Editorial Comment from Dr Fang to Increased expression of CYP17 and CYP11B1 in subclinical Cushing's syndrome due to adrenal adenomas

Abstract

Subclinical Cushing's syndrome (SCS) is characterized by altered hypothalamic–pituitary–adrenal axis secretion and subtle hypersecretion of cortisol, but without the specific symptoms and/or signs of classic Cushing's syndrome.1-3 In addition, SCS may be referred to as subclinical hypercortisolism or preclinical Cushing's syndrome.4-6 The first report of SCS was in a patient with adrenal incidentaloma in 1973.7 With the increased availability of high-resolution ultrasound devices and computed tomography, the prevalence of adrenal incidentaloma is now reported to be 4%, with its prevalence increasing to 7% in individuals >70 years of age.4, 8, 9 In patients with adrenal incidentaloma, the incidence of SCS is up to 30%. Therefore, SCS is a common disease.10 The natural history of SCS is unknown and data regarding long-term morbidity and mortality are lacking.3, 11, 12 However, increasing evidence suggests that SCS may lead to long-term consequences as a result of cortisol excess, such as obesity, diabetes, hypertension, and osteoporosis.11, 13-18 Clinically, it is necessary to differentiate SCS from adrenal incidentaloma. Unfortunately, there is no consensus yet as to the clinical and/or biochemical criteria, including 24 hr urinary free cortisol, serum adrenocorticotrophin, and 1 or 3 mg dexamethasone suppression test, to screen for this disease, resulting in difficulties in properly managing patients with SCS. In the adrenal gland, cytochrome P-450 cholesterol side-chain cleavage enzyme (P450scc or CYP11A1), 17α-hydroxylase/17,20-lyase (CYP17), CYP21 and 11β-hydroxylase (CYP11B1) are important enzymes associated with the biosynthesis of cortisol.19 Although the roles of these enzymes in the overproduction of cortisol and aldosterone in adenomas have not been defined,20, 21 several studies have suggested their association in this regard.22-25 Because the key feature of SCS is subtle cortisol hypersecretion,1-3 it is reasonable to hypothesize that cortisol hypersecretion in SCS may be associated, at least in part, with the abnormal expression of these enzymes. In this issue of the Journal, Cao et al. investigated the mRNA and protein expression of CYP17 and CYP11B1 in SCS, cortisol-producing adenoma, non-functional adenoma (NFA), and normal adrenal gland.26 Because the key issue is how to differentiate SCS from adrenal incidentaloma or NFA, differences in the expression of CYP17 and CYP11B1 between them will be emphasized here. The authors first showed that morning serum cortisol in the SCS group was higher than that in the NFA group. They further showed that the mRNA and protein expression of CYP17 and CYP11B1 in the SCS group was higher than in the NFA group. These results suggest that higher serum cortisol levels are associated with the higher expression of both CYP11B1 and CYP17 in SCS. Unexpectedly, no correlation was found between serum cortisol and the expression of CYP11B1 or CYP17 in SCS when Spearman's rank correlation was used for correlation analysis. This may be due to the smaller sample size in the SCS group compared with the NFA group. Furthermore, 24 h urine cortisol may be a good parameter for inclusion in future studies.1 It is also of interest to further investigate the expression of other enzymes, such as CYP11A1 and CYP21, in SCS as well as NFA.20, 22 Clearly, further studies are needed to address these issues. Nevertheless, molecular biological analysis of surgical samples seems promising to provide additional diagnostic parameters to differentiate SCS from NFA, as suggested by this study.26 None declared.