Description of Procedure or Service

Definition

Testing of hormone levels in the saliva has been proposed as a noninvasive method to measure free (unbound to carrier proteins and thus active) steroid hormones (estrogen, progesterone, androgens, cortisol, etc) for diagnosis of hormonal imbalance and administration of individualized hormone replacement therapy (ACOG & ASRM, 2012).

Hypercortisolism can occur in several disorders including Cushing's syndrome (pituitary hypersecretion of corticotropin) or as a result of glucocorticoid administration(Quddusi, Browne, Toivola, & Hirsch, 1998) resulting in obesity, hypertension, menstrual irregularity, and glucose intolerance (Lacroix, Feelders, Stratakis, & Nieman, 2015; L. Nieman, 2017a; L. K. Nieman et al., 2008)

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for salivary hormone testing when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When salivary hormone testing is covered

Late Night Salivary Cortisol testing is considered medically necessary for diagnosing Cushing’s Syndrome.

When salivary hormone testing is not covered

Salivary hormone testing for the screening, diagnosis, and/or monitoring of menopause or diseases related to aging is considered not medically necessary.

Salivary hormone tests include but are not limited to the following:

• Estrogen
• Melatonin
• Progesterone
• Testosterone
• DHEA

Policy Guidelines

Background

The possible presence of Cushing's syndrome (CS) is suggested by symptoms and signs of hypercortisolism including proximal muscle weakness, facial plethora, wasting of the extremities with increased fat in the abdomen and face, wide purplish striae, bruising with no obvious trauma, and supraclavicular fat pads (L. K. Nieman, 2015; L. K. Nieman et al., 2008; Ross & Linch, 1982). Unfortunately, none of these are pathognomonic, and many are nonspecific (eg, obesity, hypertension, menstrual irregularity, and glucose intolerance). As a result, the diagnosis must be confirmed by biochemical tests (L. Nieman, 2017b).

The initial diagnostic tests for hypercortisolism are highly sensitive, even though the diagnosis may be excluded later by more specific tests (Arnaldi et al., 2003; Newell-Price, Trainer, Besser, & Grossman, 1998). Late night salivary cortisol, along with 24-hour urinary free cortisol (UFC) excretion, and/or overnight dexamethasone suppression test (DST) are first line diagnostic tests as indicated by diagnostic approach outlined by the 2008 Endocrine Society clinical guidelines (L. K. Nieman et al., 2008) UFC and late-night salivary cortisol measurements are each obtained at least twice because the hypercortisolism in CS may be variable. Two measurements must be abnormal for the test to be considered abnormal; for patients with mild or fluctuating disease, this may require collecting a number of salivary cortisols or UFCs over weeks. The diagnosis of CS is established when at least two different first-line tests are unequivocally abnormal. Once the diagnosis is established, additional evaluation is done to identify the cause of the hypercortisolism(L. Nieman, 2017b).

Normal women have menopause at a mean age of 51 years, with 95 percent becoming menopausal between the ages of 45 to 55 years. Menopausal hormone therapy (MHT, estrogen alone or combined with a progestin) is currently indicated for management of menopausal symptoms and is highly effective for the management of hot flashes, vaginal atrophy, and, in some cases, the mood lability that many women experience during the menopausal transition(Martin & Barbieri, 2017; Taylor & Manson, 2011).

Salivary hormone level testing is often highly recommended by advocates and compounders of bioidentical hormones as a means of offering individualized therapy (Boothby, Doering, & Kipersztok, 2004). However, individualized testing and monitoring is only indicated when a narrow therapeutic window exists for a drug or a drug class. Steroid hormones, such as estrogen and progesterone do not meet these criteria and, thus, do not require individualized testing(ACOG & ASRM, 2012; Conaway, 2011).

Furthermore, there is no evidence that hormonal levels in saliva are biologically meaningful. Saliva is an ultra- filtrate of the blood and in theory should be amenable to testing for free (unbound or active) concentrations of hormones, however salivary testing does not currently offer an accurate or precise method of hormone testing(Flyckt et al., 2009; Lewis, McGill, Patton, & Elder, 2002). Studies suggest that salivary assessments of hormone levels are inaccurate and do not correlate with levels determined from serum (Conaway, 2011) as there is large within patient variability in salivary hormone concentrations, especially when exogenously administered hormones are given(Hardiman, Thomas, Osgood, Vlassopoulou, & Ginsburg, 1990; Klee & Heser, 2000; Lewis et al., 2002; Meulenberg, Ross, Swinkels, & Benraad, 1987; Wren et al., 2000). Salivary levels of hormones seem to vary greatly on the basis of foods, herbs, and spices consumed prior to sampling, and time of testing(Bolaji, Tallon, O'Dwyer, & Fottrell, 1993; Klee & Heser, 2000; Lewis et al., 2002; Raff et al., 1999; Zava, Dollbaum, & Blen, 1998).

Although more sensitive testing is becoming, there are few indications for the measurement of hormone levels to ascertain success of therapy when treating a postmenopausal woman with hormones. If treatment is initiated for symptom control, therapy should be titrated to the alleviation of symptoms, not to a laboratory value (ACOG & ASRM, 2012).

Applicable State/Federal Regulations

N/A

Guidelines and Recommendations

The recent review by Raff (2015) concludes that “late-night salivary cortisol measurement is an optimal approach to screen patients for endogenous hypercortisolism”. Screening with late night serum cortisol was reported to be both more sensitive (93%) and specific (96%) than the overnight low-dose dexamethasone test, and a 24-hour urine-free cortisol.

Practice Guidelines and Position Statements

American Association of Clinical Endocrinologists (AACE)

AACE published medical guidelines (Goodman, Cobin, Ginzburg, Katz, & Woode, 2011) for the clinical practice of diagnosing and treating menopause which recommend: "Salivary hormone level testing is recommended by many bioidentical hormone proponents as a means of providing patients with “individualized” therapy. Yet these methods are not approved by either the FDA or the Clinical Laboratory Improvement Amendments (the US Health and Human Services agency regulating laboratory standards). Accurate studies have revealed large intrasubject variability in salivary sex hormone concentrations, which fluctuate depending on numerous variables, including diet, hydration, and circadian rhythm. These conditions are difficult to standardize. Standardized blood tests, which are available for sex steroids, are well established but have limited clinical value in evaluating MHT. Because it is expected that postmenopausal women will have low levels of all sex steroids, any measure of these hormones in postmenopausal women has no predictive value of what the “normal” or “individualized” therapeutic levels of sex hormones should be. Moreover, such a measurement cannot be used for achieving these goals through administration of various proportions of sex hormones and routes of delivery." The AACE guidelines on the diagnosis of Cushings syndrome (L. K. Nieman et al., 2008) recommend: “For the initial testing for Cushing's syndrome, we recommend one of the following tests based on its suitability for a given patient: Urine free cortisol (at least two measurements), Late-night salivary cortisol (two measurements), 1-mg overnight dexamethasone suppression test (DST), Longer low-dose DST (2 mg/d for 48 h). The AACE guidelines on the treatment of Cushings syndrome (L. K. Nieman et al., 2015) recommend: “measuring late-night salivary or serum cortisol in patients with eucortisolism after TSS, including those cases where eucortisolism was established by medical treatment before surgery.”

The American College of Obstetricians and Gynecologists (ACOG) and the American Society of Reproductive Medicine Practice Committee (ASRM)

In 2012, ACOG and ASRM published guidelines for compounded hormone therapy which found: “There is no evidence that hormonal levels in saliva are biologically meaningful. In addition, whereas saliva is an ultrafiltrate of the blood and in theory should be amenable to testing for “free” (unbound) concentrations of hormones, salivary testing does not currently offer an accurate or precise method of hormone testing. There are several problems with salivary testing and monitoring of free hormone levels. First, salivary levels do not consistently provide a reasonable representation of endogenous, circulating serum hormones. There is large within patient variability in salivary hormone concentrations, especially when exogenously administered hormones are given. Salivary hormone levels vary depending on diet, time of testing, and the specific hormone being tested. Second, because the pharmacokinetics of exogenously administered compounded hormones cannot be known, it is not possible to estimate with reliability how and when to test saliva to obtain a representative result. Third, saliva contains far lower concentrations of hormone than serum and is prone to contamination with blood, infectious agents, and epithelial cells—all of which may affect the level of hormone to be measured.” They concluded that: “Despite claims to the contrary, evidence is inadequate to support increased efficacy or safety for individualized hormone therapy regimens based on salivary, serum, or urinary testing.”

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes:

Scientific Background and Reference Sources

ACOG, & ASRM. (2012). Compounded bioidentical menopausal hormone therapy. Fertil Steril, 98(2), 308-312. doi:10.1016/j.fertnstert.2012.06.002

Arnaldi, G., Angeli, A., Atkinson, A. B., Bertagna, X., Cavagnini, F., Chrousos, G. P., Boscaro, M. (2003). Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab, 88(12), 5593-5602. doi:10.1210/jc.2003-030871

Bolaji, II, Tallon, D. F., O'Dwyer, E., & Fottrell, P. F. (1993). Assessment of bioavailability of oral micronized progesterone using a salivary progesterone enzymeimmunoassay. Gynecol Endocrinol, 7(2), 101-110.

Boothby, L. A., Doering, P. L., & Kipersztok, S. (2004). Bioidentical hormone therapy: a review. Menopause, 11(3), 356-367.

Conaway, E. (2011). Bioidentical hormones: an evidence-based review for primary care providers. J Am Osteopath Assoc, 111(3), 153-164.

Flyckt, R. L., Liu, J., Frasure, H., Wekselman, K., Buch, A., & Kingsberg, S. A. (2009). Comparison of salivary versus serum testosterone levels in postmenopausal women receiving transdermal testosterone supplementation versus placebo. Menopause, 16(4), 680-688. doi:10.1097/gme.0b013e318199d5c4

Goodman, N. F., Cobin, R. H., Ginzburg, S. B., Katz, I. A., & Woode, D. E. (2011). American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of menopause. Endocr Pract, 17 Suppl 6, 1-25.

Hardiman, P., Thomas, M., Osgood, V., Vlassopoulou, V., & Ginsburg, J. (1990). Are estrogen assays essential for monitoring gonadotropin stimulant therapy? Gynecol Endocrinol, 4(4), 261- 269.

Klee, G. G., & Heser, D. W. (2000). Techniques to measure testosterone in the elderly. Mayo Clin Proc, 75 Suppl, S19-25.

Lacroix, A., Feelders, R. A., Stratakis, C. A., & Nieman, L. K. (2015). Cushing's syndrome. Lancet, 386(9996), 913-927. doi:10.1016/s0140-6736(14)61375-1

Lewis, J. G., McGill, H., Patton, V. M., & Elder, P. A. (2002). Caution on the use of saliva measurements to monitor absorption of progesterone from transdermal creams in postmenopausal women. Maturitas, 41(1), 1-6.

Martin, K., & Barbieri, R. (2017). Menopausal hormone therapy: Benefits and risks - UpToDate. In K. Martin (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/menopausal-hormone-therapy-benefits-andrisks?source=search_result&search=menopause&selectedTitle=4~150.

Meulenberg, P. M., Ross, H. A., Swinkels, L. M., & Benraad, T. J. (1987). The effect of oral contraceptives on plasma-free and salivary cortisol and cortisone. Clin Chim Acta, 165(2-3), 379- 385.

Newell-Price, J., Trainer, P., Besser, M., & Grossman, A. (1998). The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev, 19(5), 647-672. doi:10.1210/edrv.19.5.0346

Nieman, L. (2017a). Causes and pathophysiology of Cushing's syndrome - UpToDate. In K. Martin (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/causes-and-pathophysiology-of-cushingssyndrome?source=search_result&search=cushings%20disease&selectedTitle=5~110.

Nieman, L. (2017b). Establishing the diagnosis of Cushing's syndrome - UpToDate. In K. Martin (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/establishing-the-diagnosis-of-cushingssyndrome?source=see_link#H9.

Nieman, L. K. (2015). Cushing's syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol, 173(4), M33-38. doi:10.1530/eje-15-0464

Nieman, L. K., Biller, B. M., Findling, J. W., Murad, M. H., Newell-Price, J., Savage, M. O., & Tabarin, A. (2015). Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 100(8), 2807-2831. doi:10.1210/jc.2015-1818

Nieman, L. K., Biller, B. M., Findling, J. W., Newell-Price, J., Savage, M. O., Stewart, P. M., & Montori, V. M. (2008). The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 93(5), 1526-1540. doi:10.1210/jc.2008-0125

Quddusi, S., Browne, P., Toivola, B., & Hirsch, I. B. (1998). Cushing syndrome due to surreptitious glucocorticoid administration. Arch Intern Med, 158(3), 294-296.

Raff, H. (2015). Cushing syndrome: update on testing. Endocrinol Metab Clin North Am, 44(1), 43-50. doi:10.1016/j.ecl.2014.10.005

Raff, H., Raff, J. L., Duthie, E. H., Wilson, C. R., Sasse, E. A., Rudman, I., & Mattson, D. (1999). Elevated salivary cortisol in the evening in healthy elderly men and women: correlation with bone mineral density. J Gerontol A Biol Sci Med Sci, 54(9), M479-483.

Ross, E. J., & Linch, D. C. (1982). Cushing's syndrome--killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet, 2(8299), 646-649.

Taylor, H. S., & Manson, J. E. (2011). Update in hormone therapy use in menopause. J Clin Endocrinol Metab, 96(2), 255-264. doi:10.1210/jc.2010-0536

Wren, B. G., McFarland, K., Edwards, L., O'Shea, P., Sufi, S., Gross, B., & Eden, J. A. (2000). Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric, 3(3), 155-160.

Zava, D. T., Dollbaum, C. M., & Blen, M. (1998). Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med, 217(3), 369-378. 

Policy Implementation/Update Information

1/1/19 New policy developed. BCBSNC will provide coverage for salivary hormone testing when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (an)