Adrenal steroids biosynthesis

High-dose progestins are used as last-line endocrine therapy [223]. They inhibit the adrenal steroid biosynthesis. The decrease of estrogen levels is comparable to that caused by the administration of aromatase inhibitors. In post-menopausal women, the progestin megestrol acetate (MGA) decreases serum plasma level of DEAH, androstenedione and cortisol to less than 10% [223,224]. 

Primary aldosteronism usually results from the excessive production of aldosterone by an adrenal adenoma. However, it may also result from abnormal secretion by hyperplastic glands or from a malignant tumor. The clinical findings of hypertension, weakness, and tetany are related to the continued renal loss of potassium, which leads to hypokalemia, alkalosis, and elevation of serum sodium concentrations. This syndrome can also be produced in disorders of adrenal steroid biosynthesis by excessive secretion of deoxycorticosterone, corticosterone, or 18-hydroxycorticosterone—all compounds with inherent mineralocorticoid activity. 

Weber MM, Lang J, Abedinpour F, Zeilberger K, Adelmann B, Engelhardt D. Different inhibitory effect of etomidate and ketoconazole on the human adrenal steroid biosynthesis. Clin Investig 1993 71(ll) 933-8. 

FIGURE 29-1 Pathways of adrenal steroid biosynthesis. Cholesterol is the precursor for the three steroid hormone pathways. Note the similarity between the structures of the primary mineralocorticoid (aldosterone), the primary glucocorticoid (cortisol), and the sex hormones (testosterone, estradiol). See text for further discussion. 

In the safety pharmacology protocol, the interaction of multiple endocrine systems in test animals is addressed. As discussed by Harvey (1996) and by Harvey and Everett (2003), effects on adrenocortical function are frequently found in toxicology studies, sometimes related to enzyme induction and effects on steroid biosynthesis (Loose et al. 1983, Nebert and Russell 2002, Weber et al. 1993). Test procedures in animals are required when there is a reason for concern. Frequently however the effects observed are due to stress rather than specific interaction with the target organ, and may involve effects on catecholamine release from the adrenal medulla (Tucker 1996). Recently, much new evidence has been accumulated from the testing of industrial chemicals with effects on adrenal steroid biosynthesis (Harvey and Johnson 2002). 

For serum corticosterone, preferably a stimulation test with ACTH after low dose dexamethasone blockage of spontaneous secretion may be included. Rats are injected with 0.5 mg/kg oft dexamethasone 18 hours before the stimulation test. The test is then performed by a injection of synthetic ACTH (1-24), which is readily available as a clinical diagnostic tool. The clinical test procedures have been reviewed (Weiss and Patel 2002). Extended investigations are the assessment of effects on other steroid secreting organs (gonadal system), and the assessment of hypothalamic-pituitary changes at the end of the treatment period. Determination of pituitary ACTH content may be particularly useful in case of inhibitory effects on adrenal steroid biosynthesis. 

Temple TE, Liddle GW (1970) Inhibitors of adrenal steroid biosynthesis. Ann Rev Pharmacol 10 199-218... 

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. 

Physical and occupational therapists will encounter many patients who are receiving adrenal steroids for hormone replacement or for various other therapeutic reasons. This chapter discusses the biosynthesis of the adrenal steroids in an effort to show some of the structural and functional similarities between various... 

In male animals, weight of the adrenals, testes, seminal vesicles and ventral prostate is recorded (because the effects on steroid biosynthesis frequently involve both the adrenal and gonadal system). In female animals, weight of the adrenals, ovaries and uterus is recorded. As an added investigation, the hypothalamus of the animals may be dissected out and shock frozen immediately for assay of corticotropin releasing hormone (CRH), and the adenohypophysis... 

The method is suitable to detect changes in steroid in biosynthesis induced by test compounds. In endocrine safety evaluation, it is however recommended to apply measurement of corticosterone and adrenal steroid in metabolites in the tissue as an ex-vivo investigation to test material from animals previously treated in a repeated dose protocol. 

G-12) (G-13) 21-bydroxylase deficiency. This is the most common hereditary enzyme defect in steroid biosynthesis. There is decreased glucocorticoid and mineralocorticoid production, as the enzyme is common to both pathways. This leads to increased ACTH production, which in turn causes adrenal hyperplasia and increased pregnenolone production. This results in increased androgen production and virilization. Therapy consists in administering glucocorticoids. This decreases ACTH production by negative feedback. 

The resolution of two high spin forms in adrenal mitochondria has been exploited in studies of the stimulation of steroid biosynthesis by ACTH and the effects of stress. Mitochondria from stressed rats showed increased amounts of high spin P-450, most notably in that corresponding to cholesterol side chain cleavage and similar but not identical effects were observed when hypophysectomised rats were treated with ACTH [118]. This supports the thesis that ACTH stimulation increases the availability of cholesterol for side chain cleavage. In adrenals, ESR can also be used to monitor the presence of reducing equivalents to P-450 as, in this case, the P-450 is linked to NADPH via an iron-sulphur protein, adrenal ferredoxin. This shows typical signals on reduction at g = 2.01, 1.94 [119]. A similar iron-sulphur protein (g = 2.03, 1.94) occurs in mammalian testes connected with a P-450 system [120]. 

In the first place the discovery of the secretion of DHA-sulfate by the adrenal cortex in apparently major quantities suggested a hitherto completely unsuspected role of steroid sulfates in steroid biosynthesis and metabolism. Second, a number of steroid metabolites conjugated with two molecules of glucuronic or sulfuric acid were discovered, particularly in pregnancy urine, amniotic fluid, and in perfused placentofetal preparations. Finally, isotopic studies revealed several cases in which administered doubly labeled steroid conjugates were metabolized in the steroid part of the molecule without hydrolysis of the conjugate (e.g., D4, R5 cf. B5). 

Hydroxylation of Adrenal Steroids Studies of the biosynthesis of corticosteroids by adrenal glands, either perfused, minced, or in isolated mitochondria do not reveal any increased reaction with ascorbic acid, although the high ascorbic acid content of the adrenals has prompted many such experiments. Under certain conditions such an effect can be observed on the hydroxylation reactions which require molecular oxygen. An example of such a reaction is the... 

FIGURE 10.3.2 Steroid biosynthesis in the adrenal cortex. The relevant enzymes are in italics and boxes indicate where the enzymes catalyze more than one reaction. 

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