Adrenal steroids, synthesis

Adrenal steroid synthesis. The adrenal cortex consists of three histologically distinct zones the zona glomerulosa, zona fasciculata, and an innermost layer called the zona reticularis. Each zone is responsible for production of different hormones. (17 =... 

Adrenocorticotropic hormone (ACTH] t adrenal steroid synthesis (e.g., cortisol]... 

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. 

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations that encode for enzyme involved in one of the various steps of adrenal steroid synthesis. These defects result in the absence or the decreased synthesis of cortisol from its cholesterol precursor. The anterior pituitary secretes excess ACTH via feedback regulation by cortisol, which results in overstimulation of the adrenals and causes hyperplasia. 

E. Inhibitors of Steroid Synthesis Ketoconazole, an antifungal agent, inhibits gonadal and adrenal steroid synthesis. The drug has been used to suppress adrenal steroid synthesis in patients with steroid-responsive metastatic tumors. 

Pont A, Williams PL, Loose DS et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982 97 370-72. 

Cortisone Reductase DeGciency. In hirsutism and virilization in females, cortisone reductase deficiency has been described. Patients with this disorder convert all their cortisol into cortisone. This gives rise to an apparent cortisol deficiency. Adrenocorticotropic hormone increases and stimulates the adrenal steroid synthesis. The urinary steroid profile is characterized by a very high excretion of THE, cortolones, and adrenal androgens, and low excretion of THF and 5a-THF [33]. 

The 17- and 21-hydroxylase enzymes are associated with microsomes, whereas the ll- -hydroxylase has a mitochondrial origin. Since the last-named enzyme is not detectable in other steroid-producing tissues, the term 11-oxygenated steroids is considered synonymous with adrenal steroids. Aldosterone synthesis involves an essential 18-hydroxylation step catalyzed by P450d8 with corticosterone as the precursor this reaction also takes place within the mitochondria. 

Mechanism of Action A glucocorticoid that stimulates initial reaction in synthesis of adrenal steroids from cholesteroL Therapeutic Effect Increases endogenous corti-coid synthesis. 

A direct effect on the adrenal cortex the regulation of steroid synthesis... 

Abiraterone is the newest of the steroid synthesis inhibitors to enter clinical trials. It blocks 17a-hydroxylase (P450cl7) and 17,20-lyase (Figure 39-1), and predictably reduces synthesis of cortisol and gonadal steroids in the adrenal and gonadal steroids in the gonads. A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone. Abiraterone is an orally active steroid prodrug and has been studied in the treatment of refractory prostate cancer. 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

The synthesis of adrenal steroids and major excreted metabolites is illustrated in Fig. 5.3.1. Little secreted steroid product is excreted unchanged and most of the catabolism takes place in the liver, although cortisol metabolism by the kidney is clinically important and microbial metabolism in the gut can be quantitatively significant. The major metabolic transformations of hormonal steroids and precursors are detailed by Makin [54] and summarized in Fig. 5.3.2. GC-MS steroid profiling is the technique of choice for measurement of important urinary constituents. 

The step-by-step synthesis of the steroid hormones pregnenolone and progesterone from cholesterol (C27) was presented in chapter 20 (see fig 20.22). Note that pregneno-lone (C2i) and progesterone (table 20.4) (C2 ) are intermediates in the biosynthesis of all of the major adrenal steroids, including cortisol (C2i), corticosterone (C21), and aldosterone (C21). The same two compounds are intermediates in the synthesis of the gonadal steroid hormones, testosterone (C,9) and 17/3-estradiol (CI8). Because the synthesis of all these hormones follows a common pathway, a defect in the activity or amount of an enzyme along that pathway can lead to both a deficiency in the hormones beyond the affected step and an excess of the hormones, or metabolites, prior to that step. 

B53. Brown, M. S., Kovanen, P. T., and Goldstein, J. L., Receptor-mediated uptake of lipoprotein cholesterol and its utilization for steroid synthesis in the adrenal cortex. Rec. Prog. Horn. Res. 35, 215-257 (1979). 

Although cholesterol is accepted as the major precursor of steroid hormones as a result of side-chain cleavage to pregnenolone (see below), research over the past decade or so has focused on the mechanisms by which steroidogenic tissues obtain cholesterol. It should be borne in mind that such tissues require cholesterol, not only for steroid synthesis but also for membrane synthesis, and hence require more of the precursor sterol than other tissues. Morris and Chaikoff [1] showed that the bulk of rat adrenal cholesterol was derived from circulating cholesterol, and later work revealed a similar state of affairs in humans. 

Several substances have proven to be useful as inhibitors of the synthesis of adrenal steroids metyrapone [me TEER a pone], aminoglutethimide [a mee noe glu TETH i mide], ketoconazole [kee toe KON a zole], and spironolactone. Mifepristone competes with glucocorticoids for the receptor. 

Ketoconazole (an antifungal agent, see p. 340) strongly inhibits all gonadal and adrenal steroid hormone synthesis. It is used in the treatment of patients with Cushing s syndrome. 

Amri, H. Drieu, K. Papadopoulos, V. Transcriptional suppression of adrenal cortical peripheral-t5fpe benzodiazepine receptor gene and inhibition of steroid synthesis by ginkgolide B. Biochem. Pharmacol, 2003, 65 717-729. 

Direct central nervous system effects of volatile nitrites have not yet been determined. In the body, nitrites are rapidly broken down into alcohol and nitrite ions, so the parent nitrite drugs may not reach the brain in concentrations comparable to those found in the blood. In one study, isoamyl nitrite concentrations were measured in the brains of rats exposed to the compound by inhalation. The drug was found to inhibit the synthesis or release of some adrenal steroids in the hypothalamus that are involved with stress. To understand the abuse potential of volatile nitrites, many more studies are needed to establish direct effects of the drugs on the brain. 

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