Cortisol, synthesis

Cortisol synthesis requires three hydroxylases located in the fasciculata and reticularis zones of the adrenal cortex that act sequentially on the Cjy, C21, and Cjj positions. The first two reactions are rapid, while Cu hydroxylation is relatively slow. If the C, position is hydroxylated first, the action of 17a-hydroxylase is impeded and the mineralocorticoid pathway is followed (forming corti-... 

Secondary adrenal insufficiency occurs as a result of a pituitary gland dysfunction whereby decreased production and secretion of ACTH leads to a decrease in cortisol synthesis. Tertiary adrenal insufficiency is a disorder of the hypothalamus that results in decreased production and release of CRH, which, in turn, decreases pituitary ACTH production and release. In contrast to Addison s disease (i.e., primary adrenal insufficiency), aldosterone production is unaffected in the secondary and tertiary forms of the disease. Chronic adrenal insufficiency often has a good prognosis if diagnosed early and treated appropriately. 

Metyrapone inhibits 11-hydroxylase activity, resulting in inhibition of cortisol synthesis. Initially, patients can demonstrate an increase in plasma ACTH concentrations because of a sudden drop in cortisol. This can cause an increase in androgenic and mineralocorticoid hormones resulting in hypertension, acne, and hirsutism. Nausea, vomiting, vertigo, headache, dizziness, abdominal discomfort, and allergic rash have been reported after oral administration. 

Primary adrenal insufficiency (Addison s disease) most often involves the destruction of all regions of the adrenal cortex. There are deficiencies of cortisol, aldosterone, and the various androgens. Medications that inhibit cortisol synthesis (e.g., ketoconazole) or accelerate cortisol metabolism (e.g., phenytoin, rifampin, phenobarbital) can also cause primary adrenal insufficiency. 

Etomidate hardly affects the autonomic nervous system. Since it inhibits cortisol synthesis, it can be used in the treatment of adrenocortical overactivity (Cushing s disease). 

E) It preferentially blocks cortisol synthesis as opposed to testosterone production. 

Thakore JH, Dinan TG Cortisol synthesis inhibition a new treatment strategy for the clinical and endocrine manifestations of depression. Biol Psychiatry 37 364-368, 1995... 

Inhibition of adrenocortical synthetic function. Etomidate inhibits the activity of ll-p-hydroxylase, an enzyme necessary for the synthesis of cortisol, aldosterone, 17-hydroxyprogesterone, and corticosterone. Even after a single dose, adrenal suppression persists for 5-8 hours. Although the clinical significance of short-term suppression of cortisol synthesis is unknown, maintenance infusions for anaesthesia cannot be recommended. 

Attenuated conversion of cortisol to cortisone in AME causes inhibition of cortisol synthesis (negative feedback), and excretion of total cortisol metabolites is typically 50% lower than normal. The condition is most commonly diagnosis by determining... 

The primary glucocorticoid released in humans is cortisol (also known as hydrocortisone). Cortisol synthesis and secretion are under the control of specific hypothalamic and pituitary hormones.7,24 31 Corticotropinreleasing hormone (CRH) from the hypothalamus stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH travels in the systemic circulation to reach the adrenal cortex, where it stimulates cortisol synthesis. Cortisol then travels in the bloodstream to various target tissues to exert a number of physiologic effects (see Physiologic Effects of Glucocorticoids, later). 

Ketoconazole [kee toe KON a zole], a substituted imidazole, is one of a family of azoles useful in treating systemic mycoses. In addition to its antifungal activity, ketoconazole also inhibits gonadal and adrenal steroid synthesis in humans by blocking C17-20 lyase, Up-hydroxylase, and cholesterol side-chain cleavage thus, it suppresses testosterone and cortisol synthesis. 

The anesthetic effect of (+)-etomidate subsides within a few minutes owing to redistribution of the drug. Etomidate can provoke myoclonic movements that can be prevented by premedication with a benzodiazepine or an opioid. Because it has little effect on the autonomic nervous system, it is suitable for induction in combination anesthesia. Etomidate inhibits cortisol synthesis in subanesthetic doses and can therefore be used in the long-term treatment of adrenocortical overactivity (Cushing disease). 

Other adrenal disorders are relatively uncommon in the elderly. For example, both ACTH and cortisol synthesis remain constant throughout life. Thus, in general, blood levels are not altered during aging (W13). 

Rationale Metyrapone inliibits 1 iP-hydroxylase, the enzyme that catalyzes the step immediately preceding cortisol synthesis. As the blood concentration of cortisol falls, the negative feedback effect is diminished, causmg release of ACTH from the pituitary gland. The stimulatory effect of ACTH on the adrenal cortex leads to a rise in 11-deoxycortisol, the compound immediately preceding cortisol in the biosynthetic pathway. 

Interference with protein synthesis and the signaling pathways leading to cortisol synthesis... 

Lacroix, M. and A. Hontela. Regulation of acute cortisol synthesis by cAMP-dependant protein kinase and protein kinase C in a teleost species, the rainbow trout (Oncorhynchus mykiss). J. Endocrinol. 169 71 -78, 2001. 

D. A CRH-secreting tnmor of the adrenal glands is stimnlating cortisol synthesis and is no longer responding to the negative feedback loop... 

To achieve the synthesis of cortisol, and possibly to a lesser extent corticosterone, it seems probable that the fetus and newborn infant can utilize a pathway which bypasses progesterone. The low activity of ZjS-HSD in the fetus and in infancy which has already been mentioned in Section 4 would be expected to cause an inhibition in the normal pathway of cortisol synthesis at the stage of conversion of pregnenolone into progesterone. Increased use of secondary pathways for corticoid synthesis via 21-OH-pregnenolone or 17a-OH-pregnenolone would then occur, with... 

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