Individuals who work night or rotating shifts are more susceptible to disruption of circadian melatonin release by the pineal gland, as this hormone is only released in the dark (which corresponds to our sleep period). In other words, exposure to light during the dark phase completely inhibits melatonin synthesis by the pineal gland. Night shift workers are frequently subject to psychological, social, and family problems, and tend to have unhealthy lifestyle habits, such as smoking, poor diet, and sedentary behavior. These effects result from the interference of their activities with the normal circadian cycle, indicating that body temperature and melatonin secretion contribute to variations in alertness (Xia et al., 2019).

Melatonin is synthesized in various immunocompetent cells, tissues, and organs, including the retina, bone marrow, gastrointestinal tract, lymphocytes, leukocytes, skin, and tests. However, it is secreted mainly in the pineal gland during the dark phase of the circadian cycle, showing the highest secretion levels at night in most species (Santos et al., 2018). Melatonin synthesis and secretion occur when pinealocytes absorb free tryptophan from the blood and convert it into serotonin, a process involving the enzymes tryptophan-5-hydroxylase and 5-hydroxytryptophan decarboxylase that successfully hydroxylate and decarboxylate tryptophan, respectively. At night, serotonin is converted into N-acetylserotonin by N-acetyltransferase. Subsequently, the enzyme hydroxyindole-O-methyltransferase acts on N-acetylserotonin, causing its methylation and forming melatonin. In animals, including primates and humans, melatonin reaches its peak levels around the middle of the dark period (02:00 h), and remains relatively low during the day (Cengiz et al., 2012).

Factors such as aging, the presence of certain diseases (primary degeneration of the autonomic nervous system and diabetic neuropathy, certain neoplasms, and Alzheimer's disease), and certain medications (β-blockers, clonidine, naloxone, and non-steroidal anti-inflammatory drugs) drastically reduce nocturnal melatonin production and are associated with impaired sleep. Notably, melatonin is not restricted to circadian functions. Its intermediate metabolites are free radical scavengers and stimulators of antioxidant enzymes. Through these antioxidant actions, melatonin protects cells during severe inflammatory processes and reduces oxidative damage. Intense inflammation contributes to the development of certain types of cancer, cell damage caused by ionizing radiation, alterations in metabolism, and destruction of essential molecules and cells. Furthermore, melatonin plays an immunomodulatory role by regulating the secretion of interleukin-2 (IL-2) and interferon-alpha and the consequent activation of CD4 + lymphocytes (Cengiz et al., 2012).

Once in the bloodstream, melatonin is also released into saliva. The proportion of plasma melatonin that enters the mouth through the salivary glands appears relatively stable, ranging from 24 % to 33 %. It is widely accepted that 70 % of plasma melatonin is bound to albumin. Since only free melatonin in the plasma enters saliva, salivary levels reflect the proportion of free circulating melatonin. Given its numerous properties and its presence in the oral cavity, its effect on oral health warrants further investigation (Amstrup et al., 2013).

Periodontal disease is a public health concern because it is a major contributor to tooth loss, and is associated with other chronic pathologies, such as metabolic syndrome and diabetes mellitus (Kayal, 2013). The etiology of periodontal disease involves pathological alterations in the periodontium caused by pathogenic microorganisms that release toxic products, such as bacterial lipopolysaccharide (LPS), which makes up the membrane of gram-negative bacteria (Sun et al., 2018). LPS activates Toll-like receptor 4 (TLR4), a cell-surface receptor that plays a role in activating innate immunity and inducing inflammatory responses. TLR4 activation can increase the inflammatory process through the production of cytokines, such as tumor necrosis factor-alpha (TNF-α) and IL-6 (Bletsa et al., 2006).

Furthermore, studies indicate that melatonin has a direct role in bone remodeling, supporting bone metabolism through bone anabolism and anti-resorptive effects. These benefits occur through multiple mechanisms, such as the differentiation of human mesenchymal stem cells into the osteoblastic cell lineage, reducing bone resorption, increasing the synthesis of osteoprotegerin (OPG), a receptor that prevents Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) from binding to its receptor, and reducing RANKL synthesis, thereby preventing further bone resorption (Amstrup et al., 2013, Santos et al., 2023).

Therefore, investigating whether patients with periodontal disease experience a significant decrease in salivary melatonin (S-MEL) levels is essential, as understanding this relationship can contribute to the development of more effective therapeutic and diagnostic techniques (for example, as a biomarker) for oral pathologies. This is particularly relevant because inflammatory cytokines released during the inflammatory process contribute to alveolar bone loss, thus altering the balance between bone resorption and formation. We aimed to evaluate, through a systematic review and meta-analysis, the differences in S-MEL levels between patients with periodontal disease and healthy individuals. Based on the data available in the literature, we sought to quantify the magnitude of this difference, examine the consistency of the findings among the studies, and explore factors that may influence this relationship, such as the severity of periodontitis, characteristics of the samples evaluated, and laboratory methods used.