Salivary Tests

Number: 0608

Policy

Aetna considers late night salivary cortisol medically necessary for diagnosing Cushing's syndrome.

Aetna considers the following experimental and investigationa because the effectiveness of these approaches has not been established:

  • Cordant Health Solutions Comprehensive Oral Fluid Rx Evaluation (CORE) (prescription drug monitoring using oral fluid)
  • Measurement of diurnal salivary cortisol patterns for prediction of infant birth weight
  • Salivary antibody testing (IgA, IgG, IgM) for the diagnosis of Sicca syndrome
  • Salivary testing for anti-tissue transglutaminase for the diagnosis of celiac disease
  • Salivary testing of biomarkers for the diagnosis of cancers (e.g., breast cancer, head and neck carcinoma, oral pre-cancer and oral squamous cell carcinoma (e.g.,CYFRA 21-1, interleukin-8, or mRNAs of dual specificity phosphatase 1 (DUSP1), ornithin decarboxylase antizyme 1 (OAZ1), and S100 calcium-binding protein P (S100P))
  • Salivary tests of cortisol for the screening, diagnosis, or monitoring of menopause or diseases related to aging, or any other indications (e.g., diagnosis of adrenal insufficiency in preterm infants, diagnosis of bipolar disorder, depression, or eating disorders)
  • Salivary tests of dehydroepiandrosterone (DHEA), estrogen, melatonin, progesterone, or testosterone for the screening, diagnosis, or monitoring of menopause or diseases related to aging, or any other indications
  • Salivary testing of mutans streptococci for determining the risk of developing dental caries
  • Salivary testing of pepsin for the diagnosis of gastro-esophageal reflux disease
  • Salivary testing of telomere length for the diagnosis of depression

Note: In addition, laboratory tests are not covered unless they are ordered by a physician or other qualified health professional.  Please check benefit plan descriptions.

Background

Salivary hormone testing is purported to aid in the diagnosis and treatment of menopause and other diseases related to aging. These tests measure the amount of free hormones (dehydroepiandrosterone [DHEA], estrogen, melatonin, progesterone and/or testosterone) found in the saliva of women. Most hormone tests are now available on the internet and can be obtained without a prescription.

Salivary hormone levels may vary according to the time of day, diet or hydration; therefore, the timing of saliva collection may affect results. Salivary flow rate can also affect the concentration of certain hormones. Different laboratories may require different testing methods, such as obtaining several samples over a couple of weeks at specific times of the day.

Salivary tests of estrogen, progesterone, testosterone, melatonin, cortisol and dehydroepiandrosterone (DHEA) have become available to consumers over the Internet.  Some of these websites include a questionnaire to allow consumers to determine whether they need saliva testing, and a form that allows consumers to order these tests online.  The results of these tests are purportedly used to determine the need prescriptions of DHEA, vitamins, herbs, phytoestrogens, and other anti-aging regimens.

The medical literature on salivary testing correlates salivary levels with serum levels, the gold standard measurement.  However, the medical literature fails to demonstrate that salivary tests are appropriate for screening, diagnosing, or monitoring patients with menopause, osteoporosis, or other consequences of aging.

Evidence-based clinical practice guidelines from the American Association of Clinical Endocrinologists outline the appropriate methods of screening and diagnosing menopause and osteoporosis.  The primary test for menopause screening is serum follicle-stimulating hormone, for thyroid dysfunction serum thyroid-stimulating hormone, and bone density measurement is the primary method of screening for osteoporosis.  None of these guidelines indicates salivary testing as an appropriate method of screening, diagnosing, or monitoring these disorders.

According to available guidelines, primary hypoadrenalism (Addison’s disease) is suggested by a markedly elevated plasma adrenocorticotrophic hormone (ACTH) with low or normal serum cortisol.  The diagnosis of adrenocortical insufficiency is established primarily by use of the rapid ACTH stimulation test, which involves assessment of the response of serum aldosterone and cortisol to ACTH infusion.

Furthermore, there is inadequate evidence of the value of measuring salivary components to guide prescription of "anti-aging" regimens.  The clinical value of these tests depends not only on how well the salivary testing corresponds to some gold standard (i.e., a serum test), but also upon the evidence of the effectiveness of the particular intervention (anti-aging regimen) that would be prescribed based on the results of the salivary test.  Meta-analyses of the literature have questioned the value of supplementation with DHEA and melatonin on improving patient outcomes.

According to a committee opinion by the American College of Obstetricians and Gynecologists (ACOG, 2005), there is no scientific evidence to support claims of increased safety or effectiveness for individualized estrogen or progesterone regimens prepared by compounding pharmacies.  Furthermore, hormone therapy does not belong to a class of drugs with an indication for individualized dosing.  The opinion by ACOG also pointed out that salivary hormone level testing used by proponents to "tailor" this therapy isn't meaningful because salivary hormone levels vary within each woman depending on her diet, the time of day, the specific hormone being tested, and other variables.

A National Institutes of Health State-of-the-Art Conference Statement on Management of Menopausal Symptoms (2005) reached the following conclusions about salivary hormone testing and bioidential hormones: "Bioidentical hormones, often called "natural" hormones, are treatments with individually compounded recipes of a variety of steroids in various dosage forms, with the composition and dosages based on a person’s salivary hormone concentration.  These steroids may include estrone, estradiol, estriol, DHEA, progesterone, pregnenolone, and testosterone.  There is a paucity of data on the benefits and adverse effects of these compounds."

An assessment by the Institute for Clinical Systems Improvement (2006) concluded: "Currently, there is insufficient evidence in the published scientific literature to permit conclusions concerning the use of salivary hormone testing for the diagnosis, treatment or monitoring of menopause and aging."

The North American Menopause Society (2005) has concluded: "Salivary testing is not considered to be a reliable measure of testosterone levels."

Flyckt and colleagues (2009) compared salivary versus serum measurements of total testosterone (TT), bioavailable testosterone (BT; consisting of free testosterone [FT] and albumin-bound testosterone), and FT from samples collected simultaneously in women who were either receiving transdermal testosterone patch supplementation (300 microg/d) or a placebo patch.  Naturally and surgically post-menopausal women receiving concomitant hormone therapy were recruited to participate in a 24- to 52-week phase III trial of a 300 microg/day transdermal testosterone patch for the treatment of hypoactive sexual desire disorder.  Initial analysis demonstrated high correlations between TT, BT, and FT levels (r = 0.776 to 0.855).  However, there was no correlation with salivary testosterone levels for any of the serum testosterone subtypes (r = 0.170 to 0.261).  After log transformation, salivary testosterone correlated modestly with BT (r = 0.436, p < 0.001), FT (r = 0.452, p < 0.001), and TT (r = 0.438, p < 0.001).  The authors concluded that although salivary testing of testosterone concentrations is an appealing alternative because it is inexpensive and non-invasive, these findings do not support the routine use of salivary testosterone levels in post-menopausal women.

Salivary hormone tests are purported to predict spontaneous premature labor by measuring salivary estriol, an estrogen hormone. A surge in the levels of salivary estriol typically occurs several weeks prior to the onset of spontaneous labor.  Klebanoff and colleagues (2008) examined if salivary progesterone (P) or estriol (E3) concentration at 16 to 20 weeks' gestation predicts preterm birth or the response to 17alpha-hydroxyprogesterone caproate (17OHPC).  Baseline saliva was assayed for P and E3.  Weekly salivary samples were obtained from 40 women who received 17OHPC and 40 who received placebo.  Both low and high baseline saliva P and E3 were associated with a slightly increased risk of preterm birth.  However, 17OHPC prevented preterm birth comparably, regardless of baseline salivary hormone concentrations.  Thus, salivary P or E3 does not appear to predict preterm birth.

Groschl (2008) provided an overview of the current applications of salivary hormone analysis.  The author noted that although saliva has not yet become a mainstream sample source for hormone analysis, it has proven to be reliable and, in some cases, even superior to other body fluids.  Nevertheless, much effort will be needed for this approach to receive acceptance over the long-term, especially by clinicians.  Such effort entails the development of specific and standardized analytical tools, the establishment of defined reference intervals, and implementation of round-robin trials.  One major obstacle is the lack of compliance sometimes observed in outpatient saliva donors.  Moreover, the author stated that there is a need for standardization of both collection and analysis methods in order to attain better comparability and evaluation of published salivary hormone data.

Late Night Salivary Cortisol

Cushing’s Disease is characterized by abnormal accumulations of facial and trunk fat, fatigue, hypertension and osteoporosis, caused by hyperfunction of the adrenal cortex or administration of adrenal cortical hormones.

Measurement of late-night and/or midnight salivary cortisol currently used in the United States and European countries is a simple and convenient screening test for the initial diagnosis of Cushing's syndrome (CS).  Salivary hormone testing for cortisol may be utilized as part of a two-step process to screen for and diagnose Cushing’s disease. If screening tests are positive, confirmatory tests are then performed. Initial testing could include urine cortisol or late night salivary cortisol. Secondary testing may also include one of these tests or a blood test. 

Carroll et al (2008) stated that making a definite diagnosis of CS is a challenging problem.  Unsuspected CS occurs in 2 to 3 % of patients with poorly controlled diabetes, 0.5 to 1 % with hypertension, 6 to 9 % with incidental adrenal masses, and 11 % with unexplained osteoporosis and vertebral fractures.  The increasing recognition of this syndrome highlights the need for a simple, sensitive, and specific diagnostic test.  Patients with CS consistently do not reach a normal nadir of cortisol secretion at night.  The measurement of late-night salivary cortisol levels might, therefore, provide a new diagnostic approach for this disorder.  Salivary cortisol concentrations reflect those of active free cortisol in plasma and saliva samples can easily be obtained in a non-stressful environment (e.g., at home).  Late-night salivary cortisol measurement yields excellent overall diagnostic accuracy for CS, with a sensitivity of 92 to 100 % and a specificity of 93 to 100 %.  Several factors can, however, make interpretation of results difficult; these factors include disturbed sleep-wake cycles, contamination of samples (particularly by topical corticosteroids), and illnesses known to cause physiologic activation of the pituitary-adrenal axis.

Elamin et al (2008) summarized the evidence on the accuracy of common tests for diagnosing CS.  These investigators searched electronic databases (Medline, Embase, Web of Science, Scopus, and citation search for key articles) from 1975 through September 2007 and sought additional references from experts.  Eligible studies reported on the accuracy of urinary free cortisol (UFC), dexamethasone suppression test (DST), and midnight cortisol assays versus reference standard in patients suspected of CS.  Reviewers working in duplicate and independently extracted study characteristics and quality and data to estimate the likelihood ratio (LR) and the 95 % confidence interval (CI) for each result.  These researchers found 27 eligible studies, with a high prevalence [794 (9.2 %) of 8,631 patients had CS] and severity of CS.  The tests had similar accuracy: UFC (n = 14 studies; LR+ 10.6, CI: 5.5 to 20.5; LR- 0.16, CI: 0.08 to 0.33), salivary midnight cortisol (n = 4; LR+ 8.8, CI: 3.5 to 21.8; LR- 0.07, CI: 0 to 1.2), and the 1-mg overnight DST (n = 14; LR+ 16.4, CI: 9.3 to 28.8; LR- 0.06, CI: 0.03 to 0.14).  Combined testing strategies (e.g., a positive result in both UFC and 1-mg overnight DST) had similar diagnostic accuracy (n = 3; LR+ 15.4, CI: 0.7 to 358; LR- 0.11, CI: 0.007 to 1.57).  The authors concluded that commonly used tests to diagnose CS appear highly accurate in referral practices with samples enriched with patients with CS.

Doi et al (2008) assessed the usefulness of the measurement of late-night salivary cortisol as a screening test for the diagnosis of CS in Japan.  These investigators studied 27 patients with various causes of CS, consisting of  ACTH-dependent Cushing's disease (n = 5) and ectopic ACTH syndrome (n = 4) and ACTH-independent adrenal CS (n = 11) and subclinical CS (n = 7).  Eleven patients with type 2 diabetes and obesity and 16 normal subjects served as control group.  Saliva samples were collected at late-night (23:00) in a commercially available device and assayed for cortisol by radioimmunoassay.  There were highly significant correlations (p < 0.0001) between late-night serum and salivary cortisol levels in normal subjects (r = 0.861) and in patients with CS (r = 0.788).  Late-night salivary cortisol levels in CS patients (0.975 +/- 1.56 microg/dL) were significantly higher than those in normal subjects (0.124 +/- 0.031 microg/dL) and in obese diabetic patients (0.146 +/- 0.043 microg/dL), respectively.  Twenty-five out of 27 CS patients had late-night salivary cortisol concentrations greater than 0.21 microg/dL, whereas those in control group were less than 0.2 microg/dL.  Receiver operating characteristic curve (ROC) analysis showed that the cut-off point of 0.21 microg/dL provides a sensitivity of 93 % and a specificity of 100 %.  The authors concluded that the measurement of late-night salivary cortisol is an easy and reliable non-invasive screening test for the initial diagnosis of CS, especially useful for large high-risk populations, such as diabetes and obesity.

The Endocrine Society's clinical practice guideline on the diagnosis of CS (Nieman et al, 2008) stated that after excluding exogenous glucocorticoid use, testing for CS in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and patients with adrenal incidentaloma is recommended.  It recommends the initial use of one test with high diagnostic accuracy such as urine cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-hr DST.  The guideline also recommends that patients with an abnormal result see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone-corticotropin-releasing hormone test.  Patients with concordant abnormal results should undergo testing for the cause of Cushing's syndrome.  Patients with concordant normal results should not undergo further evaluation.  The guideline also recommends additional testing in patients with discordant results, normal responses suspected of cyclic hypercortisolism, or initially normal responses who accumulate additional features over time.

Knorr et al (2010) examined if salivary cortisol differs for patients with depression and control persons.  These investigators performed a systematic review with sequential meta-analysis and meta-regression according to the PRISMA Statement based on comprehensive database searches for studies of depressed patients compared to control persons in whom salivary cortisol was measured.  A total of 20 case-control studies, including 1,354 patients with depression and 1,052 control persons were identified.  In a random-effects meta-analysis salivary cortisol was increased for depressed patients as compared to control persons on average 2.58 nmol/L (95 % CI: 0.95 to 4.21; p = 0.002) in the morning and on average 0.27 nmol/L (95 % CI: 0.03 to 0.51; p=0.03) in the evening.  In a fixed-effects model the mean difference was 0.58 nmol/L (95 % CI).  Study sequential cumulative meta-analyses suggested random error for the finding of this rather small difference between groups.  The reference intervals for morning salivary cortisol in depressed patients (0 to 29 nmol/L) and control persons (1 to 23 nmol/L) showed substantial overlap suggesting lack of discriminative capacity.  These results should be interpreted with caution as the heterogeneity for the morning analysis was large and a funnel plot, suggested presence of bias.  Further, in meta-regression analyses higher intra-assay coefficients of variation in cortisol kits (p = 0.07) and mean age (p = 0.08) were associated with a higher mean difference of morning salivary cortisol between depressed and controls, while gender and depression severity were not.  The authors concluded that based on the available studies, there is not firm evidence for a difference of salivary cortisol in depressed patients and control persons and salivary cortisol is unable to discriminate between persons with and without depression.

Monteleone and colleagues (2011) noted that the stress response involves the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS).  As a role for stress in determining of the onset and the natural course of eating disorders has been proposed, the study of the psychobiology of the stress response in patients with anorexia nervosa (AN) and bulimia nervosa (BN) should be helpful in understanding the pathophysiology of these disorders.  The 2 neurobiological components of the stress response can be easily explored in humans by the measurement of salivary cortisol and α-amylase response to a stressor.  Thus, these researchers assessed salivary cortisol and α-amylase responses to the Trier Social Stress Test (TSST) in symptomatic patients with AN (n = 7) and BN (n = 8) compared to age-matched healthy females (n = 8).  Subjects underwent the TSST between 1530 and 1700 hr.  Salivary cortisol and α-amylase levels were measured by an enzyme-linked immunosorbent assay (ELISA).  Compared to healthy women, AN patients showed a normal cortisol response to the TSST, although this occurred at significantly increased hormone levels, and an almost complete absence of response of α-amylase.  BN women, however, exhibited enhanced pre-stress levels of salivary α-amylase but a normal response of the enzyme and cortisol to the TSST.  The authors concluded that these findings demonstrated, for the first time, the occurrence of an asymmetry between the HPA axis and SNS components of the stress response in the acute phase of AN but not in BN.  Moreover, they stated that pathophysiological significance of this asymmetry remains to be determined.

Kamali and associates (2012) compared HPA axis activity in bipolar individuals with and without suicidal behavior and unaffected healthy controls through measurement of salivary cortisol.  Salivary cortisol was collected for 3 consecutive days in 29 controls, 80 bipolar individuals without a history of suicide and 56 bipolar individuals with a past history of suicide.  Clinical factors that affect salivary cortisol were also examined.  A past history of suicide was associated with a 7.4 % higher bedtime salivary cortisol level in bipolar individuals.  There was no statistical difference between non-suicidal bipolar individuals and controls in bedtime salivary cortisol, and awakening salivary cortisol was not different between the 3 groups.  The authors concluded that bipolar individuals with a past history of suicidal behavior exhibit hyperactivity in the HPA axis.  This biological marker remains significant regardless of demographic factors, mood state, severity and course of illness.  This finding in bipolar disorder is consistent with the evidence for altered HPA axis functioning in suicide and mood disorders and is associated with a clinical subgroup of bipolar patients at elevated risk for suicide based on their history, and in need of further attention and study.  The drawbacks of this study were
  1. measure of salivary cortisol was a home-based collection by the study subjects, and
  2. the retrospective clinical data was primarily based on their historical account.

Salivary Test for Bioidentical Hormone Therapy

The American Association of Clinical Endocrinologists (AACE) Reproductive Medicine Committee’s position statement on bioidentical hormones (2007) noted that “Salivary hormone level testing is recommended by many BH proponents as a way of providing patients with “individualized” therapy.  Such tests are available to consumers over the Internet.  Some of the websites include elaborate questionnaires supposedly designed to establish the type of saliva testing needed.  The results of these tests are subsequently used to determine the type and dosage of compounded formulations.  Only a few types of salivary hormone testing methods are FDA/CLIA approved.  In fact, the vast majority of the salivary hormone tests results contain the disclaimer that those tests are not FDA/CLIA approved and should be used only for research purposes.  Yet such tests are still utilized to support clinical decisions by some supporters of BH …. the limited research, although interesting, does not prove that salivary testing can be used as reliable ancillary tests for clinical purposes …. the evidence often quoted by Salivary Test promoters simply do not pass the muster of the level 1 or even 2 of the Level of Evidences (LOE) as endorsed by AACE ”.

The North American Menopause Society’s position statement on “Hormone Therapy” (2012) stated that “Use of BHT (bioidentical hormone therapy) has escalated in recent years, along with the use of salivary hormone testing, which has been proven to be inaccurate and unreliable …. The Food and Drug Administration also states that there is no scientific basis for using saliva testing to adjust hormone levels”.

Salivary Testing for Anti-Tissue Transglutaminase

Bonamico et al (2011) stated that the high prevalence of celiac disease (CD) prompted them to evaluate a new, non-invasive disease screening strategy.  The aim was to identify CD in 6- to 8-year old children for a timely diagnosis, start gluten-free diet (GFD) in compliant subjects, achieve the growth target, and prevent CD complications.  A total of 5,0000 subjects were invited to participate in the study; 4,048 saliva samples were tested for anti-tissue transglutaminase (tTG) immunoglobulin (Ig)A using a fluid-phase radioimmunoprecipitation method.  Positive children were tested for serum radioimmunoassay tTG IgA, ELISA tTG IgA, and anti-endomysium IgA.  Children confirmed as positive by serum assays underwent endoscopy with duodenal biopsies and, at the diagnosis of CD, were suggested to start GFD.  Consent was obtained from 4,242 parents (84.8 %) for the screening to be performed, and adequate saliva samples were collected from 4,048 children (95.4 %).  Thirty-two children were found to be salivary tTG IgA positive and 9 with borderline autoantibody levels; 31 of the 32 and 3 of the 9 subjects were also serum positive.  Twenty-eight children showed villous atrophy when undergoing intestinal biopsy, whereas 1 had Marsh 1 lesions; 3 children were suggested to start GFD without performing endoscopy.  Celiac disease prevalence in the population investigated (including 19 CD known cases) was 1.16 %.  The ratio between screening-detected patients and those diagnosed before the screening was 3:2.  The ratio between symptomatic and asymptomatic patients was 1:1.6.  The authors concluded that it is possible to perform a simple and sensitive CD screening using saliva.

However, the American College of Gastroenterology’s clinical guideline on “Diagnosis and management of celiac disease” (Rubio-Tapia et al, 2013) stated that “Stool studies or salivary tests are neither validated nor recommended for use in the diagnosis of CD”

Salivary Tests of Cortisol for Diagnosis of Adrenal Insufficiency in Preterm Infants

Maas and colleagues (2014)
  1. examined the relationship of salivary and plasma cortisol levels in preterm infants with a focus on the usability of salivary cortisol in diagnostic work-up of infants at risk of adrenal insufficiency, and
  2. performed a systematic review addressing this question.

These researchers conducted a prospective observational single-center study in preterm infants.  They analyzed plasma and saliva cortisol concentrations by enzyme immunoassay.  Correlation analysis was used to determine the relation between salivary and plasma cortisol levels and the agreement of the measurement methods was analyzed according to Bland-Altman.  Furthermore, these investigators performed a systematic literature search (PubMed and Embase) on the relationship of salivary and plasma cortisol levels in neonates.  These researchers enrolled 58 preterm infants (median (inter-quartile range [IQR]) gestational age at birth was 31.4 (28.1 to 32.7) weeks, birth weight 1,340 (974 to 1,745) g, respectively).  Correlation analyses revealed a relationship of plasma cortisol and salivary cortisol levels.  Rank correlation coefficient was 0.6.  Estimating plasma cortisol levels based on measured salivary cortisol levels showed poor agreement of the 2 methods for determining plasma cortisol levels (direct and via salivary cortisol).  Sensitivity and specificity of salivary cortisol for the detection of adrenal insufficiency were 0.66 and 0.62, respectively.  A total of 6 studies in preterm infants and term neonates depicting the correlation of salivary and plasma cortisol were identified with a range of saliva-plasma correlation coefficients from 0.44 to 0.83.  The authors concluded that substitution of plasma cortisol by salivary cortisol determination cannot be recommended in preterm infants because of unsatisfactory agreement between methods.

Salivary Testing of Mutans Streptococci for Risk Assessment of Dental Caries

Senneby et al (2015) evaluated the accuracy of different methods used to identify individuals with increased risk of developing dental coronal caries. Studies on following methods were included: Previous caries experience, tests using microbiota, buffering capacity, salivary flow rate, oral hygiene, dietary habits and socio-demographic variables.  QUADAS-2 was used to assess risk of bias.  Sensitivity, specificity, predictive values, and likelihood ratios (LR) were calculated.  Quality of evidence based on greater than or equal to3 studies of a method was rated according to GRADE.  PubMed, Cochrane Library, Web of Science and reference lists of included publications were searched up to January 2015.  From 5,776 identified articles, 18 were included.  Assessment of study quality identified methodological limitations concerning study design, test technology and reporting.  No study presented low risk of bias in all domains; 3  or more studies were found only for previous caries experience and salivary mutans streptococci and quality of evidence for these methods was low.  Evidence regarding other methods was lacking.  For previous caries experience, sensitivity ranged between 0.21 and 0.94 and specificity between 0.20 and 1.  Tests using salivary mutans streptococci resulted in low sensitivity and high specificity.  For children with primary teeth at baseline, pooled LR for a positive test was 3 for previous caries experience and 4 for salivary mutans streptococci, given a threshold greater than or equal to 10(5) colony forming unit (CFU)/ml.  The authors concluded that the evidence on the validity of analyzed methods used for caries risk assessment is limited.  As methodological quality was low, there is a need to improve study design.

Measurement of Diurnal Salivary Cortisol Patterns for Prediction of Infant Birth Weight

Guardino and colleagues (2016) noted that elevated maternal psychosocial stress during pregnancy and accompanying changes in stress hormones may contribute to risk of adverse birth outcomes such as low birth weight and preterm birth.  Relatedly, research on fetal programming showed intriguing associations between maternal stress processes during pregnancy and outcomes in offspring that extend into adulthood.  These researchers  examined if HPA patterns in mothers during the period between 2 pregnancies (i.e., the inter-pregnancy interval) and during the subsequent pregnancy predict infant birth weight.  This study sampled salivary cortisol before and during pregnancy in a diverse community sample of 142 women enrolled in the Community Child Health Network study.  Using multi-level modeling, these investigators found that flatter diurnal cortisol slopes in mothers during the interval between one birth and a subsequent pregnancy predicted lower infant birth weight of the subsequent child.  This inter-pregnancy cortisol pattern in mothers also correlated with significantly shorter inter-pregnancy intervals, such that women with flatter cortisol slopes had more closely spaced pregnancies.  After adding demographic co-variates of household income, cohabitation with partner, and maternal race to the model, these results were unchanged.  For subjects who provided both inter-pregnancy and pregnancy cortisol data (n = 73), these researchers found that inter-pregnancy cortisol slopes predicted infant birth weight independent of pregnancy cortisol slopes.  The authors concluded that the these novel findings on inter-pregnancy HPA axis function and subsequent pregnancy outcomes supported life course health approaches and underscored the importance of maternal stress physiology between pregnancies.  The clinical value of measurement of diurnal salivary cortisol patterns for prediction of infant birth weight needs to be validated by well-designed studies.

Salivary Testing of Biomarkers for the Diagnosis of Cancers

Breast Cancer

Porto-Mascarenhas and colleagues (2017) assessed the capability of salivary biomarkers in the diagnosis and monitoring of breast cancer (BC).  Studies were eligible for inclusion if they evaluated the potential diagnostic value or other discriminatory properties of biomarkers in saliva of patients with BC.  The search was performed in 6 electronic databases (Cochrane, LILACS, PubMed, Science Direct, Scopus, Web of Science).  In addition, the biomarkers were classified according to their potential clinical application.  These researchers identified 567 pertinent studies, of which 13 met the inclusion criteria.  Combined biomarker approaches demonstrated better ability to predict BC patients than individual biomarkers.  As single biomarker, namely proline, reported great capacity in both early and late stage BC diagnosis; taurine showed interesting capability to identify early BC individuals.  Furthermore, valine also demonstrated excellent diagnostic test accuracy for advanced stages of BC.  Only 7 studies reported sensitivity and specificity, which varied considerably from 50 % to 100 %, and from 51 % to 97 %, respectively.  In general, salivary biomarkers identified advanced stages BC better than early stages.  The authors concluded that there is currently limited evidence to confirm the putative implementation of salivary biomarkers as diagnostic tools for BC; however, this review provided new research directions.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Breast cancer” (Version 2.2017) does not mention testing of salivary biomarkers as a management tool.

Head and Neck Carcinoma

In a systematic review and meta-analysis, Guerra and associates (2015) evaluated the diagnostic value of salivary biomarkers in the diagnosis of head and neck carcinoma (HNC).  Studies were gathered by searching Cochrane, Embase, LILACS, Medline, and PubMed.  The references were also cross-checked and a partial grey literature search was undertaken using Google Scholar.  The methodology of selected studies was evaluated using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies.  After a 2-step selection process, 15 articles were identified and subjected to qualitative and quantitative analyses.  The studies were homogeneous, and all had high methodological quality.  Combined biomarkers demonstrated better accuracy with higher sensitivity and specificity than those tested individually.  Furthermore, the salivary biomarkers reviewed predicted the early stages of HNC better than the advanced stages.  A restricted set of 5 single biomarkers (interleukin-8 [IL-8], choline, pipecolinic acid, l-phenylalanine, and S-carboxymethyl-l-cysteine) as well as combined biomarkers demonstrated excellent diagnostic test accuracy.  The authors concluded that the present systematic review confirmed the potential value of a selected set of salivary biomarkers as diagnostic tools for HNC.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Head and neck cancers” (Version 2.2017) does not mention testing of salivary biomarkers as a management tool.

Oral Pre-Cancer and Oral Squamous Cell Carcinoma

Punyani and SathawaPe (2013) noted that due to the pro-angiogenic characteristic of interleukin 8 (IL-8), it may play a vital role in tumor angiogenesis and progression.  These researchers estimated the levels of salivary IL-8 in oral pre-cancer and oral squamous cell carcinoma (OSCC) patients and compared them with healthy controls.  The aim was to evaluate its effectiveness as a potential biomarker for these diseases.  Each group comprised 25 individuals.  The salivary IL-8 levels were determined by ELISA.  The levels of salivary IL-8 were found to be significantly elevated in patients with OSCC as compared to the pre-cancer group (p < 0.0001) and healthy controls (p < 0.0001).  However, the difference in salivary IL-8 concentrations among the pre-cancer group and controls was statistically non-significant (p = 0.738).  The authors concluded that these findings suggested that salivary IL-8 can be utilized as a potential biomarker for OSCC.  Salivary IL-8 was found to be non-conclusive for oral pre-malignancy in this preliminary study.  Hence, its possible role in transition from pre-malignancy to malignancy needs further research with larger sample sizes.  They stated that the role of IL-8 in oral cancer if validated further by future research can provide an easy diagnostic test as well as a prognostic indicator for patients undergoing treatment.  Thus, if the role of Il-8 in tumor genesis can be sufficiently assessed, it could open up new avenues to find out novel treatment modalities for oral cancer.

Rajkumar et al (2015) stated that CYFRA 21-1, a constituent of the intermediate filament proteins of epithelial cells, is known to be increased in many cancers.  These investigators estimated the levels of salivary and serum CYFRA 21-1 in patients with oral pre-cancer and OSCC and compared them with healthy controls.  Each group comprised of 100 subjects.  Saliva and blood samples were collected from patients with OSCC, pre-malignant (PML) subjects, and normal healthy subjects.  Serum and salivary CYFRA 21-1 levels were measured by ELISA.  Appropriate statistical tests were employed to assess diagnostic potency of CYFRA 21-1.  These researchers found a significant increase in CYFRA 21-1 level in OSCC compared with PML and healthy subjects.  Salivary CYFRA 21-1 levels in OSCC was 3-fold higher when compared to serum levels.  Pre-malignant group showed increased salivary CYFRA 21-1 when compared to control subjects, but it was significantly lower compared with OSCC.  Receiver operator characteristic curve analysis showed salivary CYFRA 21-1 to have superior sensitivity in detecting OSCC compared with serum CYFRA 21-1.  The authors concluded that the outcome of this study suggested that salivary CYFRA 21-1 can be utilized as a biomarker in early detection of oral cancer.  These findings need to be validated by well-designed studies.

Cheng and colleagues (2014) gathered preliminary data concerning the feasibility of using 7 salivary mRNAs: IL-8; IL-1β; dual specificity phosphatase 1 (DUSP1); H3 histone family 3A (H3F3A); ornithin decarboxylase antizyme 1 (OAZ1); S100 calcium-binding protein P (S100P); and spermidine/spermine N1-acetyltransferase 1 (SAT1) for detecting development of OSCC in oral lichen planus (OLP) patients and OSCC patients whose disease was in remission.  Saliva samples were collected from 5 study groups (25 subjects per group): newly diagnosed OSCC, OSCC-in-remission, disease-active OLP, disease-inactive OLP, and normal controls.  The salivary mRNA levels were determined by a pre-amplification reverse transcription quantitative polymerase chain reaction (RT-qPCR) approach with nested gene-specific primers.  Mean fold changes between each pair of study groups were analyzed by the Mann-Whitney U test.  Salivary levels of OAZ1, S100P, and DUSP1 mRNAs were significantly higher in newly diagnosed OSCC patients, compared to:
  1. normal controls (p = 0.003; p = 0.003; and p < 0.001, respectively);
  2. OSCC-in-remission (p < 0.001; p = 0.001; and p < 0.001, respectively);
  3. disease-active OLP (p < 0.001; p = 0.016; and p < 0.001, respectively); and
  4. disease-inactive OLP (p = 0.043; p < 0.001; and p < 0.001, respectively).

No significant differences were found in the levels of salivary IL-8, IL-1β, H3F3A, and SAT1 mRNAs between newly diagnosed OSCC patients and the normal controls (p = 0.093, 0.327, 0.764, and 0.560, respectively).  The authors concluded that salivary OAZ1, S100P, and DUSP1 mRNAs are candidate biomarkers for detecting OSCC development in OSCC patients in remission and in OLP patients.  Moreover, they state that these findings serve as the basis for a further large-scale study that may lead to a non-invasive screening method for early detection of OSCC.

Furthermore, an UpToDate review on “Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma” (DeSimone et al, 2014) does not mention salivary testing of CYFRA 21-1, IL-8, or mRNAs of DUSP1, OAZ1, and S100P, as a management tool.

Novy et al (2014) noted that the use of saliva as a diagnostic fluid has the potential to shape the role of oral health care professionals in the health care system.  While more than a handful of chair-side diagnostic tests are available for use by private practitioners, the evidence supporting their use continues to emerge.  These investigators performed an electronic search of the literature indexed on the PubMed electronic database to identify human clinical trials utilizing commercially available salivary diagnostics.  Papers meeting the inclusion criteria, and any applicable references were critically appraised following Strength of Recommendation Taxonomy (SORT) guidelines.  The authors concluded that while the literature concerning salivary analysis is continuously growing, the limited literature that is available doesn't focus on patient oriented health outcomes.  This “infant” literature is focused on validating metrics and identifying biomarkers with diagnostic potential.  As such, the evidence level of the literature is graded as level 3.  The authors stated that despite the lower grade, the research in this area showed consistent results, coherent conclusions, and research identifying new biomarkers will provide additional dimensions to salivary diagnostics.

Macey et al (2015) stated that oral squamous cell carcinoma is the most common form of malignancy of the lip and oral cavity, often being preceded by potentially malignant disorders (PMD).  Early detection can reduce the malignant transformation of PMD and can improve the survival rate for oral cancer.  The current standard of scalpel biopsy with histology is painful for patients and involves a delay while histology is completed; other tests are available that are unobtrusive and provide immediate results.  Ina Cochrane review, these investigators estimated the diagnostic accuracy of index tests for the detection of oral cancer and PMD of the lip and oral cavity, in people presenting with clinically evident lesions.  They also estimated the relative accuracy of the different index tests.  The electronic databases were searched on April 30, 2013.  These investigators searched MEDLINE (OVID) (1946 to April 2013) and 4 other electronic databases (the Cochrane Diagnostic Test Accuracy Studies Register, the Cochrane Oral Health Group's Trials Register, EMBASE (OVID) and MEDION (Ovid)).  There were no restrictions on language in the searches of the electronic databases.  They conducted citation searches and screened reference lists of included studies for additional references.  These researchers selected studies that reported the diagnostic test accuracy of the following index tests when used as an adjunct to conventional oral examination in detecting PMD or oral squamous cell carcinoma of the lip or oral cavity: vital staining, oral cytology, light-based detection and oral spectroscopy, blood or saliva analysis (which test for the presence of biomarkers in blood or saliva).  Two review authors independently screened titles and abstracts for relevance.  Eligibility, data extraction and quality assessment were carried out by at least 2 authors, independently and in duplicate.  Studies were assessed for methodological quality using QUADAS-2.  Meta-analysis was used to combine the results of studies for each index test using the bivariate approach to estimate the expected values of sensitivity and specificity.  The authors included 41 studies, recruiting 4,002 participants, in this review.  These studies evaluated the diagnostic accuracy of conventional oral examination with: vital staining (14 studies), oral cytology (13 studies), light-based detection or oral spectroscopy (13 studies).  Six studies assessed 2 combined index tests.  There were no eligible diagnostic accuracy studies evaluating blood or salivary sample analysis.  The summary estimates for vital staining obtained from the meta-analysis were sensitivity of 0.84 (95 % CI: 0.74 to 0.90) with specificity of 0.70 (95 5 CI: 0.59 to 0.79), with 14 studies were included in the meta-analysis.  For cytology, sensitivity was 0.91 (95 % CI: 0.81 to 0.96) and specificity was 0.91 (95 5 CI: 0.81 to 0.95) with 12 studies included in the meta-analysis.  For light-based detection, sensitivity was 0.91 (95 5 CI: 0.77 to 0.97) and specificity was 0.58 (95 5 CI: 0.22 to 0.87) with 11 studies included in the meta-analysis.  The relative test accuracy was assessed by adding covariates to the bivariate analysis, no difference in model fit was observed.  The authors concluded that the overall quality of the included studies was poor.  None of the adjunctive tests can be recommended as a replacement for the currently used standard of a scalpel biopsy and histological assessment.  They stated that given the relatively high values of the summary estimates of sensitivity and specificity for cytology, this would appear to offer the most potential; and combined adjunctive tests involving cytology warrant further investigation.

In a systematic review, Gualtero and Suarez Castillo (2016) examined the capacity of salivary biomarkers in the early diagnosis of oral squamous cell carcinoma (SCC).  These investigators performed a systematic review of the literature based on the English titles listed in the PubMed, EBSCO, Cochrane, Science Direct, ISI web Science and SciELO databases using the following search descriptors: Oral cancer, diagnosis, biomarkers, saliva and oral squamous cell carcinoma.  Abstracts and full-text articles were assessed independently by 2 reviewers.  International check-lists for assessment of methodological quality were used.  Levels of evidence and grades of recommendation through the Scottish Intercollegiate Guidelines Network (SIGN) template were recognized.  The units of analysis were identified through a reference matrix.  Through the research strategy and after application of different filters and considering choosing criteria, a total of 6 studies were obtained for analysis.  Salivary biomarkers for oral cancer most frequently found were mRNA and proteins for IL-8, CD44 (a cell-surface glycoprotein), matrix metalloproteinase-1 (MMP-1) and MMP-3.  New peptide-biomarkers such as Cyfra 21-1 and zinc finger protein 510 (ZNF510) were found; ZNF 510 was the only biomarker that increased in the population with tumor stage T1 + T2 and T3 + T4.  Only 1 study showed a sensitivity and specificity of 96 % when the biomarker ZNF 510 was employed to discriminate early and late tumor stages.  The authors concluded that there is insufficient evidence to support the use of the identified salivary biomarkers for the early diagnosis of oral cancer (sub-clinical stages of the pathogenic period before cancer phenotypes are manifested).

Salivary Testing of Pepsin for the Diagnosis of  Gastro-Esophageal Reflux Disease

Dy and colleagues (2016) examined the sensitivity of salivary pepsin compared with multi-channel intraluminal impedance with pH testing (pH-MII), endoscopy, and gastro-esophageal reflux disease (GERD) questionnaires.  These investigators prospectively recruited 50 children from Boston Children's Hospital who were undergoing pH-MII to evaluate for GERD.  Subjects completed 24-hour pH-MII testing, completed symptom and quality of life (QOL) questionnaires, and provided a saliva specimen that was analyzed using the PepTest lateral flow test.  A subset of patients also underwent bronchoscopy and esophago-gastro-duodenoscopy (EGD); receiver operating characteristic curve (ROC) analyses were performed to determine the sensitivity of salivary pepsin compared with each reference standard; 21 of the 50 patients (42 %) were salivary pepsin-positive, with a median salivary pepsin concentration of 10 ng/ml (IQR, 10 to 55 ng/ml).  There was no significant difference in the distributions of acid, non-acid, total reflux episodes, full column reflux, or any other reflux variable in patients who were pepsin-positive compared with those who were pepsin-negative (p > 0.50).  There was no significant correlation between the number of reflux episodes and pepsin concentration (p > 0.10).  There was no positive relationship between salivary pepsin positivity, any extra-esophageal symptoms or QOL scores, or inflammation on bronchoscopy or EGD (p > 0.30).  The authors concluded that salivary pepsin measurement had a low sensitivity for predicting pathological GERD in children.

Salivary Testing of Telomere Length for the Diagnosis of Depression

Whisman and Richardson (2017) examined the association between depressive symptoms and salivary telomere length in a probability sample of middle-aged and older adults, and evaluated age and sex as potential moderators of this association and examined if this association was incremental to potential confounds.  Subjects were 3,609 individuals from the 2008 wave of the Health and Retirement Study; telomere length assays were performed using quantitative real-time polymerase chain reaction (qRT-PCR) on DNA extracted from saliva samples.  Depressive symptoms were assessed via interview, and health and lifestyle factors, traumatic life events, and neuroticism were assessed via self-report.  Regression analyses were conducted to examine the associations between predictor variables and salivary telomere length.  After adjusting for demographics, depressive symptoms were negatively associated with salivary telomere length (b = -0.003; p = 0.014).  Furthermore, this association was moderated by sex (b = 0.005; p = 0.011), such that depressive symptoms were significantly and negatively associated with salivary telomere length for men (b = - 0.006; p < 0.001); but not for women (b = - 0.001; p = 0.644).  The negative association between depressive symptoms and salivary telomere length in men remained statistically significant after additionally adjusting for cigarette smoking, body mass index (BMI), chronic health conditions, childhood and lifetime exposure to traumatic life events, and neuroticism.  The authors concluded that higher levels of depressive symptoms were associated with shorter salivary telomeres in men, and this association was incremental to several potential confounds.  They stated that shortened telomeres may help account for the association between depression and poor physical health and mortality.

Cordant Health Solutions Comprehensive Oral Fluid Rx Evaluation (CORE)

Cordant Health Solutions’ Comprehensive Oral fluid Rx Evaluation (CORE), a new drug testing technology, is designed to correlate drug concentrations in oral fluid with drug levels in blood plasma; it is used for individualized drug testing for pain management.

Borg and colleagues (2017) noted that synthetic cannabinoids are a group of psycho-active compounds that mimic the effects of Δ9-tetrahydrocannabinol, the primary psycho-active constituent of marijuana.  The Drug Enforcement Administration (DEA) has classified many of the most common cannabinoids as Schedule 1 controlled substances.  As a result, several novel synthetic cannabinoid series have emerged in the illicit drug market, including PINACA, FUBINACA, PB-22, AKB-48 and multiple derivatives of these compounds.  The authors’ laboratory developed and validated an analytical method for the analysis 32 synthetic cannabinoid metabolites in urine samples.  Included in this method are metabolites that are constituents of the new generation of synthetic cannabinoids.  Following enzymatic hydrolysis, target analytes were recovered by liquid-liquid extraction utilizing 1-chlorobutane:isopropyl alcohol (70:30) as the organic ratio.  Chromatographic separation and detection was achieved using an Agilent Technologies 1290 liquid chromatograph (LC) coupled to a 6460-triple quadrupole mass spectrometer (MS) with a Jetstream electrospray source.  Linearity for all analytes was established along the range of 0.5 to 200 ng/ml.  Both intra-day and inter-day accuracy as well as precision data were all within acceptable limits, ± 20 % error and ± 15 % relative standard deviation (SD), respectively.  Recovery ranged from 48 % to 104 %.  This method has shown to be selective and specific, providing no evidence of interference or carry-over concerns.  Finally, 11 distinct synthetic cannabinoids were detected in 23 of 25 donor samples analyzed with the method.  The authors concluded that these data represented a validated LC tandem-MS method to accurately identify and quantitate synthetic cannabinoid metabolites in urine samples, incorporating new generation derivatives.

Shaparin and associates (2017) stated that interpretation limitations of urine drug testing and the invasiveness of blood toxicology have motivated the desire for the development of simpler methods to evaluate biologically active drug levels on an individualized patient basis.  Oral fluid is a matrix well-suited for the challenge because collections are based on simple non-invasive procedures and drug concentrations better correlate to blood drug levels as oral fluid is a filtrate of the blood.  Well-established pharmacokinetic models were utilized to generate oral fluid steady state concentration ranges to assess the interpretive value of the alternative matrix to monitor steady state plasma oxycodone levels.  Paired oral fluid and plasma samples were collected from patients chronically prescribed oxycodone and quantitatively analyzed by LC tandem-MS.  Steady state plasma concentration ranges were calculated for each donor and converted to an equivalent range in oral fluid.  Measured plasma and oral fluid oxycodone concentrations were compared with respective matrix-matched steady state ranges, using each plasma steady state classification as the control.  A high degree of correlation was observed between matrices when classifying donors according to expected steady state oxycodone concentration.  Agreement between plasma and oral fluid steady state classifications was observed in 75.6 % of paired samples.  The authors concluded that the findings of this study supported novel application of basic pharmacokinetic knowledge to the pain management industry, simplifying and improving individualized drug monitoring and risk assessment through the use of oral fluid drug testing.  They stated that many benefits of established therapeutic drug monitoring in plasma can be realized in oral fluid for patients chronically prescribed oxycodone at steady state.

There is currently insufficient evidence to support the clinical value of Cordant Health Solutions’ Comprehensive Oral Fluid Rx Evaluation (CORE).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

82530 Cortisol; free [other than late night salivary cortisol for diagnosing Cushing's syndrome]
82533     total [other than late night salivary cortisol for diagnosing Cushing's syndrome]

CPT codes not covered for indications listed in the CPB (not all-inclusive):

0011U Prescription drug monitoring, evaluation of drugs present by LC-MS/MS, using oral fluid, reported as a comparison to an estimated steady-state range, per date of service including all drug compounds and metabolites
82530 Cortisol; free
82533     total
82626 Dehydroepiandrosterone (DHEA)
82627 Dehydroepiandrosterone-sulfate (DHEA-S)
82670 Estradiol
82671 Estrogens; fractionated
82672     total
82677 Estriol
82679 Estrone
83516 Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; qualitative or semiquantitative, multiple step method [salivary testing for anti-tissue transglutaminase for the diagnosis of celiac disease]
83520     quantitative, not otherwise specified [not covered for measurement of salivary level of interleukin-8 as biomarkers for oral pre-cancer and oral squamous cell carcinoma] [not covered for salivary antibody testing (IgA, IgG, IgM) for the diagnosis of Sicca syndrome]
84144 Progesterone
84402 Testosterone; free
84403     total
84436 Thyroxine; total
84437     requiring elution (eg, neonatal)
84439     free
84443 Thyroid stimulating hormone (TSH)
84479 Thyroid hormone (T3 or T4) uptake or thyroid hormone binding ratio (THBR)
84480 Triidothyronine T3; total (TT-3)
84481     free
86316 Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each [not covered for measurement of salivary level of CYFRA 21-1 as biomarkers for oral pre-cancer and oral squamous cell carcinoma]
88341 Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)
88342 Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure
88344 Immunohistochemistry or immunocytochemistry, per specimen; each multiplex antibody stain procedure

HCPCS codes not covered for indications listed in the CPB:

S3650 Saliva test, hormone level; during menopause

ICD-10 codes covered if selection criteria are met:

E24.0 - E24.9 Cushing's syndrome

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C00.0 - C10.9 Malignant neoplasm of lip and oral cavity [oral squamous cell carcinoma]
C44.02 Squamous cell carcinoma of skin of lip
E27.0 - E27.9 Other disorders of adrenal gland
E28.310 - E28.319 Premature menopause
E89.40 - E89.41 Postprocedural ovarian failure
E89.6 Postprocedural adrenocortical (-medullary) hypofunction
F30.10 - F30.9 Manic episode
F31.0 - F31.9 Bipolar disorder
F32.0 - F32.9 Major depressive disorder, single episode
F33.3 Major depressive disorder, recurrent, severe with psychotic symptoms
F34.1 Dysthymic disorder
F50.00 - F50.02 Anorexia nervosa
F50.2 - F50.9 Other eating disorders [bulimia nervosa, Pica, unspecified]
K13.21 Leukoplakia of oral mucosa, including tongue
K13.29 Other disturbances of oral epithelium, including tongue
K90.0 Celiac disease
M35.00 - M35.09 Sicca syndrome [Sjögren]
M80.00x+ - M81.8 Osteoporosis
N92.4 Excessive bleeding in the premenopausal period
N95.0 - N95.9 Menopausal and other perimenopausal disorders
O09.00 - O31.8X99 Pregnancy [prediction of infant birth weight]
P07.00 - P0739 Immaturity of newborn
Z01.20 Encounter for dental examination and cleaning without abnormal findings
Z01.21 Encounter for dental examination and cleaning with abnormal findings
Z12.0 - Z12.9 Encounter for screening for malignant neoplasms
Z13.810 - Z13.818 Encounter for screening for digestive system disorders [diagnosis of gastro-esophageal reflux disease]
Z13.820 Encounter for screening for osteoporosis
Z13.84 Encounter for screening for dental disorders
Z13.850 - Z13.858 Encounter for screening for nervous system disorders [diagnosis of depression]
Z78.0 Asymptomatic menopausal state
Z79.890 Hormone replacement therapy (postmenopausal)

The above policy is based on the following references:

  1. American Association of Clinical Endocrinologists (AACE). Medical guidelines for clinical practice for management of menopause. Endocrine Pract. 1999;5:355-366. Available at: http://www.aace.com/clin/guides/menopause.pdf. Accessed February 15, 2002.
  2. Hodgson SF, Watts NB, Bilezikian JP, et al. .American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract. 2003;9(6):544-564..
  3. AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8(6):457-469..
  4. Huppert FA, Van Niekerk JK. Dehydroepiandrosterone (DHEA) supplementation for cognitive function. Cochrane Database Syst Rev. 2006:(2):CD000304.
  5. Grimley Evans J, Malouf R, Huppert F, van Niekerk JK. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people. Cochrane Database Syst Rev. 2006;(4):CD006221.
  6. Herbert V, Kava R. The miracle of melatonin? Priorities (American Council on Science and Health). 1995;7(4). Available at: http://www.hcrc.org/contrib/acsh/articles/melaton.html. Accessed February 15, 2002.
  7. No authors listed. Melatonin: Interesting, but not miraculous. Prescrire Int. 1998;7(38):180-187.
  8. Contreras LN, Arregger AL, Persi GG, et al. A new less-invasive and more informative low-dose ACTH test: Salivary steroids in response to intramuscular corticotrophin. Clin Endocrinol (Oxf). 2004;61(6):675-682.
  9. No authors listed. Chronic hypoadrenalism. GPNotebook. General Practitioner Notebook. Warwickshire, UK: Oxbridge Solutions, Ltd.; 2005. Available at: http://www.gpnotebook.co.uk/simplepage.cfm?ID=2127560704. Accessed September 16, 2005.
  10. Odeke S, Nagelberg SB. Addison disease. eMedicine Endocrinology Topic 42. Omaha, NE: eMedicine.com; updated November 25, 2003. Available at: http://www.emedicine.com/med/topic42.htm. Accessed September 16, 2005.
  11. Rubin GJ, Hotopf M, Papadopoulos A, Cleare A. Salivary cortisol as a predictor of postoperative fatigue. Psychosom Med. 2005;67(3):441-447.
  12. American College of Obstetricians and Gynecologists (ACOG) Committee on Gynecologic Practice. ACOG Committee Opinion #322: Compounded bioidentical hormones. Obstet Gynecol. 2005;106(5 Pt 1):1139-1140.
  13. National Institutes of Health (NIH). NIH State-of-the-Science Conference Statement on Management of Menopause-Related Symptoms. NIH Consensus and State-of-the-Science Statements. Bethesda, MD: NIH: March 21-23; 22(1). 
  14. Institute for Clinical Systems Improvement (ICSI). Menopause and hormone therapy (HT): Collaborative decision-making and management. Bloomington, MN: ICSI; October 2006.
  15. The North American Menopause Society. The role of testosterone therapy in postmenopausal women: Position statement of The North American Menopause Society. Menopause. 2005;12(5):497-511.
  16. Carroll T, Raff H, Findling JW. Late-night salivary cortisol measurement in the diagnosis of Cushing's syndrome. Nat Clin Pract Endocrinol Metab. 2008;4(6):344-350.
  17. Elamin MB, Murad MH, Mullan R, et al. Accuracy of diagnostic tests for Cushing's syndrome: A systematic review and metaanalyses. J Clin Endocrinol Metab. 2008;93(5):1553-1562.
  18. Doi M, Sekizawa N, Tani Y, et al. Late-night salivary cortisol as a screening test for the diagnosis of Cushing's syndrome in Japan. Endocr J. 2008;55(1):121-126.
  19. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.
  20. Klebanoff MA, Meis PJ, Dombrowski MP, et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Salivary progesterone and estriol among pregnant women treated with 17-alpha-hydroxyprogesterone caproate or placebo. Am J Obstet Gynecol. 2008;199(5):506.e1-e7.
  21. Gröschl M. Current status of salivary hormone analysis. Clin Chem. 2008;54(11):1759-1769.
  22. Carroll T, Raff H, Findling JW. Late-night salivary cortisol for the diagnosis of Cushing syndrome: A meta-analysis. Endocr Pract. 2009;15(4):335-342.
  23. Raff H. Utility of salivary cortisol measurements in Cushing's syndrome and adrenal insufficiency. J Clin Endocrinol Metab. 2009;94(10):3647-3655.
  24. Flyckt RL, Liu J, Frasure H, Wekselman K, et al. Comparison of salivary versus serum testosterone levels in postmenopausal women receiving transdermal testosterone supplementation versus placebo. Menopause. 2009;16(4):680-688.
  25. Alexandraki KI, Grossman AB. Novel insights in the diagnosis of Cushing's syndrome. Neuroendocrinology. 2010;92 Suppl 1:35-43.
  26. Sereg M, Toke J, Patócs A, et al. Diagnostic performance of salivary cortisol and serum osteocalcin measurements in patients with overt and subclinical Cushing's syndrome. Steroids. 2011;76(1-2):38-42.
  27. Knorr U, Vinberg M, Kessing LV, Wetterslev J. Salivary cortisol in depressed patients versus control persons: A systematic review and meta-analysis. Psychoneuroendocrinology. 2010;35(9):1275-1286.
  28. Monteleone P, Scognamiglio P, Canestrelli B, et al. Asymmetry of salivary cortisol and α-amylase responses to psychosocial stress in anorexia nervosa but not in bulimia nervosa. Psychol Med. 2011;41(9):1963-1969.
  29. Kamali M, Saunders EF, Prossin AR, et al. Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder. J Affect Disord. 2012;136(3):350-358.
  30. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists (AACE) Reproductive Medicine Committee position statement on bioidentical hormones. July, 2007. Available at: https://www.aace.com/files/position-statements/aacebhstatement071507.pdf.
  31. Institute for Clinical Systems Improvement (ICSI). Health care guideline: Menopause and hormone therapy (HT): Collaborative decision-making and management. Bloomington, MN: ICSI; October 2008.
  32. Committee on Gynecologic Practice and the American Society for Reproductive Medicine Practice Committee. Committee opinion no. 532: Compounded bioidentical menopausal hormone therapy. Obstet Gynecol. 2012;120(2 Pt 1):411-415.
  33. North American Menopause Society. The 2012 hormone therapy position statement of the North American Menopause Society. 2012. Available at: http://www.menopause.org/docs/default-document-library/psht12.pdf?sfvrsn=2.
  34. Bonamico M, Nenna R, Montuori M, et al. First salivary screening of celiac disease by detection of anti-transglutaminase autoantibody radioimmunoassay in 5000 Italian primary schoolchildren. J Pediatr Gastroenterol Nutr. 2011;52(1):17-20.
  35. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: Diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656-676.
  36. Punyani SR, Sathawane RS. Salivary level of interleukin-8 in oral precancer and oral squamous cell carcinoma. Clin Oral Investig. 2013;17(2):517-524.
  37. Rajkumar K, Ramya R, Nandhini G, et al. Salivary and serum level of CYFRA 21-1 in oral precancer and oral squamous cell carcinoma. Oral Dis. 2015;21(1):90-96.
  38. DeSimone JA, Karia PS, Schmults, CD. Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma. UpToDate Inc., Waltham, MA. Last reviewed April 2014.
  39. Cheng YS, Jordan L, Rees T, et al. Levels of potential oral cancer salivary mRNA biomarkers in oral cancer patients in remission and oral lichen planus patients. Clin Oral Investig. 2014;18(3):985-993.
  40. Maas C, Ringwald C, Weber K, et al. Relationship of salivary and plasma cortisol levels in preterm infants: Results of a prospective observational study and systematic review of the literature. Neonatology. 2014;105(4):312-318.
  41. Novy BB. Saliva and biofilm-based diagnostics: A critical review of the literature concerning sialochemistry. J Evid Based Dent Pract. 2014;14 Suppl:27-32.
  42. Macey R, Walsh T, Brocklehurst P, et al. Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev. 2015;5:CD010276.
  43. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing's syndrome: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831.
  44. Senneby A, Mejare I, Sahlin NE, et al. Diagnostic accuracy of different caries risk assessment methods. A systematic review. J Dent. 2015 ;43(12):1385-1393.
  45. Guardino CM, Schetter CD, Saxbe DE, et al. Diurnal salivary cortisol patterns prior to pregnancy predict infant birth weight. Health Psychol. 2016;35(6):625-633.
  46. Guerra EN, Acevedo AC, Leite AF, et al. Diagnostic capability of salivary biomarkers in the assessment of head and neck cancer: A systematic review and meta-analysis. Oral Oncol. 2015;51(9):805-818.
  47. Gualtero DF, Suarez Castillo A. Biomarkers in saliva for the detection of oral squamous cell carcinoma and their potential use for early diagnosis: A systematic review. Acta Odontol Scand. 2016;74(3):170-177.
  48. Dy F, Amirault J, Mitchell PD, Rosen R. Salivary pepsin lacks sensitivity as a diagnostic tool to evaluate extraesophageal reflux disease. J Pediatr. 2016;177:53-58.
  49. Porto-Mascarenhas EC, Assad DX, Chardin H, et al. Salivary biomarkers in the diagnosis of breast cancer: A review. Crit Rev Oncol Hematol. 2017;110:62-73.
  50. National Comprehensive Cancer Network. Clinical practice guideline: Breast cancer. Version 2.2017. NCCN: Fort Washington, PA.
  51. National Comprehensive Cancer Network. Clinical practice guideline: Head and neck cancers. Version 2.2017. NCCN: Fort Washington, PA.
  52. Whisman MA, Richardson ED. Depressive symptoms and salivary telomere length in a probability sample of middle-aged and older adults. Psychosom Med. 2017;79(2):234-242.
  53. Borg D, Tverdovsky A, Stripp R. A fast and comprehensive analysis of 32 synthetic cannabinoids using agilent triple quadrupole LC-MS-MS. J Anal Toxicol. 2017;41(1):6-16.
  54. Shaparin N, Mehta N, Kunkel F, et al. A novel chronic opioid monitoring tool to assess prescription drug steady state levels in oral fluid. Pain Med. 2017 Feb 23 [Epub ahead of print].