Cortisol secretion

Between 5,000 and 100,000 GR molecules are found within almost every cell of the organism. The affinity constant for cortisol comes to around 30 nM, which is in the range of the concentration of free hormone in the plasma under normal conditions. Consequently, receptor occupancy can be expected to be 10-70%. This suggests that changes in cortisol secretion such as under stress conditions, directly translate into alterations in GR occupancy, leading to transcriptional responses. 

Normally, circulating glucocorticoids (of which cortisol is the most prominent in humans) cause feedback inhibition of ACTH release so that cortisol secretion is, to some extent, self-limiting. However, many patients suffering from major depression have an increased concentration of plasma cortisol but reduced ACTH secretion. The latter abnormality seems to be partly due to a reduction in the number of CRF receptors in the pituitary, although it is thought that decreased ACTH secretion could provoke the adrenal hyperplasia which is common in depression. This would result in excessive secretion of cortisol and contribute to the inhibition of ACTH release (Musselman and Nemeroff 1993). 

Also, a high proportion of depressed patients do not show the reduction in cortisol secretion which is seen when normal subjects are challenged with the synthetic glucocorticoid, dexamethasone, that normally decreases further release through feedback... 

N3. Naruse, M., Obana, K Naruse, K., Yamaguchi, H Demura, H., Inagami, T., and Shizume, K., Atrial natriuretic polypeptide inhibits cortisol secretion as well as aldosterone secretion in vitro from human adrenal tissue. J. Clin. Endocrinol. Metab. 64, 10-16 (1987). 

Schussler, P., Uhr, M., Ising, M. et al. (2006). Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans. Psychoneuroendocrinology 31, 915-23. 

Cortisol secreted in response to stress, is permissive for glucagon in hypoglycemia and acts through an intracellular receptor, which, like other steroid receptors, is a zinc-finger DNA binding protein,... 

I. Replacement therapy. The adrenal cortex (AC) produces the glucocorticoid cortisol (hydrocortisone) and the mine-ralocorticoid aldosterone. Both steroid hormones are vitally important in adaptation responses to stress situations, such as disease, trauma, or surgery. Cortisol secretion is stimulated by hypophyseal ACTH, aldosterone secretion by angiotensin 11 in particular (p. 124). In AC failure (primary AC insuffiency ... 

Abnormality in the regulatory feedback mechanism may explain the overactivity of the HPA axis seen in depressed patients, since a lack of dexam-ethasone suppression of cortisol secretion is observed (Carroll et al., 1981). In addition, despite a hypercortisolaemia, depressive patients generally do not demonstrate Cushingoid features, possibly because of a reduction in the function of corticosteroid receptors. It has therefore been hypothesised that the primary abnormality in depression may thus be an impairment of corticosteroid receptor function (Barden et al., 1995). 

Whereas several peptides besides AVP are known to act synergistically with CRH, the only peptide candidate in humans that inhibits the HPA system at all regulatory levels of the system seems to be atrial natriuretic peptide (ANP). ANP has been shown to inhibit the stimulated release of CRH and ACTH in vitro and in vivo. This could be observed in humans as well, where ANP inhibits the CRH-induced ACTH (Keller et al. 1992), prolactin (Wiedemann et al. 1995), and cortisol secretion (StrOhle et al. 1998). ANP is not only synthesized by atrial myocytes (deBold et al. 1985) and released into the circulation, but is also found in neurons of different brain regions (Tanala et al. 1984) where specific receptors have been found. ANP receptors and immunoreactivity have been found in periventricular and paraventricular hypothalamic nuclei, the LC, and the central nucleus of the amygdala. 

As a possible consequence of direct neurotoxic effects of sustained hypercortisolism, hippocampal atrophy has now repeatedly been reported for depressed patients (Sheline et ah, 1996 Bremner et al., 2000a). Hippocampal atrophy may be associated with disinhi-bition of CRF secretion and further increases in cortisol secretion, which in turn may further damage the hippocampus. Impaired inhibition of the HPA axis is also evidenced by nonsuppression of cortisol by dexame-thasone and decreased GR numbers in depressed patients both findings parallel those in maternally separated rats. 

As mentioned above, most of the preclinical studies on the effects of early stress have examined the impact of these experiences on adult animals. The preliminary work discussed in this section highlights the need for more developmentally focused preclinical studies of the effects of early stress. In addition, there is a need for more research on the development of the CC, and circadian control of cortisol secretion. 

When underweight people with AN have increased plasma cortisol secretion (Walsh et ah, 1978) that is thought to be a consequence of hypersecretion of endogenous corticotropin-releasing hormone (CRH)... 

Nocturnal plasma cortisol levels increase earlier (i.e., HPA activity is active at night and time span between sleep onset and cortisol secretion nadir is shortened ... 

Plasma ACTH and cortisol secretion is enhanced in response to a combined dexamethasone-CRH challenge... 

Sachar EJ, Heilman L, Roffwarg HP, et al Disrupted 24 hour patterns of cortisol secretion in psychotic depressives. Arch Gen Psychiatry 28 19-24, 1973 Sack RL, Blood ML, Lewy AJ Melatonin administration to night shift workers an update. Sleep Research 24 539, 1995... 

Metyrapone is commonly used in tests of adrenal function. The blood levels of 11-deoxycortisol and the urinary excretion of 17-hydroxycorticoids are measured before and after administration of the compound. Normally, there is a twofold or greater increase in the urinary 17-hydroxycorticoid excretion. A dose of 300-500 mg every 4 hours for six doses is often used, and urine collections are made on the day before and the day after treatment. In patients with Cushing s syndrome, a normal response to metyrapone indicates that the cortisol excess is not the result of a cortisol-secreting adrenal carcinoma or adenoma, since secretion by such tumors produces suppression of ACTH and atrophy of normal adrenal cortex. 

Weiner P, Berar-Yanay N, Davidovich A, Magadle R. Nocturnal cortisol secretion in asthmatic patients after inhalation of fluticasone propionate. Chest 1999 116(4) 931 —4. 

Derom E, Van DV, V, Marissens S, Engelstatter R, Vincken W, Pauwels R. Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5 monophosphate in asthmatic patients. Pulm Pharmacol Ther 2005 18 328-36. 

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