Cortisol excess

Recognize the clinical presentation of Cushing s syndrome and the physiologic consequences of cortisol excess. 

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. 

ACTH is a polypeptide hormone with 39 ammo acids and an MW of 4500 that is produced by the corticotropic cells of the anterior pituitary gland (see Chapter 50). In 1928 a patient was described having a small ceU carcinoma of the lung who had the signs and symptoms of what is now known to be cortisol excess. A small number of these carcinomas can produce pro-ACTH, the precursor to ACTH. This precursor has an MW of 22,000, a 5% bioactivity, and most of the immunoactivity of ACTH. Traditional RIA measures both the precursor and the hormone. One immunometric assay in use is specific for ACTH. 

This may not nece.ssarily be accompanied by cortisol excess, and signs of Cushing s syndrome may be absent. Patients with congenital adrenal hyperplasia (p. 87) may also present with signs of increased androgen production. 

Retinoic acid can also play a potential role in Cushing disease. This malady, i.e. cortisol excess due to an Adre-cocorticotropic Hormone (ACTH)-secreting pituitary adenoma, is a rare disorder with considerable morbidity and mortality but not satisfactory medical treatment as yet. Experimental data have recently shown that retinoic acid restrains Adrecocorticotropic Hormone (ACTH) secrehon by tumoural corticotropes. The aim of the present study was to evaluate the efficacy and safety profile of retinoic acid treatment in pahents with Cushing disease [74 ]. 

Cortisol-Cortisone Conversion. Under normal conditions, this equilibrium slightly favors the oxidized compound. Similarly, the conversion of corticosterone to 11-deoxycorticosterone is also mediated by the liP-hydroxysteroid dehydrogenase enzyme system and requites NAD(P) /NAD(P)H. This conversion is especially important both in the protection of the human fetus from excessive glucocorticoid exposure, and in the protection of distal nephron mineral ocorticoid receptors from glucocorticoid exposure (14). The impairment of this conversion is thought to result in hypertension associated with renal insufficiency (15). 

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). 

Adrenal hormone production is controlled by the hypothalamus and pituitary gland. Corticotropin-releasing hormone (CRH) is secreted by the hypothalamus and stimulates secretion of adrenocorticotropic hormone (ACTH), also known as corticotropin from the anterior pituitary. ACTH, in turn, stimulates the adrenal cortex to produce cortisol. When sufficient or excessive cortisol levels are reached, a negative feedback is exerted on the secretion of CRH and ACTH, thereby decreasing overall cortisol production. The control of adrenal androgen synthesis also follows a similar negative-feedback mechanism. 

Congenital adrenal hyperplasia A rare inherited condition resulting from a deficiency in cortisol and aldosterone synthesis with resulting excess androgen production. The clinical presentation depends on the variant of the condition, but it typically manifests as abnormalities in sexual development and/or adrenal insufficiency. 

Hyperfunction of the adrenal glands occurs in Cushing s syndrome, a disorder caused by excessive secretion of cortisol by the adrenal gland (hypercortisolism). Other causes of adrenal gland hyperfunction include primary and secondary aldosteronism (not discussed in this chapter refer to textbook Chap. 79 for more information on these disorders). 

Theory Cortisol (or hydrocortisone) was introduced in the year 1951, for the treatment of rheumatoid arthritis. It has a significant effect on protein metabolism. It also exerts widespread effects on carbohydrates, lipid and protein synthesis (or anabolism). The cardinal side effects such as excessive potassium excretion and sodium retention, enhanced gastric acidity, oedema, psychosis and negative nitogen balance are some of the exaggerated manifestations of the normal metabolite functions of cortisol. 

An excess of insulin can cause hypoglycaemia and the hormones that respond to this condition to restore normal glucose levels are known as the counter-regulatory hormones. They are adrenaline, glucagon, growth hormone and cortisol. An increase in the blood levels of these hormones can sometimes be used to conhrm a diagnosis of hypoglycaemia. 

Inhibitory NE/p-adrenergic Mediai prefrontai cortex, baso- Excessive stress-mediated release of CRH, cortisol, and NE will facilitate development of indelible fear memories. Chronic anxiety and phobic symptoms may result from excessive contextual fear conditioning CRH antagonists and p-adrenergic recep-... 

In the treatment of secondary adrenocortical insufficiency, lower doses of cortisol are generally effective, and fluid and electrolyte disturbances do not have to be considered, since patients with deficient corticotrophin secretion generally do not have abnormal function of the zona glomerulosa. Since cortisol replacement therapy is required for life, adequate assessment of patients is critical to avoid the serious long-term consequences of excessive or insufficient treatment. In many cases, the doses of glucocorticoid used in replacement therapy are probably too high. Patients should ideally be administered three or more doses daily. To limit the risk of osteoporosis, replacement therapy should be carefully assessed on an individual basis and overtreatment avoided. 

Fahlke, C., Lorenz, J.G., Long, J., Champoux, M., Suomi, S.J., and Higley, J.D. (2000) Rearing experiences and stress-induced plasma cortisol as early risk factors for excessive alcohol consumption in nonhuman primates. Alcohol Clin Exp Res 24 644-650. 

An example of the importance of enzymatic modification of hormones for the tissue specificity of hormone action is the effect of the mineral corticoid aldosterone in the presence of a large excess of the glucocorticoid cortisol. Aldosterone regulates the Na -export and K -retention in the kidney by binding on the aldosterone receptor. 

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