Adrenal steroids cholesterol synthesis

Endocrine effects Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Small declines in total testosterone with no commensurate elevation in LH have been noted with the use of fluvastatin. Pravastatin showed inconsistent results with regard to possible effects on basal steroid hormone levels atorvastatin, lovastatin, rosuvastatin, and simvastatin did not reduce basal plasma cortisol concentration or basal plasma testosterone concentration or impair adrenal reserve. Appropriately evaluate patients who display clinical evidence of endocrine dysfunction. Exercise caution when administering HMG-CoA reductase inhibitors with drugs that affect steroid levels or activity, such as ketoconazole, spironolactone, and cimetidine. 

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

In the animal body three important groups of hormones are formed by the metabolism of cholesterol the progestins, the sex hormones, and the adrenal cortical hormones 249 Their synthesis occurs principally in mitochondria of the adrenal cortex and the gonads. Steroid hormone synthesis is regulated by hormones, such as corticotropin (ACTH), from the anterior pituitary250 (see Chapter 30) and is also dependent upon the recently discovered steroidogenic acute regulatory protein, which in some way promotes the movement of stored cholesterol into mitochondrial membranes.251 252 Some major pathways of... 

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. 

Studies by Bell and coworkers have shown that DEHP also can alter sterologenesis in rodents, which may have an impact on steroid-dependent functions, such as reproductive functions. For example, feeding female rats DEHP at an estimated dose of 500 mg/kg/day for 13 days significantly inhibited sterologenesis from 14C-mevalonate in liver and adrenal minces (Bell 1980). DEHP also inhibited cholesterol synthesis in the liver from male rats and rabbits as well as in rats testes (Bell 1982). In a subsequent study, Bell and Buthala (1983) demonstrated that the inhibition of cholesterol synthesis in the liver was due to a reduction in the activity of microsomal acylCoA cholesterol acyltransferase, an enzyme responsible for the esterification of cholesterol. 

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. 

Endocrine function HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. 

LDL takes place by way of specific ceE surface LDL receptors on the adrenal gland surface that internalize the cholesterol moiety, releasing it as substrate for steroidogenesis however, ail steroidogenic cells are capable of de novo synthesis from acetyl coenzyme A. To ensure a continuous supply of free cholesterol for steroid synthesis, lipoprotein cholesterol uptake is coordinated with intracellular cholesterol synthesis and with the mobilization of intracellular cholesteryl ester pools. When the rate of cholesterol uptake exceeds the rate of steroidogenesis, intracellular cholesterol synthesis is suppressed, and cholesterol in excess of cellular needs is esterified and stored for future use. 

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. 

This process is important for proliferating cells, in which cholesterol is reqnired for formation of new membranes, and for some endocrine cells (in the testis, ovary and adrenal cortex) for the synthesis of steroid hormones. 

All growing animal tissues need cholesterol for membrane synthesis, and some organs (adrenal gland and gonads, for example) use cholesterol as a precursor for steroid hormone production (discussed below). Cholesterol is also a precursor of vitamin D (see Fig. 10-20a). 

Mitochondrial system The function of the mitochondrial cyto chrome P450 monooxygenase system is to participate in the hydroxylation of steroids, a process that makes these hydropho bic compounds more water soluble. For example, in the steroid hormone-producing tissues, such as the placenta, ovaries, testes, and adrenal cortex, it is used to hydroxylate intermediates in the conversion of cholesterol to steroid hormones. The liver uses this system in bile acid synthesis (see p. 222), and the kidney uses it to hydroxylate vitamin 25-hydroxycholecalciferol (vitamin D, see p. 384) to its biologically active 1,25-hydroxylated form. 

Cholesterol, which is essential for the synthesis of adrenal, ovarian, and testicular steroid hormones, originates from two sources. The body synthesizes approximately 2 g of cholesterol per day, according to the following pathway ... 

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). 

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