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

The circadian rhythm derives from the integration of many signals that shape the expression of clock-related genes in a 24-h cycle. Biological tasks, including cell proliferation, differentiation, energy storage, and immune regulation, are preferentially confined to specific periods. A gating system, supervised by the central and peripheral clocks, coordinates the endogenous and exogenous signals and prepares for transition to activities confined to periods of light or darkness. The fluctuations of cortisol and its receptor are crucial in modulating these signals. Glucocorticoids and the autonomous nervous system act as a bridge between the suprachiasmatic master clock and almost all peripheral clocks. Additional peripheral synchronizing mechanisms including metabolic fluxes and cytokines stabilize the network. The pacemaker is amplified by peaks and troughs in cortisol and their response to food, activity, and inflammation. However, when the glucocorticoid exposure pattern becomes chronically flattened at high- (as in Cushing's syndrome) or low (as in adrenal insufficiency) levels, the system fails. While endocrinologists are well aware of cortisol rhythm, too little attention has been given to interventions aimed at restoring physiological cortisol fluctuations in adrenal disorders. However, acting on glucocorticoid levels may not be the only way to restore clock-related activities. First, a counterregulatory mechanism on the glucocorticoid receptor itself controls signal transduction, and second, melatonin and/or metabolically active drugs and nutrients could also be used to modulate the clock. All these aspects are described herein, providing some insights into the emerging role of chronopharmacology, focusing on glucocorticoid excess and deficiency disorders.

l-Lysine Acts as a Serotonin Type 4 Receptor Antagonist to Counteract In Vitro and In Vivo the Stimulatory Effect of Serotonergic Agents on Aldosterone Secretion in Man.

In the normal human adrenal gland, serotonin (5-HT) stimulates aldosterone secretion through the 5-HT4 receptor (5-HT4R). However, the physiological role of the serotonergic control of adrenocortical function is not known. In the present study, we have investigated the ability of l-Lysine, which has been shown to act as a 5-HT4 receptor antagonist, to counteract in vitro and in vivo the stimulatory effect of 5-HT4R agonists on aldosterone production. l-Lysine was found to inhibit aldosterone production induced by 5-HT and the 5-HT4R agonists BIMU8 from cultured human adrenocortical cells. The action of l-Lysine (4.95 g/day orally) on the adrenal cortex was also evaluated in 20 healthy volunteers in a double blind, cross-over, placebo controlled study. l-Lysine had no significant influence on basal plasma aldosterone levels and the aldosterone responses to upright posture, tetracosactide, and low sodium diet (10 mmol/day for 3 days). Conversely, l-Lysine significantly reduced the surge of plasma aldosterone induced by metoclopramide indicating that l-Lysine is able to efficiently antagonize the adrenal 5-HT4 receptors in vivo. These results suggest that l-Lysine supplementation may represent a new treatment of primary adrenal diseases in which corticosteroid hypersecretion is driven by overexpressed 5-HT4 receptors.

Prevention of CCl(4)-induced oxidative damage in adrenal gland by Digera muricata extract in rat.

Digera muricata (L.) Mart. is a weed and commonly found in waste places, road sides and in maize fields during the summer season. It possesses antioxidant capacity and is locally used for various disorders such as inflammation, urination, as refrigerant, aperient and in sexual anomalies. In this study antioxidant potential of Digera muricata methanol extract (DMME) and n-hexane extract (DMHE) was evaluated against CCl(4)-induced oxidative stress in adrenal gland of Sprague-Dawley male rats. 42 rats were equally divided into 7 groups of 6 rats in each. Group I remained untreated, while Group II treated with vehicles. Group III received only CCl(4) (1 ml/kg b.w., 10% in olive oil) once a week for 16 weeks. Group IV and VI received DMME and DMHE at a dose of 200 mg/kg b.w. along with CCl(4). Animals of Group V and VII administered with DMME and DMHE alone at a dose of 200 mg/kg b.w. once a week for 16 weeks. Lipid peroxidation significantly increased while activities of antioxidant enzymes (CAT, SOD, GST, GSR and GSH-Px) were reduced in adrenal gland samples by the administration of CCl(4). Glutathione (GSH) concentration was significantly decreased whereas DNA fragmentation% and AgNORs count was increased in adrenal gland by CCl(4) administration. Treatment of rat by both the extracts (DMME, DMHE) and CCl(4) increased the glutathione level and activities of antioxidant enzymes while reduced the lipid peroxidation, DNA fragmentation percent and AgNORs count in adrenal gland. These results indicate that Digera muricata extract is able to ameliorate oxidative stress in adrenal gland induced by CCl(4) in rat.

[Current views on the role of dehydroepiandrosterone in physiology, pathology and therapy]. / Wspólczesne poglady na temat roli dehydroepiandrosteronu w fizjologii, patologii i terapii.

Dehydroepiandrosterone (DHEA) and its sulfate metabolite (DHEAS) are the major androgens secreted by the human adrenal gland. The decline in their production is the most characteristic age-related change in the adrenal cortex. This process, known as 'adrenopause' may contribute to the increased incidence of atherosclerosis, cancer, or dementia in older people. The possibility of using DHEA in management has attracted considerable attention over recent years. Whereas DHEA therapy seems to be effective in treating patients with adrenal insufficiency and systemic lupus erythematosus, clinical studies investigating the potential efficacy of DHEA therapy in multiple other disorders (Alzheimer disease, depression, cardiovascular disease, osteoporosis, sexual dysfunctions) have not provided consistent results. Further research is also needed to better assess the efficacy and safety of DHEA supplementation in patients with advanced age. This review evaluates current understanding of physiology and pathology of DHEA production and summarizes the possible therapeutic value of this hormone.

Selenium 75 selenomethyl cholesterol: a new agent for quantitative functional scintigraphy of the adrenals: physical aspects.

Fifty-two patients with suspected or known adrenal disorders have been studied with 75Se selenomethyl cholesterol using a rectilinear scanner or gamma camera computer system. Radiation dosimetry was estimated from the blood clearance and whole body retention of 75Se selenomethyl cholesterol. A method of quantitation of adrenal uptake is described, use of which is essential for the separation of normal from hyperactive adrenal glands. The adrenal depth was found to vary between 4.4 and 12 cm. The lack of need for thyroid suppression and the availability and ease of handling and storage of 75Se selenomethyl cholesterol make it preferable to 131I iodo-cholesterol derivatives and the current agent of choice for adrenal imaging.