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Background
Salivary tests of estrogen, progesterone, testosterone, melatonin, cortisol and 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 FSH, for thyroid dysfunction serum TSH, 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."
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). 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 (e.g., 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 8631 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 adrenocorticotropic hormone (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-h 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.
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