Regulation of cortisol secretion in humans: relation to vasopressin action at the adrenals in macronodular and micronodular adrenocortical tumours; and well-being in Addison’s Disease.

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis exhibits tight physiological regulation on a circadian and ultradian basis in humans. Key central regulators include the peptides corticotrophin-releasing hormone (CRH) and arginine vasopressin (VP), acting at the pituitary, and at peripheral structures relevant to the HPA axis and other components of the stress system. Altered regulation has many causes, frequently related to tumorigenesis, and can lead to disease due to an excess of the HPA axis end-organ hormone cortisol, as in Cushing’s syndrome (CS), or cortisol deficiency, as in Addison’s disease. More subtle alterations of HPA axis function have been associated with many diseases. It may be that a lack of normal circadian and ultradian regulation leads to altered well-being. Studies of three families with the rare cause of cortisol excess, ACTH-independent macronodular adrenal hyperplasia (AIMAH) revealed that adrenal function could be directly stimulated by an aberrant response to exogenous vasopressin (VP; VPs-AIMAH). In addition, it appeared possible to define subtle forms of adrenal dysregulation or early tumour formation, short of clinical CS, thereby expanding the range of phenotypic expression of this disorder for the first time, and further highlighting the familial nature of VPs-AIMAH. Studies of germline DNA, as well as expression of genes potentially relevant to the VP response in adrenal tumours, did not reveal any abnormality to explain heritable VPs-AIMAH. A SNPbased linkage study in the largest (seven affected) family revealed a single potential locus (LOD score 1.83) leading to sequencing of a number of positional candidates. Further studies have included gene expression studies of the familial AIMAH tumours, the most extensive of these studies internationally, in vivo stimulation studies of adrenal steroid intermediates, and finally whole exome capture and next-generation sequencing, all of which has led to increased knowledge in the AIMAH field, but without final gene/mutation identification to date. Parallel studies examined VP responses in a convenience sample of patients presenting with adrenocortical hormone hypersecretion states or incidentally discovered adrenal tumours, and an attempt to simultaneously examine the negative predictive value of nocturnal salivary cortisol (NSC) sampling to detect the prevalence of mild CS in patients with type 2 diabetes mellitus led to the conclusion that aberrant VP responses are less frequent in adrenocortical tumours, the NSC has a low false positive rate compared with other screening tests, and that mild CS is not prevalent in local diabetes cohorts, consistent with more recent international data. Finally, a study aimed at determining the importance of circadian and ultradian HPA axis responses was embarked upon in patients with Addison’s disease, a patient group with an unmet need relating to poor well-being. Dose-response dynamic biochemical studies established the feasibility of continuous subcutaneous hydrocortisone infusion (CSHI) to produce physiological ultradian responses to daily life stress. The feasibility of longer term CSHI was studied in a randomised, double-blind, placebo-controlled clinical trial. Recruitment rates have led to this study being adopted at a multicentre level. Ultimately, this study will address the question of the importance of cortisol rhythmicity and responsiveness to well-being in humans.