Cortisol formation

The zona fasciculata is the exclusive site of cortisol formation. 

ACTH acts mainly on the cells of the zona fasciculata of the adrenal cortex to stimulate the synthesis and release of cortisol (Chapter 32). It also stimulates the secretion of adrenal androgens from the zona reticularis. Binding of ACTH to receptors activates formation of cAMP, which mediates cortisol formation and secretion and protein synthesis. Deficiency of ACTH leads to reduction in size and activity of adrenocortical cells in the inner two zones. 

Fig. 1. Biosynthetic pathways for formation of cortisol from cholesterol.

Compounds having the 16,17 ketal, eg, budesonide, amcinonide, fluocinonide, halcinonide, triamcinolone acetonide, and flurandrenohde, also undergo metabohsm by routes that parahel that of cortisol metabohsm. Unsymmetrical acetals such as budesonide are also metabolized by routes not available to the more metabohcahy stable symmetrical 16a,17a-isopropyhdiene-dioxysubstituted compounds (desonide, flunisohde, and triamcinolone acetonide). Isozymes within the cytochrome P450 3A subfamily are thought to catalyze the metabohsm of budesonide, resulting in formation of 16a-hydroxyprednisolone and 6P-hydroxybudesonide (19,20) (Fig. 3) in addition to the more common metabohc steps (oxidation via reduction of A, etc). 

FIGURE 25.43 The steroid hormones are synthesized from cholesterol, with intermediate formation of pregnenolone and progesterone. Testosterone, the principal male sex hormone steroid, is a precursor to /3-estradiol. Cortisol, a glucocorticoid, and aldosterone, a mineralocorticoid, are also derived from progesterone. 

Cortisol-induced lipolysis not only provides substrates for gluconeogenesis (formation of glucose from noncarbohydrate sources) but it also increases the amount of free fatty acids in the blood. As a result, the fatty acids are used by muscle as a source of energy and glucose is spared for the brain to use to form energy. 

The answer is a. (Hardman, pp 1482—1483. Katzung, pp 673-674.) Metyrapone inhibits 11-hydroxylation of steroid precursors, which prevents formation of cortisone and cortisol. These precursors are then diverted into aldosterone and androgen production pathways, which explains the adverse effects of hirsutism and edema... 

An account of the principles which help to understand how hormones achieve their roles in the body is given in Chapter 12. The understanding is based on separation of the effects of hormones into three components the action, the effects (biochemical and physiological) and the function. A steroid hormone binds to a cytosolic intracellular receptor, which then moves into the nucleus where it binds to DNA at a specific site (the steroid response element) and activates genes which result in the formation of proteins that elicit biochemical and physiological effects. This is discussed for cortisol in Chapter 12 and aldosterone in Chapter 22. Much of the interest in the reproductive steroid hormones is in the physiological effects and how these account for their functions. 

The synthesis and degradation of muscle proteins are regulated by hormones. Cortisol leads to muscle degradation, while testosterone stimulates protein formation. Synthetic anabolics with a testosterone-like effect have repeatedly been used for doping purposes or for intensive muscle-building. 

Congenital defects in the biosynthesis of steroid hormones can lead to severe developmental disturbances, in the adrenogenital syndrome (AGS), which is relatively common, there is usually a defect in 21-hydroxylase, which is needed for synthesis of cortisol and aldosterone from progesterone. Reduced synthesis of this hormone leads to increased formation of testosterone, resulting in masculin-ization of female fetuses. With early diagnosis, this condition can be avoided by providing the mother with hormone treatment before birth. 

The administration of spironolactone (Aldactone) interferes in the determination of 11-hydroxy corticosteroid by methods that depend on formation of fluorescence in strong sulfuric acid (W15). In 5 patients, the administration of the drug produced as much as a 5-fold increase in the apparent plasma cortisol levels. Aspirin interferes in the determinations of homovanillic acid (HVA) by a fluorometric method. The HVA fluorophore occurs at 320 nm and 420 nm, and acetylsalicylic acid produces fluorescence at 305 to 405 nm (H12). 

Several successful attempts were done to transfer classical CEIA to a microchip-based format. This kind of miniaturization is a trend that can overcome the limitations of CE in high-throughput systems. On-chip CE offers both parallel analysis of samples and short separation times. Koutny et al. showed the use of an immunoassay on-chip (32). In this competitive approach fluorescein-labeled cortisol was used to detect unlabeled cortisol spiked to serum (Fig. 8). The system showed good reproducibility and robustness even in this problematic kind of sample matrix. Using serum cortisol standards calibration and quantification is possible in a working range of clinical interest. This example demonstrated that microchip electrophoretic systems are analytical devices suitable for immunological assays that can compete with common techniques. 

Cortisol into 7- 3-hydroxycortisol. Epoxidation Benzene into benzene 1,2-epoxide. N-oxidation Drug containing amino groups can undergo N-oxidation i.e. imipramine into imipramine N-oxide. 0-dealkylation This reaction probably Involves formation of an unstable hydroxy methyl Intermediate I.e. codeine Into morphine. 

Within the adrenal cortex (the outer portion of the adrenal glands) progesterone is converted into two groups of hormones of which cortisol and aldosterone are representative.263 Two different cytochrome P450 hydroxylases, found in the ER and specific for C-21 and C-17a, respectively, together with a mitochondrial cytochrome P450 specific for C-lip (Eq. 18-55) participate in formation of cortisol.264 Two of the same enzymes together with additional hydroxylases are required to form aldosterone. 

According to the available returns the average reported dosages were 500-750mg daily to inhibit excessive estrogen formation from AAS aromatization and 1000-2000mg daily for the purpose of cortisol inhibition. Most reported a scaled weekly dosage... 

Glucocorticoids Cortisol Adrenals Bone formation, wound healing, growth, development... 

R. Bucala, J. Fishman, and A. Cerami, Formation of covalent adducts between cortisol and 16a-hydroxyestrone and protein Possible role in the pathogenesis of cortisol toxicity and systemic lupus erythematosus, Proc. Natl. Acad. Sci. USA 79 3320 (1982). 

Glucocorticoids Adrenal cortex Cortisol Promotes gluconeogenesis and glycogen formation enhances fat and protein degradation... 

Prednisone [PRED ni sone] is a potent synthetic anti-inflammatory corticosteroid with less mineralocorticoid activity than cortisol (see p. 272). The use of this compound in the treatment of lymphomas arose when it was observed that patients with Cushing s syndrome (a syndrome associated with hypersecretion of cortisol) have lymphocytopenia and decreased lymphoid mass. These result from corticosteroid action on lymphocyte formation and distribution, that is, movement of these cells from the circulation to lymphoid tissue. 

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