MECHANISMS IN ENDOCRINOLOGY: A sense of time of the glucocorticoid circadian clock: from the ontogeny to the diagnosis of Cushing’s syndrome

Abstract

The circadian rhythm of glucocorticoids has long been recognised within the last 75 years. Since the beginning, researchers have sought to identify basic mechanisms underlying the origin and emergence of the corticosteroid circadian rhythmicity among mammals. Accordingly, Young, Hall and Rosbash, laureates of the 2017 Nobel Prize in Physiology or Medicine, as well as Takahashi's group among others, have characterised the molecular cogwheels of the circadian system, describing interlocking transcription/translation feedback loops essential for normal circadian rhythms. Plasma glucocorticoid circadian variation depends on the expression of intrinsic clock genes within the anatomic components of the hypothalamic-pituitary-adrenal axis, which are organised in a hierarchical manner. This review presents a general overview of the glucocorticoid circadian clock mechanisms, highlighting the ontogeny of the pituitary-adrenal axis diurnal rhythmicity as well as the involvement of circadian rhythm abnormalities in the physiopathology and diagnosis of Cushing's disease.

Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy

“…1) (Dickmeis et al 2013). The circadian clock is sustained by interlocked transcriptionaltranslational feedback loops comprised of the master genes CLOCK and BMAL1 (Nader et al 2010, Partch et al 2014, Moreira et al 2018. They heterodimerize in the cytoplasm to form a complex (CLOCK-BMAL1) that binds to E-box elements in the nuclei, thereby enhancing the target genes, including two cryptochrome genes (CRY1 and CRY2) and the core-clock 'period' genes (PER1, PER2, and PER3).…”

“…Glucocorticoid fluctuations depend on the intrinsic expression of clock genes at each anatomical site of the HPA axis, classically organized in a hierarchical manner (Moreira et al 2018). The SCN, through the activation of corticotropin-releasing hormone secretion from the paraventricular nuclei of the hypothalamus (PVN), coordinates and controls the rhythmic release of adrenocorticotropic hormone (ACTH) from the anterior pituitary.…”

“…It is characterized by high morbidity and mortality, especially due to cardiovascular, infectious, metabolic, and psychiatric conditions (Isidori et al 2015a,b, Pivonello et al 2016, Vitale et al 2017 and largely attributed to the failure of plasma cortisol levels to drop in the late evening and at night. It has been proposed that partial resistance of ACTH-secreting pituitary adenomas to the negative feedback of cortisol alters the secretion of corticotropinreleasing hormone from the hypothalamus, leading to an abnormal circadian rhythm (Moreira et al 2018). This in turn may contribute to dysregulation of the clock system in peripheral tissues, leading to intermediary metabolic alterations and the clinical features of Cushing's syndrome.…”

On the Relationships between LncRNAs and Other Orchestrating Regulators: Role of the Circadian System

“…Additionally, the circadian system controls a hormone that acts on almost all cells, melatonin [12]. It also influences many other hormones, among them the glucocorticoids, which exhibit rhythms of high amplitude and also target various different cell types [13][14][15]. Moreover, melatonin upregulates, in nontumor cells, sirtuin 1 (SIRT1) [11,16], which is not only an aging suppressor and a contributor to metabolic sensing, but, importantly, an accessory oscillator component that enhances circadian amplitudes in central and peripheral oscillators [16][17][18].…”

Modified-Release Hydrocortisone: Is It Time to Change Clinical Practice?

“…Most patients with AI receive daily immediate-release hydrocortisone; because of its short half-life (∼60 minutes), this will be usually split into two or three doses, resulting in a profile that bears little resemblance to the normal circadian pattern of cortisol secretion [6]. The importance of the normal cortisol circadian rhythmicity in setting endogenous clock genes is a key factor across metabolic, stress, and infection control [7]. Jet lag is perhaps the best example of what happens when the clock is not entrained to the external light–dark cycle and a newly imposed sleep–wake cycle requires several days to adapt.…”