Mini-review of hair cortisol concentration for evaluation of Cushing syndrome

Abstract

Introduction: The diagnosis of endogenous Cushing syndrome is often challenging and requires multiple repeated blood, urine, and saliva tests to detect elevated cortisol levels. Hair cortisol concentration has been described as a marker of long-term exposure to systemic cortisol in patients with Cushing syndrome. Like hemoglobin A1c is used to detect serum glucose exposure over months, segmental hair cortisol can help identify patients with milder forms of and/or periodic or cyclical Cushing syndrome, which may reduce time and costs associated with collection of urine, salivary, and serum cortisol.

Areas covered: Success of hair cortisol in detection of Cushing syndrome will be discussed in context of current literature, including differences between total or segmental hair cortisol in accurately determining timeline of cortisol exposure. Optimal methods of hair collection, storage, processing, and analysis and efforts toward standardization will be a major focus.

Expert commentary: Recent evidence suggests increased sensitivity and specificity of hair cortisol in detecting Cushing syndrome. Future guidelines should consider this test as a routine part of the repertoire of screening tests for Cushing syndrome. Possible confounders to explain discrepant results in the literature will be discussed.

Trial registration: ClinicalTrials.gov NCT00001595 NCT00005927.

Keywords: Cushing disease; Cushing syndrome; Hair; cortisol; hair cortisol; hypercortisolemia.

Figure 1.

Schematic of hair cortisol from collection to analysis. Systemic cortisol is currently assumed to diffuse from the dermal capillaries to the hair matrix and cortex. Cortisol can also be deposited on the hair cuticle via sweat. Hair is collected from the posterior vertex, as close to the scalp as possible, and then stored until processing. At the analyzing laboratory, hair is washed with isopropanol to remove the sweat-derived cortisol deposited on the hair cuticle. Hair is cut into 1 cm segments, weighed, minced or ground, and then incubated in methanol for cortisol extraction. Methanol solvent is separated from mixture, and then cortisol is obtained after methanol evaporation. Analysis of hair cortisol per 1 cm sample is performed with either enzyme-linked immunosorbent assay (ELISA) or liquid-chromatography/tandem mass spectroscopy (LC/MS-MS). This figure was created by Nichole Jonas and Jeremy Swanson using the program, Adobe Illustrator^® CS6.

Figure 2.

Potential confounding factors in hair cortisol analysis in Cushing syndrome patients. A) Human epidermal keratinocytes (K) and dermal fibroblasts (D) contain 11BDH type 1 and can convert cortisone to cortisol. Glucocorticoid exposure leads to increased expression of 11BDH type 1 in K and D cells [29]. Thus, K and D cells may have a role in increasing measured hair cortisol in Cushing syndrome patients. B) The outer root sheath (ORS) cells of the hair follicle in humans can synthesize cortisol under stimulation of ACTH [28]. In ACTH-dependent Cushing syndrome, it is suspected that these cells are contributing to cortisol deposited in hair matrix superimposed on systemic cortisol from elevated systemic glucocorticoid levels. In situations A and B, the measured hair cortisol concentration in final analysis should theoretically be a summation of systemically- and locally- produced cortisol. However, in a study by Hodes et al., serum ACTH and its relationships with UFC and serum midnight cortisol did not show a significant relationship [8], suggesting other confounders. C) One possible confounder that may diminish cortisol deposited in the hair matrix is dermal capillary 11BDH type 2 [30], which can convert cortisol to cortisone. This figure was modified by Nichole Jonas and Jeremy Swanson using the program, Adobe Illustrator^® CS6. Reprinted by permission from SPRINGER NATURE, Endocrine, Hodes, et al., Hair cortisol in the evaluation of Cushing syndrome, 56(1):164-174, © 2017 [8]. F=systemically-produced cortisol, n=cortisone, C=locally-produced cortisol, and A=systemically-produced ACTH.