.53, P = 0.06). But, while these two findings did not reach statistical significance, they identified significant associations with reduced total sleep time (r: 0.60, P = 0.03), night sleep duration (r: 0.59, P = 0.03), sleep efficiency (r: 0.62, P = 0.02), and physical activity (r: 0.29, P = 0.04).

In conclusion, Kamara et al [36] highlighted that patients without a measurable DLMO had longer (P = 0.005) and variable (P = 0.043) SOL, while in the subgroup with a valid DLMO, a higher BMI was associated with later onset (r: 0.48, P = 0.012). Furthermore, DLMO timing correlated positively with average waketime (r: 0.40, P = 0.042) and midsleep time (r: 0.47, P = 0.015), and negatively with the standard deviation of SOL (r: -0.47, P = 0.049).

The results of the risk of bias assessment are described in detail below and summarized in Table 2.

Click to view

Table 2. Risk of Bias Assessment

Muller et al [33] addressed obesity but overlooked other confounders. Lipton et al [34] did not consider potential confounders like BMI or circadian variations. Pickering et al [35] controlled multiple confounders by recruiting gender-, age- and BMI-matched controls and considering hypothalamic injury, hormone insufficiencies, hormone replacement therapies, and sleep characteristics. Kamara et al [36] accounted for melatonin supplementation, hypothalamic involvement, diabetes insipidus, light perception, sleep/wake cycle characteristics, age, sex, BMI, and sleep disorders.

All studies assigned participants to the patients and control groups before the start of the observations based on the presence/absence of CP diagnosis.

Muller et al [33] lacked clear selection criteria. Lipton et al [34] used a small sample size with limited details on the selection process. Pickering et al [35] and Kamara et al [36] defined detailed inclusion and exclusion criteria.

Lipton et al [34] noted one patient lost intravenous access after 40 h instead of the planned 72 h. Muller et al [33], Pickering et al [35], and Kamara et al [36] reported no deviation from the protocol.

Muller et al [33], Pickering et al [35], and Kamara et al [36] excluded non-compliant patients with missing data. Lipton et al [34] recruited only three patients and failed to provide details about one incomplete melatonin data collection.

Muller et al [33] and Pickering et al [35] assessed salivary melatonin using RIA; however, while the former did not describe the protocol in detail, the latter provided a comprehensive protocol to reduce bias. Lipton et al [34] collected plasma melatonin samples under dim light conditions (< 10 lux) but did not specify the assay used. Kamara et al [36] instructed caregivers to follow a specific protocol for sample collection and used ELISA for melatonin measurements.

Muller et al [33] reported differences in morning and nighttime melatonin levels but omitted nonsignificant results from comparisons between normal-weight CP patients and controls. Lipton et al [34] did not present polysomnography data, raising concerns about selective reporting. Pickering et al [35] and Kamara et al [36] reported all variables specified in the methods, including both significant and nonsignificant results.

The included studies varied in methodological rigor. While Kamara et al [36] and Pickering et al [35] demonstrated low risks across most domains, Lipton et al [34] presented serious concerns and Muller et al [33] had moderate risk.

Results across studies consistently indicate disrupted melatonin secretion in CP patients. However, variations in the type of alteration suggest some heterogeneity.

All four studies directly addressed melatonin secretion in patients with CP.

Some factors contribute to uncertainty, such as the small sample size and the use of plasma melatonin evaluations in the study of Lipton et al [34], and the absence of a control group in the study of Kamara et al [36].

There is no clear evidence of publication bias, but we cannot rule it out because of the limited number of studies.

We rated the certainty of the evidence for alterations in melatonin secretion in CP patients as moderate: while consistent findings support this conclusion, the small number of studies and their heterogeneity lowered the confidence.

This is the first study to systematically review the relationship between CPs and melatonin production and its clinical implications.

We found that several authors pointed out alterations in the melatonin system in CP survivors, affecting functions like metabolism and sleep. Current evidence does not allow for a definitive distinction between melatonin dysregulation caused directly by the tumor and that resulting from its treatment. However, most studies agree that hypothalamic damage, whether caused by the tumor’s location or by therapeutic interventions such as surgery or radiotherapy affecting the SCN, is the key factor influencing melatonin secretion, by impairing both the afferent and efferent neural pathways responsible for its regulation [15]. Supporting this hypothesis, other studies have described similar pathophysiology for comorbidities like hypothalamic obesity, identifying alterations in the afferent signaling mediated by leptin and in the efferent one linked to α-melanocyte stimulating hormone (α-MSH or melanocortin) [62, 63]. This disruption creates a non-ending vicious cycle of hyperphagia and reduced energy expenditure that leads to excessive weight gain [64, 65].

These findings suggest a link between CP and circadian dysfunction and the consequent hormonal imbalance in the melatoninergic system influences various clinical domains.

First, melatonin dysregulation impacts metabolism and body weight. Muller et al [33] found that CP patients with higher BMI displayed reduced nighttime melatonin and increased daytime one. This finding aligns with other studies linking melatoninergic alterations to metabolic diseases like obesity, diabetes mellitus, and metabolic syndrome [66, 67]. However, the relationship between melatonin and weight gain appears to be bidirectional: while melatonin improves insulin resistance and chronic inflammation, obesity itself associates with chronodisruption, sleep impairment, and melatonin deficiency [68-70]. Melatonin’s ability to inhibit body weight gain is well documented in rodents. For instance, Elliott et al observed that pinealectomized Djungarian hamsters failed to exhibit the typical winter-associated reduction in adiposity [71]. During this season, reduced daylight exposure leads to increased melatonin secretion and a prolonged nocturnal peak, suggesting that melatonin may play a role in promoting fat loss [72]. Supporting this hypothesis, similar findings have been reported in rats. In particular, Wolden-Hanson et al demonstrated that supplementing the drinking water of male rats with melatonin resulted in a significant reduction in body weight, visceral adiposity, leptin, and insulin levels within 2 weeks [73]. In contrast to rodents, evidence regarding the correlation between melatonin levels and metabolic alterations in humans, as well as the potential anti-obesity effects of melatonin supplementation, remains limited. However, a recent study found that in a cohort of 30 adults with metabolic syndrome, the administration of 5 mg of melatonin every evening, 2 h before bedtime, over a 2-month period led to significant improvements in metabolic parameters [74]. Therefore, further clinical trials are warranted, as melatonin supplementation may represent a promising strategy for managing obesity and metabolic syndrome.

Several studies also indicate a relationship between craniopharyngioma and impaired psychological well-being. For example, Memmesheimer et al found that young adults with childhood-onset CP reported reduced psychosocial QoL and increased depression rates, while Mehren et al identified a higher prevalence of apathy among CP patients [75, 76]. These results may be closely linked to hypothalamic and pituitary damage. Indeed, growing evidence suggests that hormone deficiency, such as oxytocin deficiency and hypothalamic obesity contribute to neurobehavioral abnormalities [77-80]. Alongside oxytocin, melatonin likely plays a key role, as circadian dysfunction is strongly associated with psychiatric conditions like major depression, seasonal affective disorder, and bipolar disorder [81-83]. Furthermore, drugs acting on the melatoninergic receptors MT-1 and MT-2, such as agomelatine, have demonstrated efficacy in patients with major depression [84].

Melatonin disruption also profoundly affects the sleep-wake cycle, as evidenced by the studies included in this review, which associate melatonin alterations with poorer sleep quality and a higher prevalence of sleep disorders, such as excessive daytime sleepiness and narcolepsy.

Finally, melatonin might contribute to thermoregulation via several mechanisms, one of which is the induction of the browning of the white adipose tissue [29, 85, 86]. Indeed, Mendes et al found that chronic melatonin supplementation increases the thermogenic potential of aged rats by promoting the conversion of white adipose tissue into beige and brown ones, upregulating uncoupling proteins like UCP1A1 and increasing energy expenditure and heat production [87]. Therefore, melatonin deficiency may be involved in temperature dysregulation like cold intolerance, often observed in CP patients [11, 88-90].

Future research should focus on large-scale, standardized studies to better assess melatonin dysregulation in CP patients and its clinical consequences. We need uniform protocols for melatonin measurement to facilitate data comparability and reliability, as well as longitudinal studies evaluating the long-term impact of altered melatonin secretion on clinical features.

Moreover, few studies have compared melatonin profiles between patients diagnosed in childhood versus adulthood. Considering that the adamantinomatous subtype, which tends to cause more extensive hypothalamic involvement, is more frequent in pediatric cases, a more severe dysregulation of melatonin could be expected in younger patients. Although their study did not focus exclusively on CP but also included other types of sellar neoplasms, Rosenkranz et al did not find any significant differences in the hourly urinary excretion of the melatonin metabolite 6-sulphatoxymelatonin (aMT6s) in relation to the age at disease onset [37].

Furthermore, they did not report any significant group differences in aMT6s excretion based on radiation technique (conformal radiation therapy and gamma knife) and the addition of chemotherapy and/or surgery to radiotherapy [37]. Nonetheless, the study did not explore the individual impact of radiotherapy, chemotherapy, or surgery as separate treatment modalities for CPs.

Future research should therefore also investigate age-related and treatment-related differences in melatonin secretion patterns in CP survivors, in order to better understand how tumor biology and age at diagnosis may influence neuroendocrine outcomes.

Little is known about melatonin’s role as a biomarker. Rosenkranz et al found that there was no significant correlation between hourly urinary excretion of the aMT6s and the presence/absence of pituitary insufficiency [37]. However, their analysis did not stratify patients based on the number of pituitary hormone deficiencies. In contrast, Pickering et al provided a detailed description of the number of affected pituitary axes among participants but did not conduct any test to correlate melatonin levels and the number of hormonal insufficiencies [35]. Thus, new studies should evaluate this correlation to see whether melatonin may be used as a biomarker of the extent of hypothalamic-pituitary damage. Furthermore, the role of melatonin supplementation in CP patients remains uncertain: although Muller et al found that a melatonin daily substitution of 6 mg significantly improved daytime sleepiness and increased physical activity with excellent tolerability, further data are necessary to confirm its benefits and safety [33]. Randomized controlled trials investigating melatonin administration could determine the optimal dosage and clarify its therapeutic potential in this vulnerable population.

Limitations of this study include the small number of articles, their heterogeneity which prevented us from conducting a metanalysis, and the moderate risk of bias which lowers the certainty of evidence and limits the generalizability of our findings. Additionally, studies reporting nonsignificant results may be underrepresented as we cannot rule out publication bias.

On the other hand, key strengths include the systematic, rigorous, and transparent methodology, and the identification of knowledge gaps that future studies should address. This allows for a comprehensive synthesis of current evidence.

In conclusion, this review highlights the significant yet underexplored role of melatonin dysregulation in craniopharyngioma patients. Our findings indicate that these patients have a higher prevalence of melatonin impairment compared to the general population, which seems to impact their QoL. It remains to be determined whether this neurohormone might have a role in diagnostic and therapeutic protocols. Therefore, further studies are needed to confirm these findings and to evaluate the potential of melatonin as a routine biomarker for hypothalamic injury, and its effects when administered as part of a hormonal replacement therapy. A better understanding of melatonin in this context may lead to more holistic strategies to improve the overall QoL of craniopharyngioma survivors.

Acknowledgments

The scientific support of Panta Rei Societa Benefit Srl (https://www.panta-rei.eu/pantarei/, accessed on May 15, 2025) is highly appreciated.

Financial Disclosure

The authors received no financial support for the research, authorship, and publication of this article.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author Contributions

SG and CDS conceived the study and drafted the manuscript. SG, RA, ML, and AR were responsible for data collection and conducted the systematic review. DF, MG, FR, DS, ES, and CD contributed to the literature search and critically reviewed the paper. CDS and AC supervised the project. All authors contributed to the article and approved the submitted version.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

Abbreviations

CPs: craniopharyngiomas; CNS: central nervous system; ACP: adamantinomatous craniopharyngioma; PCP: papillary craniopharyngioma; QoL: quality of life; SCN: suprachiasmatic nucleus; ipRGCs: intrinsically photosensitive retinal ganglion cells; PACAP: pituitary adenylate cyclase-activating polypeptide; NPY: neuropeptide-Y; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; DLMO: dim light melatonin onset; BMI: body mass index; SOL: sleep onset latency; ESS: Epworth Sleepiness Scale; ROBINS-I V2: Risk of Bias in Non-randomized Studies, of Interventions, Version 2; RIA: radioimmunoassay; ELISA: enzyme-linked immunosorbent assay; SD: standard deviation; AUC: area under the curve; α-MSH: α-melanocyte stimulating hormone; aMT6s: 6-sulphatoxymelatonin

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