Measurement of Salivary Cortisone to Assess the Adequacy of Hydrocortisone Replacement Free

Abstract

The measurement of late-night salivary cortisol has revolutionized the diagnosis of endogenous hypercortisolism—Cushing's syndrome (1–4). Furthermore, the measurement of salivary cortisol is extensively used as an index of hypothalamic-pituitary-adrenal axis dynamics in biobehavioral research (5). Although the wide acceptance of late-night salivary cortisol for the diagnosis and postoperative surveillance of Cushing's syndrome in clinical practice has developed over the past two decades (4, 6–8), the concept of measuring cortisone in addition to cortisol in saliva as a research and diagnostic tool was described over five decades ago (9–15).

Plasma free cortisol is converted to cortisone and then back to cortisol in the kidney, liver, and other organs by the different forms of 11-β-hydroxysteroid dehydrogenase (16–18). As shown in the study by Debono et al (19), the ratio of cortisol to cortisone is significantly lower in the saliva as compared to plasma, indicating the expression of 11-β-hydroxysteroid dehydrogenase-2 and conversion of cortisol to cortisone in the salivary gland. Therefore, Debono et al and others (19–21) have proposed that the measurement of salivary cortisone is a reliable index of plasma free cortisol and has utility as a surrogate for the measurement of plasma free cortisol in a variety of physiological and clinical circumstances.

Debono et al (19) have done a thorough analysis of circadian and timed measurements of salivary cortisol and cortisone and correlated them with serum total and free cortisol as well as free cortisol index calculated from serum total cortisol and serum corticosteroid binding globulin. My commentary will focus on their measurements and mathematical analyses after oral or iv administration of hydrocortisone (authentic cortisol) because the measurement of salivary cortisone may turn out to be a useful approach to evaluate hydrocortisone replacement therapy in patients with adrenal insufficiency.

It is well known to the clinical endocrinology community that adjustment and assessment of adequate physiological hydrocortisone replacement can be a challenge, particularly because measurement of plasma ACTH does not have the same utility as, for example, measuring serum TSH to assess levothyroxine replacement in primary hypothyroidism (22). It is well known that excessive glucocorticoid therapy leads to a variety of negative consequences and that weaning from excess therapy is challenging (23).

A variety of approaches have been used to assess hydrocortisone replacement (22) including cortisol “day curves,” which involves obtaining several blood samples during the day (24). Debono et al (19) now demonstrate that measuring salivary cortisone in 16 samples over a 12-hour period after oral or iv administration of hydrocortisone shows a high correlation with serum free cortisol and free cortisol index measured simultaneously. Measuring salivary cortisol after oral hydrocortisone frequently results in very high and uninterpretable concentrations of salivary cortisol due to contamination of the saliva sample (25). Because hydrocortisone pills do not contain cortisone, its measurement is not affected by contamination with oral hydrocortisone.

The measurement of salivary cortisol and cortisone can now be performed routinely with the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology (25, 26). At this point, most reference laboratories only report salivary cortisol and have not validated the measurement of salivary cortisone by LC-MS/MS sufficiently to allow them to report the concentrations of both salivary analytes to physicians. One hopes that findings such as those reported in Debono et al (19) will induce the clinical laboratories to validate and make the reporting of both salivary cortisol and cortisone by LC-MS/MS available upon request.

Several caveats are worth delving into. As the authors readily admit, this study was in only 14 subjects and only adult males. The evaluation of many more subjects of both sexes and the development of a reliable reference range for salivary cortisone are needed for this approach to be clinically useful in the routine assessment of hydrocortisone replacement. This may be very challenging because there is significant variation in patterns of hydrocortisone replacement (22). The ability to evaluate hydrocortisone replacement in children by saliva sampling would be particularly useful considering the challenge of obtaining multiple blood samples over a single day in children and the serious consequences of over-replacement.

The analysis by Debono et al (19) required many timed salivary and blood samples over a 12-hour period after administration of hydrocortisone. In my experience, one of the challenges of saliva sampling in the home is the lack of compliance of the patient with accurate timing and reporting of the sampling time. In fact, the timing compliance of unsupervised multiple saliva sampling may be as low as 70% (27). The approach by Debono et al (19) required very accurate, timed acquisition of 16 samples over 12 hours that was performed in a supervised, clinical setting. It is necessary for such a protocol to be simplified, with less intensive, home-based sampling to be of any practical clinical use. Additionally, the expense of measuring 16 salivary cortisone samples is significant and without modification would likely decrease the relevance of such testing, as does the challenge of a lack of time compliance in an unsupervised (ie, home) environment. Advances in monitoring hydrocortisone replacement for adrenal insufficiency are sorely needed and long overdue. The use of salivary cortisone provides a potential window to improve this monitoring. I encourage the authors, after they have studied more subjects, to reanalyze their data to determine whether many fewer samples could provide an accurate index of hydrocortisone replacement.

In the future, a potential major advance is that as few as one or two salivary cortisone measurements might be used to routinely assess replacement of hydrocortisone in patients with adrenal insufficiency.

Acknowledgments

The author thanks Ty B. Carroll, MD, for his critical review of the manuscript.

Disclosure Summary: The author has nothing to disclose.

Funded in part by the Aurora Research Institute.

Abbreviations

 
• LC-MS/MS

  liquid chromatography-tandem mass spectrometry.

References