The Open Dentistry Journal ISSN: 1874-2106

DOI: 10.2174/0118742106346940241212104004, 2024, 18, e18742106346940 1

SYSTEMATIC REVIEW ARTICLE OPEN ACCESS

Exploring the Potential Clinical Applications of

Salivary Cortisol in the Diagnosis and Management
of Cushing’s Syndrome, Diabetes, Depression, and
Periodontal Disease: A Systematic Review
Andrea Scribante1,* , Matteo Pellegrini2,3,*, Martina Ghizzoni2,3, Federica Pulicari2,3, Aldo
Bruno Giannì2,3 and Francesco Spadari2,3
1
Section of Dentistry, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100
Pavia, Italy
2
Maxillofacial Surgery and Dental Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan,
Italy
3
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via della Commenda 10, 20122 Milan,
Italy

Abstract:
Background: Current research primarily aims to investigate the potential of salivary cortisol for early diagnosis as
well as clinical management and monitoring of disease progression. Its utility extends to a range of multidisciplinary
settings, encompassing conditions, such as Cushing's syndrome, stress, and depression, pre-diabetes, type 2 diabetes,
and periodontal disease, within dentistry. This systematic review aimed to analyze recent literature on the use of
salivary cortisol as a biomarker for various clinical and pre-clinical conditions, including stress, depression, diabetes,
Cushing's Syndrome (CS), and periodontal disease. Specifically, the review sought to evaluate its application in
screening, diagnosis, clinical management, and monitoring disease progression.

Materials and Methods: Employing PubMed (MEDLINE) and Scopus databases, the search strategy utilized
Medical Subject Heading (MeSH) terms, including “Cushing’s syndrome”, “diabetes mellitus type 2”,
“hydrocortisone”, “saliva”, “biomarker”, “depression”, and “periodontal disease”, following the PICO model. The
Cochrane Collaboration tool was used to assess bias risk for randomized clinical studies, while the ROBINS-I tool was
used for observational studies.

Results: Adhering to PRISMA guidelines, 25 studies, comprising controlled interventions, pre-post studies, and
observational/cohort or cross-sectional studies, were analyzed. We found a correlation between salivary cortisol levels
and various health conditions. Elevated salivary cortisol was associated with increased disease severity in
periodontitis, characterized by higher probing pocket depths and a greater plaque index. Patients with chronic
periodontitis exhibited notably higher cortisol levels compared to healthy individuals, suggesting a link between
stress and inflammatory responses in periodontal disease. Furthermore, salivary cortisol was identified as a valuable
biomarker for detecting conditions, such as Cushing's syndrome and type 2 diabetes, with altered cortisol patterns
indicative of disease progression. The findings highlighted the potential of salivary cortisol as a non-invasive
diagnostic tool in assessing health status and managing related conditions.

Conclusion: Salivary cortisol serves as a crucial biomarker for the diagnosis and management of several health
conditions, including Cushing's disease, diabetes, stress, depression, and periodontal disease. Its ease of
measurement and reliability provide valuable insights into the Hypothalamic-pituitary-adrenal (HPA) axis, and the
standardization of testing methods could enhance diagnostic accuracy. Continued research is essential to elucidate
the interconnections among these conditions, which may inform future diagnostic and therapeutic strategies.

Keywords: Biomarker, Cushing's syndrome, Depression, Diabetes, Glucocorticoids, Periodontal disease, Salivary
cortisol.
2 The Open Dentistry Journal, 2024, Vol. 18 Scribante et al.

© 2024 The Author(s). Published by Bentham Open.

This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public
License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license
permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are
credited.
Received: September 14, 2024
Revised: November 01, 2024
*Address correspondence to these authors at the Section of Dentistry, Department of Clinical, Surgical, Diagnostic and
Accepted: November 19, 2024
Pediatric Sciences, University of Pavia 27100 Pavia, Italy, Maxillofacial Surgery and Dental Unit, Fondazione IRCCS Cà
Published: December 27, 2024
Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy and Department of Biomedical, Surgical and Dental Sciences,
University of Milan, Via della Commenda 10, 20122 Milan, Italy; E-mails: andrea.scribante@unipv.it and
matteo.pellegrini@unimi.it

Cite as: Scribante A, Pellegrini M, Ghizzoni M, Pulicari F, Giannì A, Spadari F. Exploring the Potential Clinical Send Orders for Reprints to
Applications of Salivary Cortisol in the Diagnosis and Management of Cushing’s Syndrome, Diabetes, Depression, and reprints@benthamscience.net
Periodontal Disease: A Systematic Review. Open Dent J, 2024; 18: e18742106346940.
http://dx.doi.org/10.2174/0118742106346940241212104004

1. INTRODUCTION significant disruptions in intermediate metabolism,

Cortisol, also known as 17-hydroxy-corticosterone, is a manifesting as abdominal obesity, insulin resistance, and
steroid hormone produced by the adrenal cortex. It plays a reduced levels of HDL-cholesterol, ultimately increasing
crucial role in regulating and maintaining overall health, the risk of developing diabetes [8].
impacting various systems, including cardiovascular, Chronic Periodontitis (CP) is a multifactorial
cognitive, immune, metabolic, musculoskeletal, respi- inflammatory disease that primarily targets the supportive
ratory, and reproductive systems, as its receptors are structures of the teeth, including the alveolar bone,
found in multiple cell types [1, 2]. Cortisol is the product periodontal ligament, and gingiva. This condition not only
of the Hypothalamic-pituitary-adrenal (HPA) axis. This results from a microbial insult, but is also significantly
signaling pathway originates from the hypothalamus, influenced by various systemic factors, including hormonal
which receives neurological inputs from the Para- changes that play a crucial role in regulating bone
Ventricular Nucleus (PVN) and the hypothalamic metabolism and immune responses. Hormonal fluc-
suprachiasmatic nucleus. In response to triggers, PVN tuations, particularly those involving cortisol, estrogen,
cells secrete Corticotropin-releasing Factor (CRF), which and parathyroid hormone, contribute to the delicate
stimulates the release of Adrenocorticotropic Hormone balance between bone resorption and formation, which is
(ACTH) from the pituitary gland. ACTH then enters the essential for maintaining periodontal health [9, 10].
bloodstream, exerting a steroidogenic effect and Elevated levels of pro-inflammatory cytokines, such as
triggering the adrenal cortex to release cortisol. Cortisol Interleukin-1 beta (IL-1β) and Tumor Necrosis Factor-
levels typically peak in the morning, around 30-50 minutes alpha (TNF-α), are strongly associated with periodontal
after waking up, and gradually decline throughout the day, tissue destruction. These cytokines promote the
following a circadian pattern, with the lowest levels recruitment and activation of osteoclasts, leading to
occurring at night time [3, 4]. increased bone resorption in the periodontal environment.
Several systemic conditions are related to altered When hormonal dysregulation occurs, it can exacerbate
levels of cortisol. Hypercortisolism presents as a clinical the inflammatory response, further promoting the
state where tissues endure extended exposure to steroid production of these cytokines and accelerating periodontal
hormones, notably cortisol, which may result in hyper- breakdown [9, 10].
cortisolemia. Prolonged hypercortisolism can precipitate Cortisol, a glucocorticoid hormone known for its
the onset of Cushing's Syndrome (CS). CS may be induced immunosuppressive effects, is produced in response to
by sustained systemic exposure to a spectrum of stress and plays a vital role in modulating immune
glucocorticoids, whether originating externally or responses. In the context of periodontitis, elevated cortisol
internally [5]. Stress-related disorders can emerge from an levels can suppress the host’s immune function, impairing
overactive Hypothalamic-Pituitary-Adrenal (HPA) axis, its ability to effectively respond to bacterial challenges
influenced by prolonged negative expectations about within the periodontal pocket. This immunosuppressive
future stressors. Individuals with heightened anticipations effect of cortisol can lead to a reduced capacity to control
tend to mentally prepare for stressful events, prolonging bacterial invasion, thereby exacerbating inflammation and
activation of the dorsolateral prefrontal cortex while accelerating bone loss in affected areas [11].
suppressing the amygdala. This dampening of the Estrogen is another hormone that significantly impacts
amygdala's response diminishes activation of the HPA bone metabolism. It is known for its protective effects on
axis, potentially exacerbating stress-related conditions [6]. bone density and structure, especially in women.
Type 2 Diabetes Mellitus (T2DM), a prevalent Decreased estrogen levels, such as those seen in
metabolic disorder, results from the combined effects of postmenopausal women, are associated with increased
impaired insulin secretion by pancreatic β-cells and the bone resorption, which heightens the risk of periodontal
diminished responsiveness of insulin-sensitive tissues to tissue degradation. The deficiency of estrogen leads to an
insulin [7]. Excessive cortisol levels, whether clinically imbalance in bone turnover, favoring osteoclastic activity
evident or experimentally induced, are linked with over osteoblastic activity, thus accelerating bone loss. This
Exploring the Potential Clinical Applications of Salivary Cortisol 3

increased susceptibility in postmenopausal women (Table 1) [21]. There is a growing consensus among
highlights the need to consider hormonal status as a factor researchers regarding the significance of diurnal
in the risk assessment and management of periodontal fluctuations in cortisol levels. Both the Cortisol Awakening
disease [12]. Response (CAR) and diurnal slope are recognized as
The regulation of bone homeostasis within the oral crucial components in assessing diurnal cortisol activity
cavity is a complex process influenced by the interplay of [21].
several hormones, including cortisol, estrogen, and
Table 1. Cortisol measures.
parathyroid hormone. Each of these hormones has a
distinct role in modulating both osteoclastic (bone- Cortisol Measures Description
resorbing) and osteoblastic (bone-forming) activities.
Cortisol Awakening Captures the cortisol surge 30-45 minutes
Parathyroid hormone, for example, influences calcium Response (CAR) after waking [17]
metabolism and stimulates bone remodeling, which can
Tracks cortisol level changes (typically
impact the structural integrity of the alveolar bone. Diurnal cortisol slope
declining) from morning to evening [25]
Together, these hormones maintain a dynamic equilibrium Area Under the daytime Signifies cumulative cortisol levels during the
essential for bone health, and any disruption in their levels cortisol Curve (AUC) day [26]
can predispose individuals to bone-related diseases, Reflects the cortisol level upon waking up
Waking cortisol
including periodontitis [13]. [25]
Cortisol measured at Analyzes cortisol levels at distinct clock
The onset and progression of periodontitis are, specific waking times points upon waking [27]
therefore, not solely attributable to microbial factors, but Bedtime cortisol Indicates cortisol levels at night [25]
are also influenced by various systemic conditions that
Gauges the rise above normal levels for a
affect the host's immune and inflammatory responses. Cortisol reactivity to
specific individual in response to immediate
momentary stressors
Chronic stress, diabetes, and smoking are recognized as stressors [28]
significant contributors to the pathogenesis of periodontal Cortisol reactivity to daily Assesses variations in cortisol levels from day
disease. Chronic stress is particularly detrimental because stressors to day in response to daily stressors [28]
it leads to prolonged elevation of cortisol levels, which can Over time, research has concentrated on salivary
exacerbate inflammatory processes and impair immune cortisol as a biomarker linked to various conditions. In the
function within the oral cavity. This prolonged exposure to literature, it has been shown that elevated IL-6 levels are
cortisol creates an environment conducive to periodontal correlated with reduced CAR, increased Area Under the
degradation by weakening the host's defenses against Curve (AUC), and flatter diurnal cortisol decline. Higher
bacterial colonization [14, 15]. TNF-α levels were linked to lower waking cortisol levels,
Moreover, diabetes is another systemic condition independent of IL-6 and IL-10. No significant associations
closely linked with periodontal disease. It is associated were found between IL-10 and cortisol parameters [22].
with an altered inflammatory response, characterized by Concerning salivary α-amylase, it increases in response to
an exaggerated release of pro-inflammatory mediators, stress, reflecting nervous system activity. It is emerging as
which not only increases the susceptibility to periodontal a diagnostic marker for oral conditions, underlining its
destruction, but also compromises the healing processes association with cortisol in stress responses [23].
within periodontal tissues. The bidirectional relationship Moreover, if cortisol is linked to autoimmune diseases,
between diabetes and periodontitis emphasizes the rheumatoid arthritis patients may exhibit higher levels of
importance of managing systemic conditions to prevent plasmatic cortisol compared to healthy subjects [24].
exacerbation of periodontal disease and promote overall Therefore, this review aimed to analyze recent
oral health [15]. literature on salivary cortisol as a biomarker for several
In the past, cortisol levels were determined by testing clinical and pre-clinical conditions, including stress,
blood and urine samples before Kirshbaum recognized depression, diabetes, CS, and periodontal disease, as well
saliva samples as a valid alternative in clinical diagnosis as assess its application in screening, diagnosis, clinical
[16]. This transition revolutionized the assessment of management, and monitoring disease progression.
cortisol secretion, shifting from a clinical setting to a
2. MATERIALS AND METHODS
multidisciplinary approach [17]. Salivary cortisol measure-
ments are considered accurate because cortisol passively 2.1. Focused Questions
flows through the salivary glands, and its concentration is
The questions included the following: Is salivary
not dependent on salivary volume. It serves as a reliable
cortisol a clinically applicable biomarker for the diagnosis,
tool for measuring biologically active cortisol, reflecting
management, and progression of Cushing’s syndrome,
the cortisol flowing through the bloodstream at any given
diabetes, depression, and periodontitis? Can salivary
moment [18, 19]. This biomarker is widely applied in
cortisol be used for the detection of pre-clinical conditions
medical and biological fields, providing valuable
(hypercortisolism, prediabetes, stress)?
information about the HPA axis, both in health and
disease, and its implications for human responsiveness 2.2. Eligibility Criteria
and adaptation to environmental changes [20]. In field-
The inclusion criteria applied in this review were as
based research, various cortisol measures are widely
follows: (I) study model: interventional studies,
utilized and closely linked to physiological phenomena
4 The Open Dentistry Journal, 2024, Vol. 18 Scribante et al.

retrospective studies, cross-sectional studies, and cohort performed on PubMed (MEDLINE) and Scopus databases
studies; (II), participants: patients with Cushing’s [32, 33].
syndrome, pre-diabetes/type 2 diabetes, stress/depression, The search string applied for the search was built as
periodontitis; (III) interventions: salivary cortisol follows: #1 “Cushing syndrome” (MESH) OR (syndrome,
measurements for screening, clinical management, and Cushing) OR (Cushing's syndrome) OR (syndrome,
disease progression; and (IV) outcome: the reliability of Cushing's) OR (hypercortisolism); #2 “diabetes mellitus,
salivary cortisol in screening, diagnosis of pre-clinical and type 2” (MESH) OR (diabetes mellitus, noninsulin-
clinical conditions, clinical management, and monitoring dependent) OR (diabetes mellitus, ketosis-resistant) OR
disease progression. (diabetes mellitus, ketosis resistant) OR (ketosis-resistant)
Following the methods of Scribante et al. [29], OR (diabetes mellitus) OR (diabetes mellitus, non-insulin
exclusively studies adhering to all the inclusion criteria dependent) OR (diabetes mellitus, non-insulin-dependent)
were examined. With respect to the exclusion criteria, the OR (non-insulin-dependent diabetes mellitus) OR (diabetes
following were considered: (I) abstract of articles mellitus, stable) OR (stable diabetes mellitus) OR (diabetes
published in non-English languages, (II) duplicate studies, mellitus, type II) OR (NIDDM) OR (diabetes mellitus,
(III) not relevant studies (full-text articles not appropriate noninsulin dependent) OR (diabetes mellitus, maturity-
to answer the focused question, analysis of different onset) OR (diabetes mellitus, maturity onset) OR
supplementary treatments, full-text content not (maturity-onset diabetes mellitus) OR (maturity onset
corresponding to abstract), (IV) ex vivo or experimental diabetes mellitus) OR (noninsulin-dependent diabetes
animal studies, (V) absence of ethics committee approval, mellitus) OR (noninsulin dependent diabetes mellitus) OR
(VI) narrative reviews, systematic reviews, or systematic (maturity-onset diabetes) OR (diabetes, type 2) OR
and meta-analysis reviews, and (VII) case report studies. (diabetes mellitus, adult-onset); #3 “hydrocortisone”
(MESH) OR (cortisol) OR (epicortisol); #4 “saliva” (MESH)
2.3. Search Strategy OR (salivas); #5 “biomarkers” (MESH) OR (biological
The PICO model (Table 2) [30] (Population, markers) OR (biomarker) OR (serum markers) OR (clinical
Intervention, Comparison, Outcome) was used to conduct markers) OR (biochemical markers) OR (laboratory
this review through a literature search of the PubMed markers); #6 “depression” (MESH) OR (depressive
(MEDLINE) and Scopus electronic databases, founded on symptoms) OR (depressive symptom) or (emotional
the following three aspects: population (people with depression) OR (depression, emotional); #7 “periodontal
Cushing’s disease, pre-diabetes/diabetes, stress/ diseases” (MESH) OR (disease, periodontal) OR (diseases,
depression, periodontal disease), concept (evidence from periodontal) OR (periodontal disease) OR (parodontosis)
clinical trials related to salivary cortisol levels and clinical OR (pyorrhea alveolaris); #8 combination of #1 AND #4
application in diagnosis and management of the AND #5 ; #9 combination of #2 AND #4 AND #5; #10
aforementioned conditions), and context (in this regard, combination of #3 AND #4 AND #7.
the review has not been circumscribed to any specific The articles published in the years 2010 to 2023 were
cultural element or setting). Studies’ abstracts that selected. The data extraction period was between
analyzed the potential of salivary cortisol levels for February 2024 and June 2024. The last search was
screening, clinical management, and monitoring disease
progression of several conditions and their predictive performed on 30th June, 2024. Two calibrated reviewers
value for pre-clinical conditions were reviewed. During (M.G. and M.P.) conducted the research.
this scoping review of the literature, the Preferred Disagreements and discrepancies were resolved by
Reporting Items for Systematic reviews and Meta-Analyses consensus, and four other reviewers were consulted (F.P.,
(PRISMA) consensus was followed (Table S1) [31]. A.S., A.B.G., and F.S.). Careful analysis of the titles and
abstracts was conducted for the initially searched articles,
Table 2. The PICO model followed. ensuring that only relevant studies were included while
non-relevant ones were excluded. All pertinent articles
1. Participants/population: patients with hypercortisolism/Cushing’s
disease, pre-diabetes/diabetes, stress/depression, and periodontal disease. underwent thorough review and scrutiny by examining
2. Intervention/exposure: salivary cortisol concentration for complete texts, documenting the discoveries, and
hypercortisolism/Cushing’s disease, pre-diabetes/diabetes, identifying any similar studies that met the chosen
stress/depression, and periodontal disease’s early diagnosis and/or inclusion criteria.
management.
3. Comparison/control: no comparison.
The present protocol has been registered within the
Open Science Framework platform (registration
4. Outcome: the role of salivary cortisol levels in early diagnosis and/or
management of hypercortisolism/Cushing’s disease, pre-diabetes/diabetes, DOI-10.17605/OSF.IO/P4KVB).
stress/depression, and periodontal disease. The elaborated strategies applied for each electronic
2.4. Research database are exhibited in Table S2 (supplementary
material).
The Medical Subject Heading (MeSH) terms used are
as follows: “Cushing syndrome”, “diabetes mellitus type 3. RESULTS
2”, “hydrocortisone”, “saliva”, “biomarker”, “depression”,
The primary search identified 439 articles based on
and “periodontal disease”; an electronic search was
MeSH terms. Following this, 402 articles were removed
Exploring the Potential Clinical Applications of Salivary Cortisol 5

(13 abstracts of articles published in non-English eligibility. Additionally, 12 full-text articles were further
languages, 198 duplicates, 68 in vitro or animal clinical excluded because they were considered irrelevant. The 25
studies, 114 because they were not pertinent, and 9 relevant articles were finally included and analyzed in this
because of the absence of ethics committee approval), and review. The flowchart of the review process is described in
37 articles were screened based on title and abstracts. Fig. (1).
The remaining 25 full-text articles were assessed for

Fig. (1). PRISMA 2020 flow diagram for systematic reviews.

6 The Open Dentistry Journal, 2024, Vol. 18 Scribante et al.

Table 3. Risk of bias of the randomized clinical studies included in this review: the green symbol represents a
low risk of bias, while the yellow symbol represents a high risk of bias.

Random Sequence Incomplete Outcome

- Allocation Concealment Blinding Selective Reporting
Generation Data

Zhang et al., 2022

[46]

Vrshek-Schallhorn et al., 2013

[47]

Table S3 shows the studies excluded from this review was observed in this review.
and the reasons for exclusion [34-45]. Table (4a-d) shows the baseline characteristics of
The studies were from two categories: 2 controlled patients included in the selected studies.
intervention studies [46, 47] and 23 observational/cohort Evidence of studies included in this systematic review
or cross-sectional studies [6, 48-69]. (study design and aim, methods, results, and conclusions) is
shown in Table S7 (supplementary material).
3.1. Literature Review Results
NHLBI quality assessment tool for controlled
In the 25 selected studies, salivary cortisol was linked to intervention studies is shown in Table S8 (supplementary
different conditions. From the 25 studies selected in this materials. NHLBI quality assessment tool for observational
review, 24% of them evaluated the relationship between cohort and cross-sectional studies is shown in Table S9.
salivary cortisol and hypercortisolism or CS [48, 49, 56, 65,
66, 69], 20% of the studies considered T2D [50, 51, 57-59], 4. DISCUSSION
20% evaluated stress or major depressive diseases [6, 48, Measurement of cortisol content in saliva provides an
54, 55, 67], and finally 36% studied the relationship with indirect assessment of overall health status [17]. In a healthy
periodontal disease [46, 52, 53, 60-64, 68]. state, cortisol levels are tightly regulated to maintain
Of the studies selected, 48% of them evaluated salivary homeostasis, as uncontrolled levels can be detrimental [71].
cortisol levels using nmol/L, 20% used ng/mL, 4% assessed Studies have demonstrated that salivary cortisol
cortisol values using mmol/dL, 4% did not specify any unit of measurement can be a simple and convenient screening tool
measure, 8% used pg/mL, and 16% applied µg/dL as a unit for individuals with CS [72]. Similarly, in patients with type
of measurement. 2 diabetes, cortisol has been shown to promote
gluconeogenesis and insulin secretion, contributing to
3.2. Risk of Bias insulin resistance [73]. In the context of stress and
The Cochrane Collaboration tool was applied to assess depressive disorders, lower salivary cortisol levels have been
the risk of bias for RCT in the articles included in this review associated with unfavorable disease progression [74].
(Table 3), using the judging criteria for risk of bias shown in Furthermore, numerous studies have established a
Table S4. Criteria for judging the risk of bias in the ROBINS- statistically significant relationship between periodontal
I assessment tool are shown in Table S5. Bias analysis using disease indexes (such as CAL and PPD) and alterations in
the ROBINS-I-tool [70] for observational studies is shown in cortisol levels, indicating a correlation with disease severity
Table S6 (supplementary material). A moderate risk of bias [75, 76].

Table 4a. Baseline characteristics of patients included in the cushing's syndrome (CS) studies.

No. of Patients and Mean Age (years, Inclusion

Authors/Refs Exclusion Criteria
% of Women SD or range) Criteria
Bäcklund et al., 2020 Test: 22 (77%) Control: 155 Test: NR HPA axis disease, glucocorticoid medication, diurnal
NR
[48] (58.7%) Control: NR rhythm issues, fever, oral problems
Normal: 47.9 ± 11.09
Normal: 57 (61.4%) Endocrine conditions, chronic pain, alcoholism, smoking,
Lages et al., 2019 Suspected: 51.54 ±
Suspected CS: 39 (64.1%) NR pregnancy, chronic diseases, psychiatric illness, shift
[49] 18.00
Proven CS: 31 (87.1%) work, certain medications
Proven: 46.19 ± 14.11
Garrahy et al., 2021
23 (78.2%) 35 (7-70) Confirmed CS Pseudo-Cushing’s, interfering medications
[56]
Ueland et al., 2021
320 (54.3%) 4-16 NR Glucocorticoids
[65]
CS: 48 (81.2%) Control: 13 CS: 43.1 ± 2.2 Control:
Lin et al., 2019
(76.9%) 39.9 ± 5.5 Normal: 29.7 NR NR
[66]
Normal: 21 (42.8%) ± 0.8
Mohamed et al., 2022 High pre-test
54 (83.3%, 21 with CS) 44.8 Cyclical, subclinical, pseudo-CS, non-compliant patients
[69] probability for CS
Exploring the Potential Clinical Applications of Salivary Cortisol 7

Table 4b. Baseline characteristics of patients included in type 2 diabetes studies.

No. of Patients and Mean Age (years, Inclusion

Authors/Refs Exclusion Criteria
% of Women SD or range) Criteria
BMI> 30, pregnancy, tobacco, drugs, alcohol, Addison’s
T2D: 44, T2D: 54 ± 5.70 (40-60), pre-
Salehi et al., 2019 disease, Cushing’s syndrome, thyroid disorders, recent
pre-diabetic: 44, diabetic: 48.07 ± 8.68 (31-60), NR
[50] injury/surgery, malignancy, corticosteroid/hormone
healthy: 44 healthy: 42.86 ± 11.90 (30-60)
therapy, mental/sleep disorders
Type 1 diabetes, glucocorticoids, dementia, acute illness,
Liu et al., 2005 T2D: 141 (0%), T2D: 61.8 ± 9.0, no diabetes:
Type 3 diabetes medications affecting cortisol, night-shift work, history
[51] no diabetes: 46 (0%) 58.7 ± 10.0
of CS, autoimmune diabetes
Johar et al., 2016
757 (48.8%) 75 (65-90) NR Missing data on type 2 diabetes and covariates
[57]
Consent to saliva
Hackett et al., 2014 samples, complete No saliva samples, cortisol values 3SD from mean,
3508 (24.9%) 61.04 ± 5.94
[58] cortisol data within steroid medication, non-white
range
Normoglycemic: 2542
(26.8%), Normoglycemic: 60.94 ± 5.90,
Hackett et al., 2016 Complete cortisol Prevalent diabetes (at phase 7), incomplete cortisol
impaired fasting impaired fasting glucose: 60.13
[59] measures sample
glucose: 518 (16.4%), ± 5.72, diabetic: 61.45 ± 6.03
diabetic: 210 (23.8%)

Table 4c. Baseline characteristics of patients included in the periodontal disease studies.

No. of Mean Age

Authors/Refs Patients and (years, Inclusion Criteria Exclusion Criteria
% of Women SD or range)
Cases: 41, Cases: 53.7 ± Cases: antibiotic/periodontal treatment in last 6/12 months, <5
Cases: 4 teeth with PD ≥4 mm and
Mesa et al., 2014 48.8% 14.7 teeth, corticoids/estrogens/immunosuppressants, systemic
AL ≥3 mm, bone loss. Controls: PD
[52] Controls: 36, Controls: 37.8 ± infection/neoplastic disease/pregnancy/breastfeeding/≥4 cups
≤3 mm and AL ≤2 mm
72.2% 19.1 coffee/tea
Group I: CP with PPD ≥5 mm, CAL
Group 1: 200 ≥5 mm, bone loss, smoking ≥10
Systemic disease/medications affecting cortisol,
Zhang et al., 2022 Group 2: 200 cig/day for 5 yrs. Group II: CP with
20-50 hyperpituitarism/pituitary/adrenal tumors, Cushing’s syndrome,
[46] Group 3: 200 PPD ≥5 mm, CAL ≥5 mm, bone loss.
high-dose corticosteroids, pregnancy
50% of 600 Group III: periodontally healthy,
non-smokers.
Group 1: periodontally healthy, non-
Group 1: 25 smokers. Group 2: severe CP,
Bawankar et al., Psychiatric disorders, systemic disease, pregnancy,
Group 2: 25 PPD/CAL ≥5 mm, bone loss,
2019 30-65 antibiotic/steroid/chemotherapy in last 6 weeks, acute illness,
Group 3: 25 current/history of smoking. Group 3:
[53] periodontal therapy in last 6 months
46.7% of 75 severe CP, PPD/CAL ≥5 mm, bone
loss, non-smokers.
Corticosteroids/immunosuppressants, Addison's
Fenol et al., 2017
70 38.56 ± 10.878 Minimum 20 teeth disease/Cushing's syndrome, smoking, systemic
[60]
conditions/psychiatric history, recent periodontal therapy
Group 1: 23, Group 1: 42.60
47.8% ± 7.32
Group 2: 23, Group 2: 40.95
Obulareddy et al., Age ≥30 years, >20 teeth, no
52.2% ± 7.48
2018 systemic diseases/medications, no Pregnant/lactating women
Group 3: 23, Group 3: 42.08
[61] recent periodontal treatment.
60.9% ± 8.97
Group 4: 23, Group 4: 45.78
60.9% ± 7.82
Periodontitis:
Periodontitis: 37.1 ± 9.8
Naghsh et al., 45, 80% (23–55) Systemic conditions, corticosteroids/immunosuppressants,
At least 15 teeth, fasting before the
2019 No No antibiotics in last 6 months, smoking/alcohol,
test
[62] periodontitis: periodontitis: pregnancy/lactation, acute illness
45, 88.9% 4.8 ± 10.7
(20–55)
Periodontitis: 36 Corticosteroids/immunosuppressants, antibiotics in last 6
Refulio et al.,
No Systemically healthy, non-smokers months, acute illness, <3 natural teeth, systemic conditions
2013 30-65
periodontitis: 34 (30-65 yrs) interfering with periodontal disease, recent antibiotics for
[63]
64.2% of 70 periodontal treatment, smoking
8 The Open Dentistry Journal, 2024, Vol. 18 Scribante et al.

(Table ) contd.....

No. of Mean Age

Authors/Refs Patients and (years, Inclusion Criteria Exclusion Criteria
% of Women SD or range)
Group 1: 30, Group 1: 49.03
60% ± 10.43 Group I: periodontally healthy, non- Psychiatric disorders, systemic disease, pregnancy, post-
Rahate et al.,
Group 2: 30, Group 2: 51.93 smokers. Group II: stage III menopausal/lactating women, recent antibiotics/hormonal
2022
46.7% ± 7.34 periodontitis, non-smokers. Group therapy, acute illness, immunosuppressive therapy, recent
[64]
Group 3: 30, Group 3: 52.23 III: stage III periodontitis, smokers. periodontal therapy
16.7% ± 7.14
Mild
Mild
periodontitis:
periodontitis:
38.23 ± 3.55
Develioglu et al., 26, 65.4% Not lactating, no prosthetic tooth Diabetes, myocardial infarction, heart disease, allergies,
(35-49)
2020 Moderate: 39, restorations, no missing data in smoking/alcohol, recent periodontal treatment/anti-
Moderate: 42.66
[68] 51.3% saliva samples/stress questionnaires inflammatory/antioxidant drugs, recent antibiotics
± 7.65 (35-62)
Severe: 15,
Severe: 55.26 ±
53.3%
6.94 (41-68)

Table 4d. Baseline characteristics of patients included in the stress and depression studies.

No. of Patients Mean Age

Authors/Refs and (years, Inclusion Criteria Exclusion Criteria
% of Women SD or range)
No use of medication affecting
Low expectancy: 27, Low expectancy: cortisol levels, cognitive and Outliers for cortisol indexes, missing data for baseline
Pulopulos et al., 2020 100% 20.52 cardiovascular activity, no current questionnaires and PASA, missing data for cortisol
[6] High expectancy: 25, High expectancy: (or history of) neurological or levels, subjects who performed similar stress tasks in
100% 21.00 psychiatric illness, <10 a previous experiment
cigarettes/day.
Corticosteroid medication, insufficient cortisol data,
no follow-up interviews after baseline interview,
Vrshek-Schallhorn et
current major depression, current or past post-
al., 2013 270, 72.2% NR NR
traumatic stress disorder at baseline, dysthymic
[47]
disorder, clinically significant psychotic symptoms, or
bipolar disorder
Clinically confirmed by indicative
Non depressive:
criteria through the Diagnostic
Non-depressive: 30, 35.73±6.89
and Statistical Manual of Mental
Khan, 2020 53.33% (20-48) Hyperaldosteronism, Cushing’s syndrome, and under
Disorders and Beck’s Inventory
[54] Depressive: 30, Depressive: treatment for exogenous steroid diseases
and acutely depressed patients
5.33% 39.10±11.65
satisfying the diagnostic criteria of
(18-70)
Beck’s scoring.
Cushing’s syndrome/disease, hyperaldosteronism
Khan et al., 2020 Healthy: 30
18-60 Depression pregnancy, antidepressants, or exogenous steroid
[55] Major depression: 30
drugs treatment
Yonekura et al., 2014
63, 41.2% 14.29 ± 0.51 NR NR
[67]

4.1. Hypercortisolism and Cushing’s Syndrome suspected undiagnosed CS [69, 78]. Salivary cortisol
Hypercortisolism is a clinical condition characterized assessments have proven equally effective as plasma
by prolonged exposure of tissues to steroid hormones, measurements and outperformed the measurement of
including cortisol. This condition is often associated with glucocorticoid excretion in urine [79]. The evaluation of
hypercortisolemia and, if prolonged, can lead to CS [5]. steroid levels using Liquid Chromatography-tandem Mass
Cushing's syndrome can be triggered by prolonged Spectrometry (LC-MS/MS) offers several advantages,
systemic exposure to various glucocorticoids, whether including increased specificity and simultaneous
they are exogenous or endogenous. Exogenous CS results quantification of multiple steroids.
from the iatrogenic use of glucocorticoids, while The ratio of cortisone to cortisol in patients with CS is
endogenous CS can be further classified as ACTH-related often associated with hypercortisolemia. Cortisone levels
or ACTH-independent [77]. In cases where CS is may be slightly but significantly more effective in
suspected, the detection of late-night salivary cortisol diagnosing CS. However, results from patients undergoing
levels can be a simple and minimally invasive screening the Dexamethasone Suppression Test (DST) showed a high
procedure. This method has a sensitivity of 92% and a level of diagnostic accuracy for both salivary
specificity of 96% and is often combined with the glucocorticoids [48]. Several studies have assessed the
simultaneous evaluation of late-night salivary cortisone efficacy of Late-night Salivary Cortisol (LNSC), but cut-off
levels, providing optimal screening for patients with levels vary among different laboratories, ranging from 3.6
Exploring the Potential Clinical Applications of Salivary Cortisol 9

nmol/L to 15.2 nmol/L for adults [80]. For this reason, an increased mean number of Decayed, Missing, and
different studies have analyzed diverse populations, such Filled permanent Teeth (DMFT) index [50]. Elevated
as Portuguese or Chinese, to establish individualized cut- salivary cortisol levels appear to elevate the susceptibility
off values. The results have validated the diagnostic to dental caries. While the precise linkage remains
effectiveness of Midnight Salivary Cortisol (MSC), for unclear, heightened cortisol levels could potentially
example, in Chinese patients with Cushing's syndrome, heighten the risk of dental caries by augmenting glucose
consistent with findings from other nationalities. Hence, concentrations in the gingival crevicular fluid, particularly
MSC is a precise biomarker useful for screening and in individuals with diabetes or pre-diabetes [50]. Patients
clinical diagnosis [49, 66]. Salivary cortisol has reduced with type 2 diabetes have been shown to have flatter
discriminatory capacity in the elderly and may be elevated diurnal cortisol secretory patterns (lower cortisol levels
in cases of hypertension or diabetes. Test ranges may during the day and higher levels in the evening) compared
need to be expanded for elderly subjects and patients with to non-diabetic individuals. Increased LNSC levels (≥4.3
type 2 diabetes compared to younger, healthy individuals nmol/L) may indicate a clinical suspicion of CS, but are not
[51]. Children with CS require specific cut-off values for necessarily associated with elevated Body Mass Index
late-night salivary cortisol tests, with a value of around 2.4 (BMI), which is commonly associated with the disorder.
nmol/L being used to distinguish between healthy children High LNSC values were found in individuals with diabetes
and those with CS. However, the lack of literature findings but without CS [51, 58, 78]. A flattened diurnal cortisol
suggests that CS is an infrequent disease affecting young secretory pattern has been identified as a predictive
individuals [65]. parameter for the subsequent onset of prediabetes or type
2 diabetes, along with increased LNSC levels. This
Additionally, various factors should be considered
suggests that evening cortisol levels serve as an early
when interpreting salivary cortisol levels. Tobacco use can
warning sign in initially non-clinical individuals [59].
increase salivary cortisol by inhibiting the expression of
Stress may be the missing puzzle piece that links the
11-β-hydroxysteroid Dehydrogenase type 2 (11 β-HSD2).
flattened diurnal cortisol slope and increased night-time
Therefore, smoking should be avoided on the day of
cortisol values. Many studies have pointed to stress and
sample collection [26, 80]. Repeated measurement of
other related factors as contributors to an increased risk
LNSC over several consecutive nights allows for the
of developing type 2 diabetes [84]. Subjects diagnosed
establishment of a secretory pattern of cortisol secretion.
with diabetes demonstrated a circadian cortisol pattern
This can be helpful in cases of cyclical CS, a rare condition
marked by diminished morning levels and increased
characterized by alternating periods of hypercortisolism
cortisol concentrations in the afternoon and evening [8,
and periods of normal cortisol levels when clinical signs 85]. The Hypothalamic-pituitary-adrenal (HPA) axis is
and symptoms of CS decrease [81]. Screening tests should activated by stress, leading to cortisol secretion. Acute
be performed more than once, particularly in cases of pre- and chronic stress factors have been associated with
test clinical uncertainty. In such circumstances, patients alterations in diurnal and nocturnal cortisol patterns [86].
may need to undergo re-evaluation over 6-12 months [56].
Incorrect timing of sample collection and other variables, 4.3. Stress and Depression
such as specimen contamination with blood and As previously mentioned, salivary cortisol serves as a
differences in collection protocols (e.g., number and valuable biomarker in the diagnosis of stress conditions
frequency of samples), can contribute to variability in the and depression [87]. The Cortisol Awakening Response
quantification of late-night salivary cortisol and late-night (CAR) and major life events have been found to
salivary cortisone [82]. independently predict the occurrence of major depressive
4.2. Pre-diabetic and Type 2 Diabetes (T2D) disorders. CAR notably predicts the onset of depression
and the recurrence of depressive episodes, with the latter
Conditions
parameter exhibiting stronger predictive power [47].
Shifting the focus to the association between Salivary When comparing individuals with severe depression to
Cortisol (SaC) and prediabetic or diabetic conditions, non-depressed individuals, it is evident that the former
there appears to be a relationship between an increase in group has elevated salivary cortisol levels. This association
SaC and glycemia. Studies have demonstrated that may also be linked to a family history of depression and
diabetic patients have higher SaC levels than pre-diabetic other notable health characteristics [54]. Salivary cortisol
individuals, and pre-diabetic patients have higher SaC has also shown utility in tracking disease progression [88].
values than healthy individuals [50]. When investigating Stress-related disorders can arise from an exaggerated
secretory cortisol patterns, it has been found that both the response of the Hypothalamic-pituitary-adrenal (HPA) axis
Cortisol Awakening Response (CAR) and Late-night to stressors. The heightened sensitivity to stressful events
Salivary Cortisol (LNSC) are increased in individuals with is influenced by prolonged negative expectations
type 2 diabetes. Higher values of Hemoglobin A1c regarding future stressors [6]. Individuals with elevated
(HbA1c), a marker of long-term glucose control, have also expectations actively foresee stressful situations,
been linked to diurnal and evening cortisol values [57, 83]. culminating in a prolonged anticipatory response of the
Moreover, oral conditions associated with diabetes, such dorsolateral prefrontal cortex and the suppression of the
as dry mouth and higher glucose levels in crevicular fluid, amygdala. This attenuation of the amygdala's reaction to
can promote the development of dental caries, resulting in stress consequently leads to diminished activation of the
10 The Open Dentistry Journal, 2024, Vol. 18 Scribante et al.

Hypothalamus-pituitary-adrenal (HPA) axis [6]. Efforts to Protein 1 (PGLYRP1) as a relevant biomarker. Elevated
reduce stress reactivity have shown promise in mitigating PGLYRP1 levels in saliva are associated with periodontal
negative health consequences associated with stress- inflammation, suggesting its role in the immune response
related factors [89]. In addition to salivary cortisol, to bacterial infection. Similarly, Macrophage Inflammatory
depression has also been found to be associated with Body Protein-1α (MIP-1α) is a significant biomarker, with higher
Mass Index (BMI). Recognizing this relationship can aid in salivary levels indicating the recruitment of inflammatory
the identification of individuals in the pre-clinical stage, cells to periodontal tissues. Recent studies have further
and early intervention and treatment can improve clinical explored the association between PGLYRP1 and
outcomes [55]. Elevated cortisol levels among individuals periodontal inflammation. For example, research has
with depression suggest a potential link between these shown that salivary PGLYRP1 levels correlate with
levels and the predictive value of the HPA axis in disease gingival inflammation and the presence of caries,
onset and prognosis. Addressing the risk factors indicating its potential as an early diagnostic marker for
associated with depression's emergence holds paramount periodontal disease [95]. Another study examined the
importance. Implementing counseling and advocating for impact of peri-implant treatment on salivary PGLYRP1
lifestyle adjustments among the general populace could levels, showing a significant reduction post-treatment,
contribute to BMI enhancement. Prolonged and excessive suggesting that PGLYRP1 could be valuable in monitoring
cortisol secretion contributes to metabolic disturbances, treatment response [96].
increasing susceptibility to obesity and exacerbating Regarding MIP-1α, research indicates that salivary
depressive symptoms in patients [54]. In adolescent concentrations of this protein are elevated in patients with
subjects, the analysis of salivary cortisol twice daily (in the periodontitis, reflecting disease severity and response to
morning and at night time) for three consecutive days is treatment [97]. Furthermore, MIP-1α plays a crucial role
indicative of their depressive states. Single measurements in recruiting inflammatory cells to inflammation sites and
may not be sufficient to distinguish between healthy bone resorption areas, highlighting its importance in the
individuals and those with depression [67]. pathogenesis of periodontal diseases [98].
4.4. Periodontal Disease These studies support the use of PGLYRP1 and MIP-1α
In the current review, nine out of the 25 studies as salivary biomarkers for diagnosing and monitoring
examined the relationship between salivary cortisol and periodontal diseases, providing non-invasive tools to
periodontitis. Patients with periodontitis exhibited assess inflammation and treatment response. In addition
concurrent clinical signs of the disease, such as a higher to these biomarkers, there has been found a significant
Plaque Index (PI), gingival inflammation/Bleeding on association between SCL and responses to Spielberger
Probing (BOP), and tooth loss. The underlying hypothesis State-Trait Anxiety Inventory (STAI) questionnaires [62].
for these findings may be related to more frequent risky When comparing STAI questionnaire scores between CP
behaviors, poor oral hygiene, and increased tobacco patients and gingivitis patients, higher scores were
consumption [52, 90]. Elevated levels of salivary cortisol observed in the CP group [68]. It is plausible to suggest
have been associated with greater Probing Pocket Depths that the correlation between cortisol and CP could stem
(PPD) in patients with periodontitis (ranging from 5-7 mm) from the suppressive influence of the HPA axis on the
[60]. When contrasting healthy individuals with those inflammatory response, given that cortisol inhibits all
diagnosed with Chronic Periodontitis (CP), healthy aspects of the immune reaction [63]. Cortisol's effect
subjects exhibited minimal cortisol levels. This observation includes a reduction in the migration of white blood cells
implies that within a healthy oral setting, cortisol might to the inflamed region and a decrease in the phagocytosis
contribute to facilitating controlled chemotaxis and of impaired cells [60]. Cortisol levels are closely related to
governing immune and inflammatory reactions [61, 91]. the severity of periodontal disease, and in smokers,
salivary cortisol levels may be higher, leading to increased
In addition to the correlation between Salivary Cortisol
Levels (SCL) and PPD, recent literature highlights other tissue destruction, which reflects an explicit, but
significant salivary biomarkers associated with temporary impact on the neuroendocrine system [64].
periodontitis. Matrix Metalloproteinase-8 (MMP-8) has been However, smoking presents itself as a potential
widely studied, with elevated salivary levels consistently confounder. Extensive scrutiny of the literature indicated
linked to periodontal tissue destruction and inflammation. a consensus on the adverse influence of smoking on both
This enzyme, involved in collagen degradation, serves as a the incidence and progression of periodontitis. Therefore,
reliable marker for detecting periodontal disease severity the salivary cortisol levels observed in periodontal patients
[92]. Another noteworthy biomarker is Interleukin-1β who smoke may be attributable to a cumulative effect [53,
(IL-1β), a pro-inflammatory cytokine found in higher 64]. Moreover, it has been shown that higher levels of
concentrations in periodontitis patients, correlating with cortisol are strictly related to the presence of
the extent of periodontal inflammation [93]. Similarly, C- Porphyromonas gingivalis in subjects affected by chronic
reactive Protein (CRP) in saliva, reflecting systemic periodontitis [99]. The diagnosis, staging, and clinical
inflammation, has shown elevated levels in periodontitis management of CP should consider both physical and
patients, indicating its potential as a marker for disease risk psychological aspects, and salivary biomarkers,
and progression [94]. particularly cortisol, MMP-8, IL-1β, CRP, PGLYRP1, and
The literature highlights Peptidoglycan Recognition MIP-1α, may serve as useful indicators in identifying
Exploring the Potential Clinical Applications of Salivary Cortisol 11

underlying physiological factors associated with CONCLUSION

periodontal disease and smoking. Salivary cortisol is a key biomarker for diagnosing and
Salivary cortisol is a reliable parameter (p<0.0001) managing various conditions, like Cushing's disease,
compared to serum cortisol (p > 0.05), as it reflects the diabetes, stress, depression, and periodontal disease. Its
biologically active unbound cortisol in serum and is not simplicity and reliability offer insights into the body's HPA
affected by variations in the concentration of cortisol- axis, with standardized testing potentially improving
binding globulin, which can alter cortisol level readings precision. Ongoing research aims to uncover connections
[53]. It should be noted that other conditions that have not between these conditions, shaping future diagnostic and
been investigated extensively, such as rheumatoid arthritis treatment approaches. This review encourages further
or lichen planus, may also be related to alterations in exploration into salivary cortisol's role across different
salivary cortisol. Indeed, given that around 50% of OLP health issues to refine healthcare strategies.
patients experience sleep disturbances, anxiety, and
depression, it becomes imperative to evaluate the AUTHORS’ CONTRIBUTION
psychological well-being of all individuals affected by this F.S., A.B.G., and A.S.: Contributed to
condition, but more in-depth studies are needed [100, conceptualization, methodology, visualization, supervision,
101]. and project administration; M.P. and A.S.: Curated the
software; A.S. and F.S.: Contributed to validation, formal
4.5. Limitations of this Study and Future Perspective
analysis, resource allocation, and data curation; F.P. and
Acknowledging certain limitations within this report is F.S.: Performed investigation; M.G. and M.P.: Prepared
crucial. The electronic search process lacked the the original draft; M.G., M.P., and A.S.: Conducted writing,
involvement of information specialists or academic review, and editing. All authors have read and agreed to
librarians, potentially affecting search comprehensiveness. the published version of the manuscript.
Moreover, the employed search criteria might have been
overly specific for the intended scoping question [102]. LIST OF ABBREVIATIONS
Additionally, challenges may have arisen in comparing CS = Cushing's Syndrome
findings due to potential variations in samples, driven by
the inherent variability of salivary cortisol influenced by HPA = Hypothalamic-Pituitary-Adrenal
individual factors and diurnal secretory patterns. Indeed, CP = Chronic Periodontitis
cortisol values can be up to 10 times higher in the morning
if compared to nighttime [64] Variability in salivary test TNF-α = Tumor Necrosis Factor alpha
characteristics and parameters, stemming from diverse CAR = Cortisol Awakening Response
laboratory practices and protocols, may have complicated
result comparisons. The wide array of salivary sampling CONSENT FOR PUBLICATION
devices in the current market may have added another Not applicable.
layer of heterogeneity, potentially influencing test
STANDARDS OF REPORTING
outcomes and subsequent clinical trial conclusions.
To address these limitations and advance our PRISMA guidelines were followed.
understanding, future investigations should explore the AVAILABILITY OF DATA AND MATERIAL
correlation between various conditions and their potential
The data sets used and/or analysed during this study
impact on salivary cortisol levels. Establishing definitive
are available from the corresponding author [A.S] upon
and standardized cut-off values for salivary cortisol testing
request.
is essential to enhance the reliability and clinical utility of
these measures. FUNDING
Additionally, other conditions should be analyzed more None.
in-depth, as only a limited number of studies have
explored the involvement of the HPA axis in individuals CONFLICT OF INTEREST
with endometriosis. In endometriosis, a chronic The author(s) declare no conflict of interest, financial
inflammatory state and heightened cardiovascular risk are or otherwise.
characteristic features akin to some other gynecological
conditions, like PCOS, which are linked to relative ACKNOWLEDGEMENTS
hyperaldosteronism. Preliminary findings indicate a Declared none.
potential association between elevated biological
aldosterone activity and endometriosis. Reduced cortisol SUPPLEMENTARY MATERIAL
levels may also play a significant role in this condition, Table S1: PRISMA 2020 checklist. Table S2: Search
particularly in its early stages. However, further research strategies for electronic databases. Table S3: Summary
is required to further investigate this novel aspect of table of studies excluded in this systematic review. Table
endometriosis pathogenesis. S4: Criteria for judging risk of bias using the “risk of bias”
assessment tool. Table S5: Criteria for judging the risk of
bias in the ROBINS-I assessment tool. Table S6: Bias
12 The Open Dentistry Journal, 2024, Vol. 18 Scribante et al.

analysis using the ROBINS-I tool for observational studies. the brain. Int Rev Neurobiol 2020; 150: 1-16.
Table S7: Evidence of studies included in this systematic http://dx.doi.org/10.1016/bs.irn.2019.12.003 PMID: 32204827
[18] Kaufman E, Lamster IB. T HE D IAGNOSTIC A PPLICATIONS OF S
review. Table S8: NHLBI quality assessment tool for
ALIVA — A R EVIEW. Crit Rev Oral Biol Med 2002; 13(2): 197-212.
controlled intervention studies. Table S9: NHLBI quality http://dx.doi.org/10.1177/154411130201300209 PMID: 12097361
assessment tool for observational cohort and cross- [19] Vining RF, McGinley RA. The measurement of hormones in saliva:
sectional studies. Possibilities and pitfalls. J Steroid Biochem 1987; 27(1-3): 81-94.
http://dx.doi.org/10.1016/0022-4731(87)90297-4 PMID: 3320544
REFERENCES [20] Jessop DS, Turner-Cobb JM. Measurement and meaning of
salivary cortisol: A focus on health and disease in children. Stress
[1] McEwen B. Allostasis and allostatic load: Implications for
2008; 11(1): 1-14.
neuropsychopharmacology. Neuropsychopharmacology 2000;
http://dx.doi.org/10.1080/10253890701365527 PMID: 17853059
22(2): 108-24.
[21] Adam EK, Kumari M. Assessing salivary cortisol in large-scale,
http://dx.doi.org/10.1016/S0893-133X(99)00129-3 PMID:
epidemiological research. Psychoneuroendocrinology 2009;
10649824
34(10): 1423-36.
[2] Kadmiel M, Cidlowski JA. Glucocorticoid receptor signaling in
http://dx.doi.org/10.1016/j.psyneuen.2009.06.011 PMID:
health and disease. Trends Pharmacol Sci 2013; 34(9): 518-30.
19647372
http://dx.doi.org/10.1016/j.tips.2013.07.003 PMID: 23953592
[22] DeSantis AS, DiezRoux AV, Hajat A, et al. Associations of salivary
[3] Ramamoorthy S, Cidlowski JA. Corticosteroids. Rheum Dis Clin
cortisol levels with inflammatory markers: The multi-ethnic study
North Am 2016; 42(1): 15-31, vii.
of atherosclerosis. Psychoneuroendocrinology 2012; 37(7):
http://dx.doi.org/10.1016/j.rdc.2015.08.002 PMID: 26611548
1009-18.
[4] Edwards S, Evans P, Hucklebridge F, Clow A. Association
http://dx.doi.org/10.1016/j.psyneuen.2011.11.009 PMID:
between time of awakening and diurnal cortisol secretory activity.
22178583
Psychoneuroendocrinology 2001; 26(6): 613-22.
[23] Lorenzo-Pouso AI, Pérez-Sayáns M, Bravo SB, et al. Protein-based
http://dx.doi.org/10.1016/S0306-4530(01)00015-4 PMID:
salivary profiles as novel biomarkers for oral diseases. Dis
11403981
Markers 2018; 2018: 1-22.
[5] Uwaifo GI, Hura DE. Hypercortisolism. StatPearls. Treasure
http://dx.doi.org/10.1155/2018/6141845 PMID: 30524521
Island, FL: StatPearls Publishing 2023.
[24] Wróbel A, Szklarczyk J, Barańska I, Majda A, Jaworek J.
[6] Pulopulos MM, Baeken C, De Raedt R. Cortisol response to stress:
Association between levels of serotonin, melatonin, cortisol and
The role of expectancy and anticipatory stress regulation. Horm
the clinical condition of patients with rheumatoid arthritis.
Behav 2020; 117: 104587.
Rheumatol Int 2023; 43(5): 859-66.
http://dx.doi.org/10.1016/j.yhbeh.2019.104587 PMID: 31639385
http://dx.doi.org/10.1007/s00296-023-05296-4 PMID: 36912941
[7] Galicia-Garcia U, Benito-Vicente A, Jebari S, et al.
[25] Cohen S, Schwartz JE, Epel E, Kirschbaum C, Sidney S, Seeman
Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci 2020;
T. Socioeconomic status, race, and diurnal cortisol decline in the
21(17): 6275.
coronary artery risk development in young adults (CARDIA)
http://dx.doi.org/10.3390/ijms21176275 PMID: 32872570
Study. Psychosom Med 2006; 68(1): 41-50.
[8] Di Dalmazi G, Pagotto U, Pasquali R, Vicennati V. Glucocorticoids
http://dx.doi.org/10.1097/01.psy.0000195967.51768.ea PMID:
and type 2 diabetes: from physiology to pathology. J Nutr Metab
16449410
2012; 2012: 1-9.
[26] Badrick E, Kirschbaum C, Kumari M. The relationship between
http://dx.doi.org/10.1155/2012/525093 PMID: 23316348
smoking status and cortisol secretion. J Clin Endocrinol Metab
[9] Genco RJ, Borgnakke WS. Risk factors for periodontal disease.
2007; 92(3): 819-24.
Periodontol 2000 2013; 62(1): 59-94.
http://dx.doi.org/10.1210/jc.2006-2155 PMID: 17179195
http://dx.doi.org/10.1111/j.1600-0757.2012.00457.x PMID:
[27] Powell LH, Lovallo WR, Matthews KA, et al. Physiologic markers
23574464
of chronic stress in premenopausal, middle-aged women.
[10] Graves D. Cytokines that promote periodontal tissue destruction. J
Psychosom Med 2002; 64(3): 502-9.
Periodontol 2008; 79(8S): 1585-91.
http://dx.doi.org/10.1097/00006842-200205000-00015 PMID:
http://dx.doi.org/10.1902/jop.2008.080183 PMID: 18673014
12021424
[11] Peruzzo DC, Benatti BB, Ambrosano GMB, et al. A systematic
[28] Adam E. Transactions among adolescent trait and state emotion
review of stress and psychological factors as possible risk factors
and diurnal and momentary cortisol activity in naturalistic
for periodontal disease. J Periodontol 2007; 78(8): 1491-504.
settings. Psychoneuroendocrinology 2006; 31(5): 664-79.
http://dx.doi.org/10.1902/jop.2007.060371 PMID: 17668968
http://dx.doi.org/10.1016/j.psyneuen.2006.01.010 PMID:
[12] Reinhardt RA, Payne JB, Maze CA, Patil KD, Gallagher SJ, Mattson
16584847
JS. Influence of estrogen and osteopenia/osteoporosis on clinical
[29] Scribante A, Ghizzoni M, Pellegrini M, Pulicari F, Spadari F. Laser
periodontitis in postmenopausal women. J Periodontol 1999;
devices and autologous platelet concentrates in prevention and
70(8): 823-8.
treatment of medication-related osteonecrosis of the jaws: A
http://dx.doi.org/10.1902/jop.1999.70.8.823 PMID: 10476887
systematic review. Medicina (Kaunas) 2023; 59(5): 972.
[13] Khosla S, Melton LJ III, Riggs BL. Estrogen and the male skeleton.
http://dx.doi.org/10.3390/medicina59050972 PMID: 37241204
J Clin Endocrinol Metab 2002; 87(4): 1443-50.
[30] Sackett DL, Rosenberg WMC, Gray J A M, Haynes RB, Richardson
http://dx.doi.org/10.1210/jcem.87.4.8417 PMID: 11932262
WS. Evidence based medicine: What it is and what it isn’t. BMJ
[14] Bathla M, Chandna S. Stress and periodontium: A review of
1996; 312(7023): 71-2.
concepts. J Oral Health Community Dent 2010; 4(Spl): 17-22.
http://dx.doi.org/10.1136/bmj.312.7023.71 PMID: 8555924
http://dx.doi.org/10.5005/johcd-4-Spl-17
[31] Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020
[15] Mealey BL, Oates TW. Diabetes mellitus and periodontal diseases.
statement: An updated guideline for reporting systematic reviews.
J Periodontol 2006; 77(8): 1289-303.
BMJ 2021; 372: n71.
http://dx.doi.org/10.1902/jop.2006.050459 PMID: 16881798
http://dx.doi.org/10.1136/bmj.n71 PMID: 33782057
[16] Kirschbaum C, Hellhammer DH. Salivary cortisol in
[32] Butera A, Pascadopoli M, Pellegrini M, Gallo S, Zampetti P,
psychobiological research: An overview. Neuropsychobiology
Scribante A. Oral microbiota in patients with peri-implant disease:
1989; 22(3): 150-69.
A narrative review. Appl Sci (Basel) 2022; 12(7): 3250.
http://dx.doi.org/10.1159/000118611 PMID: 2485862
http://dx.doi.org/10.3390/app12073250
[17] Clow A, Smyth N. Salivary cortisol as a non-invasive window on
[33] Bolouki A. Exploring the association between self-reported and
Exploring the Potential Clinical Applications of Salivary Cortisol 13

objective measures in search of the restorative quality of natural [48] Bäcklund N, Brattsand G, Israelsson M, et al. Reference intervals
environments: a systematic review. Int J Environ Health Res 2022; of salivary cortisol and cortisone and their diagnostic accuracy in
5: 1-15. Cushing’s syndrome. Eur J Endocrinol 2020; 182(6): 569-82.
PMID: 35658754 http://dx.doi.org/10.1530/EJE-19-0872 PMID: 32213657
[34] Pires ALPV, Alves LDB, da Silva AM, et al. Salivary biomarkers to [49] Lages ADS, Frade JG, Oliveira D, et al. Late-night salivary cortisol:
evaluate psychological disorders in oral lichen planus: A Cut-off definition and diagnostic accuracy for cushing’s syndrome
systematic review with meta‐analysis. Oral Dis 2023; 29(7): in a portuguese population. Acta Med Port 2019; 32(5): 381-7.
2734-46. http://dx.doi.org/10.20344/amp.11265 PMID: 31166899
http://dx.doi.org/10.1111/odi.14385 PMID: 36161740 [50] Salehi M, Mesgarani A, Karimipour S, et al. Comparison of
[35] Bargues-Navarro G, Ibáñez-del Valle V, El Mlili N, Cauli O. salivary cortisol level in type 2 diabetic patients and pre-diabetics
Salivary biomarkers associated with psychological alterations in with healthy people. Open Access Maced J Med Sci 2019; 7(14):
patients with diabetes: A systematic review. Medicina (Kaunas) 2321-7.
2022; 58(8): 1091. http://dx.doi.org/10.3889/oamjms.2019.340 PMID: 31592281
http://dx.doi.org/10.3390/medicina58081091 PMID: 36013558 [51] Liu H, Bravata DM, Cabaccan J, Raff H, Ryzen E. Elevated late‐
[36] Špiljak B, Vilibić M, Glavina A, Crnković M, Šešerko A, Lugović- night salivary cortisol levels in elderly male type 2 diabetic
Mihić L. A review of psychological stress among students and its veterans. Clin Endocrinol (Oxf) 2005; 63(6): 642-9.
assessment using salivary biomarkers. Behav Sci (Basel) 2022; http://dx.doi.org/10.1111/j.1365-2265.2005.02395.x PMID:
12(10): 400. 16343098
http://dx.doi.org/10.3390/bs12100400 PMID: 36285968 [52] Mesa F, Magán-Fernández A, Muñoz R, et al. Catecholamine
[37] Botelho J, Machado V, Mascarenhas P, et al. Stress, salivary metabolites in urine, as chronic stress biomarkers, are associated
cortisol and periodontitis: A systematic review and meta-analysis with higher risk of chronic periodontitis in adults. J Periodontol
of observational studies. Arch Oral Biol 2018; 96: 58-65. 2014; 85(12): 1755-62.
http://dx.doi.org/10.1016/j.archoralbio.2018.08.016 PMID: http://dx.doi.org/10.1902/jop.2014.140209 PMID: 24965061
30189327 [53] Bawankar PV, Kolte AP, Kolte RA. Evaluation of stress, serum and
[38] Neupane SP, Virtej A, Myhren LE, Bull VH. Biomarkers common salivary cortisol, and interleukin‐1β levels in smokers and non‐
for inflammatory periodontal disease and depression: A smokers with chronic periodontitis. J Periodontol 2018; 89(9):
systematic review. Brain Behav Immun Health 2022; 21: 100450. 1061-8.
http://dx.doi.org/10.1016/j.bbih.2022.100450 PMID: 35330865 http://dx.doi.org/10.1002/JPER.18-0028 PMID: 29752711
[39] Song M, Bai H, Zhang P, Zhou X, Ying B. Promising applications [54] Khan QU. Relationship of salivary cortisol level with severe
of human-derived saliva biomarker testing in clinical diagnostics. depression and family history. Cureus 2020; 12(11): e11548.
Int J Oral Sci 2023; 15(1): 2. http://dx.doi.org/10.7759/cureus.11548 PMID: 33365217
http://dx.doi.org/10.1038/s41368-022-00209-w PMID: 36596771 [55] Khan QU, Zaffar S, Rehan AM, Rashid RR, Ashraf H, Hafeez F.
[40] Noh J, Jang JH, Yoon HS, et al. Evaluation of salivary biomarkers Relationship of major depression with body mass index and
of periodontal disease based on smoking status: A systematic salivary cortisol. Cureus 2020; 12(1): e6577.
review. Int J Environ Res Public Health 2022; 19(21): 14619. http://dx.doi.org/10.7759/cureus.6577 PMID: 32047714
http://dx.doi.org/10.3390/ijerph192114619 PMID: 36361498 [56] Garrahy A, Forde H, O’Kelly P, et al. The diagnostic utility of late
[41] Bastin P, Maiter D, Gruson D. Le dosage du cortisol salivaire: night salivary cortisol (LNSF) and cortisone (LNSE) in Cushing’s
Aspects pré-analytiques et analytiques. Ann Biol Clin (Paris) 2018; syndrome. Ir J Med Sci 2021; 190(2): 615-23.
76(4): 393-405. [Salivary cortisol testing: preanalytic and analytic http://dx.doi.org/10.1007/s11845-020-02334-z PMID: 32803648
aspects]. [57] Johar H, Emeny RT, Bidlingmaier M, Kruse J, Ladwig KH. Sex-
PMID: 29952304 related differences in the association of salivary cortisol levels and
[42] Boroumand M, Olianas A, Cabras T, et al. Saliva, a bodily fluid type 2 diabetes. Findings from the cross-sectional population
with recognized and potential diagnostic applications. J Sep Sci based KORA-age study. Psychoneuroendocrinology 2016; 69:
2021; 44(19): 3677-90. 133-41.
http://dx.doi.org/10.1002/jssc.202100384 PMID: 34350708 http://dx.doi.org/10.1016/j.psyneuen.2016.04.004 PMID:
[43] Findling JW, Raff H. Diagnosis of endocrine disease: 27088372
Differentiation of pathologic/neoplastic hypercortisolism [58] Hackett RA, Steptoe A, Kumari M. Association of diurnal patterns
(Cushing’s syndrome) from physiologic/non-neoplastic in salivary cortisol with type 2 diabetes in the whitehall ii study. J
hypercortisolism (formerly known as pseudo-Cushing’s Clin Endocrinol Metab 2014; 99(12): 4625-31.
syndrome). Eur J Endocrinol 2017; 176(5): R205-16. http://dx.doi.org/10.1210/jc.2014-2459 PMID: 25215558
http://dx.doi.org/10.1530/EJE-16-0946 PMID: 28179447 [59] Hackett RA, Kivimäki M, Kumari M, Steptoe A. Diurnal cortisol
[44] Zhang Q, Dou J, Gu W, Yang G, Lu J. Reassessing the reliability of patterns, future diabetes, and impaired glucose metabolism in the
the salivary cortisol assay for the diagnosis of Cushing syndrome. whitehall ii cohort study. J Clin Endocrinol Metab 2016; 101(2):
J Int Med Res 2013; 41(5): 1387-94. 619-25.
http://dx.doi.org/10.1177/0300060513498017 PMID: 24065452 http://dx.doi.org/10.1210/jc.2015-2853 PMID: 26647151
[45] Choromańska K, Choromańska B, Dąbrowska E, et al. Saliva of [60] Fenol A, Jebi S, Krishnan S, et al. Association of stress, salivary
obese patients – is it different? Postepy Hig Med Dosw 2015; 69: cortisol level, and periodontitis among the inmates of a central
1190-5. prison in Kerala. Dent Res J (Isfahan) 2017; 14(4): 288-92.
http://dx.doi.org/10.5604/17322693.1176778 PMID: 26561845 http://dx.doi.org/10.4103/1735-3327.211625 PMID: 28928784
[46] Zhang H, Chen B, Pan C, Zhang A. To evaluate the serum cortisol, [61] Nagarakanti S, Obulareddy VT, Chava VK. Association of stress,
salivary cortisol, and serum interleukin-1 B level in patients of salivary cortisol, and chronic periodontitis: A clinico-biochemical
chronic periodontitis with smoking and stress and without study. Contemp Clin Dent 2018; 9(6) (Suppl. 2): 299.
smoking and stress. Medicine (Baltimore) 2021; 100(31): e26757. http://dx.doi.org/10.4103/ccd.ccd_289_18 PMID: 30294161
http://dx.doi.org/10.1097/MD.0000000000026757 PMID: [62] Karami E, Naghsh N, Mogharehabed A, Yaghini J. Comparative
34397819 evaluation of the cortisol level of unstimulated saliva in patients
[47] Vrshek-Schallhorn S, Doane LD, Mineka S, Zinbarg RE, Craske with and without chronic periodontitis. Dent Res J 2019; 16(6):
MG, Adam EK. The cortisol awakening response predicts major 421-7.
depression: predictive stability over a 4-year follow-up and effect http://dx.doi.org/10.4103/1735-3327.270786 PMID: 31803389
of depression history. Psychol Med 2013; 43(3): 483-93. [63] Refulio Z, Rocafuerte M, de la Rosa M, Mendoza G, Chambrone L.
http://dx.doi.org/10.1017/S0033291712001213 PMID: 22652338 Association among stress, salivary cortisol levels, and chronic
14 The Open Dentistry Journal, 2024, Vol. 18 Scribante et al.

periodontitis. J Periodontal Implant Sci 2013; 43(2): 96-100. PMID: 8784076

http://dx.doi.org/10.5051/jpis.2013.43.2.96 PMID: 23678393 [81] Atkinson AB, Kennedy AL, Carson DJ, Hadden DR, Weaver JA,
[64] Rahate PS, Kolte RA, Kolte AP, Lathiya VN, Gupta M, Chari S. Sheridan B. Five cases of cyclical Cushing’s syndrome. BMJ 1985;
Evaluation of stress, serum, and salivary ghrelin and cortisol 291(6507): 1453-7.
levels in smokers and non‐smokers with Stage III periodontitis: A http://dx.doi.org/10.1136/bmj.291.6507.1453 PMID: 2998540
cross‐sectional study. J Periodontol 2022; 93(8): 1131-40. [82] Calvi JL, Chen FR, Benson VB, et al. Measurement of cortisol in
http://dx.doi.org/10.1002/JPER.21-0373 PMID: 34859428 saliva: a comparison of measurement error within and between
[65] Ueland GÅ, Kellmann R, Jørstad Davidsen M, et al. Bedtime international academic-research laboratories. BMC Res Notes
salivary cortisol as a screening test for cushing syndrome in 2017; 10(1): 479.
children. J Endocr Soc 2021; 5(5): bvab033. http://dx.doi.org/10.1186/s13104-017-2805-4 PMID: 28903752
http://dx.doi.org/10.1210/jendso/bvab033 PMID: 33928203 [83] Joseph JJ, Wang X, Spanakis E, et al. Diurnal salivary cortisol,
[66] Lin DC, Tsai PS, Lin YC. Midnight salivary cortisol for the glycemia and insulin resistance: The multi-ethnic study of
diagnosis of Cushing’s syndrome in a Chinese population. atherosclerosis. Psychoneuroendocrinology 2015; 62: 327-35.
Singapore Med J 2019; 60(7): 359-63. http://dx.doi.org/10.1016/j.psyneuen.2015.08.021 PMID:
http://dx.doi.org/10.11622/smedj.2018154 PMID: 30488082 26356041
[67] Yonekura T, Takeda K, Shetty V, Yamaguchi M. Relationship [84] Pouwer F, Kupper N, Adriaanse MC. Does emotional stress cause
between salivary cortisol and depression in adolescent survivors type 2 diabetes mellitus? A review from the European Depression
of a major natural disaster. J Physiol Sci 2014; 64(4): 261-7. in Diabetes (EDID) Research Consortium. Discov Med 2010;
http://dx.doi.org/10.1007/s12576-014-0315-x PMID: 24744089 9(45): 112-8.
[68] Develioglu H, Korkmaz S, Dundar S, Schlagenhauf U. PMID: 20193636
Investigation of the levels of different salivary stress markers in [85] Lederbogen F, Hummel J, Fademrecht C, et al. Flattened
chronic periodontitis patients. J Oral Biol Craniofac Res 2020; circadian cortisol rhythm in type 2 diabetes. Exp Clin Endocrinol
10(4): 514-8. Diabetes 2011; 119(9): 573-5.
http://dx.doi.org/10.1016/j.jobcr.2020.07.020 PMID: 32874881 http://dx.doi.org/10.1055/s-0031-1275288 PMID: 21472658
[69] Mohamed RS, Abuelgasim B, Barker S, et al. Late-night salivary [86] Adam EK, Hawkley LC, Kudielka BM, Cacioppo JT. Day-to-day
cortisol and cortisone should be the initial screening test for dynamics of experience–cortisol associations in a population-
Cushing’s syndrome. Endocr Connect 2022; 11(7): e220050. based sample of older adults. Proc Natl Acad Sci USA 2006;
http://dx.doi.org/10.1530/EC-22-0050 PMID: 35671282 103(45): 17058-63.
[70] RoB 2, ROBINS-I, ROBINS-E and ROB ME are licensed under http://dx.doi.org/10.1073/pnas.0605053103 PMID: 17075058
creative commons attribution-noncommercial-noderivatives 4.0 [87] Chojnowska S, Ptaszyńska-Sarosiek I, Kępka A, Knaś M,
international license. 2016. Available Waszkiewicz N. Salivary Biomarkers of Stress, Anxiety and
from:http://www.riskofbias.info(accessed on 18-11-2024). Depression. J Clin Med 2021; 10(3): 517.
[71] Thau L, Gandhi J, Sharma S. Physiology, Cortisol. StatPearls. http://dx.doi.org/10.3390/jcm10030517 PMID: 33535653
Treasure Island, FL: StatPearls Publishing 2023. [88] Vogelzangs N, Penninx BW. Cortisol and insulin in depression and
[72] Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a metabolic syndrome. Psychoneuroendocrinology 2007; 32(7): 856.
screening test for Cushing’s syndrome. J Clin Endocrinol Metab http://dx.doi.org/10.1016/j.psyneuen.2007.04.012 PMID:
1998; 83(8): 2681-6. 18670578
http://dx.doi.org/10.1210/jc.83.8.2681 PMID: 9709931 [89] Herr R, Barrech A, Riedel N, Gündel H, Angerer P, Li J. Long-term
[73] Rosmond R. Stress induced disturbances of the HPA axis: a effectiveness of stress management at work: effects of the
pathway to Type 2 diabetes? Med Sci Monit 2003; 9(2): RA35-9. changes in perceived stress reactivity on mental health and sleep
PMID: 12601304 problems seven years later. Int J Environ Res Public Health 2018;
[74] Vreeburg SA, Hoogendijk WJG, DeRijk RH, et al. Salivary cortisol 15(2): 255.
levels and the 2-year course of depressive and anxiety disorders. http://dx.doi.org/10.3390/ijerph15020255 PMID: 29401657
Psychoneuroendocrinology 2013; 38(9): 1494-502. [90] Rai B, Kaur J, Anand SC, Jacobs R. Salivary stress markers, stress,
http://dx.doi.org/10.1016/j.psyneuen.2012.12.017 PMID: and periodontitis: A pilot study. J Periodontol 2011; 82(2): 287-92.
23313277 http://dx.doi.org/10.1902/jop.2010.100319 PMID: 20722529
[75] Ishisaka A, Ansai T, Soh I, et al. Association of salivary levels of [91] Rohini G, Kalaivani S, Kumar V, Rajasekar SA, Tuckaram J,
cortisol and dehydroepiandrosterone with periodontitis in older Pandey V. Estimation and comparison of serum cortisol levels in
Japanese adults. J Periodontol 2007; 78(9): 1767-73. periodontally diseased patients and periodontally healthy
http://dx.doi.org/10.1902/jop.2007.070044 PMID: 17760547 individuals: A clinical-biochemical study. J Pharm Bioallied Sci
[76] Hilgert JB, Hugo FN, Bandeira DR, Bozzetti MC. Stress, cortisol, 2015; 7(6) (Suppl. 2): 457.
and periodontitis in a population aged 50 years and over. J Dent http://dx.doi.org/10.4103/0975-7406.163501 PMID: 26538897
Res 2006; 85(4): 324-8. [92] Cafiero C, Spagnuolo G, Marenzi G, Martuscelli R, Colamaio M,
http://dx.doi.org/10.1177/154405910608500408 PMID: 16567552 Leuci S. Predictive periodontitis: The most promising salivary
[77] Wagner-Bartak NA, Baiomy A, Habra MA, et al. Cushing biomarkers for early diagnosis of periodontitis. J Clin Med 2021;
Syndrome: Diagnostic Workup and Imaging Features, With 10(7): 1488.
Clinical and Pathologic Correlation. AJR Am J Roentgenol 2017; http://dx.doi.org/10.3390/jcm10071488 PMID: 33916672
209(1): 19-32. [93] Melguizo-Rodríguez L, Costela-Ruiz VJ, Manzano-Moreno FJ, Ruiz
http://dx.doi.org/10.2214/AJR.16.17290 PMID: 28639924 C, Illescas-Montes R. Salivary biomarkers and their application in
[78] Carroll T, Raff H, Findling JW. Late-night salivary cortisol for the the diagnosis and monitoring of the most common oral
diagnosis of Cushing syndrome: a meta-analysis. Endocr Pract pathologies. Int J Mol Sci 2020; 21(14): 5173.
2009; 15(4): 335-42. http://dx.doi.org/10.3390/ijms21145173 PMID: 32708341
http://dx.doi.org/10.4158/EP09023OR PMID: 19502211 [94] Buduneli N. Biomarkers in saliva and serum samples for
[79] Papanicolaou DA, Mullen N, Kyrou I, Nieman LK. Nighttime periodontal disease and interactions with systemic health. Curr
salivary cortisol: a useful test for the diagnosis of Cushing’s Oral Health Rep 2019; 6(1): 31-6.
syndrome. J Clin Endocrinol Metab 2002; 87(10): 4515-21. http://dx.doi.org/10.1007/s40496-019-0207-5
http://dx.doi.org/10.1210/jc.2002-020534 PMID: 12364428 [95] Silbereisen A, Lira-Junior R, Åkerman S, Klinge B, Boström EA,
[80] Smith RE, Maguire JA, Stein-Oakley AN, et al. Localization of 11 Bostanci N. Association of salivary TREM‐1 and PGLYRP1
beta-hydroxysteroid dehydrogenase type II in human epithelial inflammatory markers with non‐communicable diseases. J Clin
tissues. J Clin Endocrinol Metab 1996; 81(9): 3244-8. Periodontol 2023; 50(11): 1467-75.
Exploring the Potential Clinical Applications of Salivary Cortisol 15

http://dx.doi.org/10.1111/jcpe.13858 PMID: 37524498 [99] Ardila CM, Guzmán IC. Association ofP orphyromonas gingivalis
[96] Teixeira Neves GS, Elangovan G, Teixeira MKS, et al. Peri-implant with high levels of stress‐induced hormone cortisol in chronic
surgical treatment downregulates the expression of sTREM-1 and periodontitis patients. J Investig Clin Dent 2016; 7(4): 361-7.
MMP-8 in patients with peri-implantitis: a prospective study. Int J http://dx.doi.org/10.1111/jicd.12175 PMID: 26194628
Environ Res Public Health 2022; 19(6): 3627. [100] Adamo D, Calabria E, Coppola N, et al. Assessment of sleep
http://dx.doi.org/10.3390/ijerph19063627 PMID: 35329310 disturbance in oral lichen planus and validation of PSQI: A case‐
[97] Sexton WM, Lin Y, Kryscio RJ, Dawson DR III, Ebersole JL, Miller control multicenter study from the SIPMO (Italian Society of Oral
CS. Salivary biomarkers of periodontal disease in response to Pathology and Medicine). J Oral Pathol Med 2022; 51(2): 194-205.
treatment. J Clin Periodontol 2011; 38(5): 434-41. http://dx.doi.org/10.1111/jop.13255 PMID: 34704302
http://dx.doi.org/10.1111/j.1600-051X.2011.01706.x PMID: [101] Azzi L, Rania S, Spadari F, et al. Genetic correlation between
21480939 rheumatoid arthritis and periodontal disease: The role of sex and
[98] Bhavsar I, Miller CS, Al-Sabbagh M. Macrophage inflammatory IL-10. J Biol Regul Homeost Agents 2017; 31(2) (Suppl. 1): 67-75.
protein-1 alpha (MIP-1 alpha)/CCL3: As a biomarker. In: Preedy V, PMID: 28691456
Patel V, Eds. General Methods in Biomarker Research and their [102] Scribante A, Ghizzoni M, Pellegrini M, et al. Full-digital
Applications Biomarkers in Disease: Methods, Discoveries and customized meshes in guided bone regeneration procedures: A
Applications. Dordrecht: Springer 2015. scoping review. Prosthesis 2023; 5(2): 480-95.
http://dx.doi.org/10.1007/978-94-007-7696-8_27 http://dx.doi.org/10.3390/prosthesis5020033