Adrenal Steroid Activity

Direct tests for adrenal steroid activity are at the entry level of endocrine safety pharmacology, such activities are usually expressed by a feedback regulation at the pituitary level, changing the ACTH response, or by one of the multiple biological effects of the adrenal steroid hormones ranging from anti-inflammatory to immunosuppressive activity (Schimmer and Parker 1995). 

Regarding the adrenal steroids, the behavioral activation of hormonal secretion in stress is part of a mechanism for restoring homeostatic balance. For example, an encounter with a predator may require rapid evasive action, in which neural activity and rapidly mobilized hormones such as epinephrine play a role. Adrenal steroid secretion is slower, reaching a peak minutes after the stressful event, and therefore is not expected to play a role in coping with the immediate situation. If the evasive action is successful and... 

Dhabhar, ES. et al., Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley, Fischer 344, and Lewis rats, J. Neuroimmunol., 56, 77, 1995. 

Crawley JN, Glowa JR, Majewska MD, et al Anxiolytic activity of an endogenous adrenal steroid. Brain Res 398 382-385, 1986... 

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. 

Cameron, H.A., Tanapat, P., Gould, E. (1998). Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neurosci, 82,349-54. 

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. 

The excessive production of thyroid hormone in Graves disease is associated with an enlarged thyroid gland, but in this case a circulating immunoglobulin that mimics the activity of thyroid stimulating hormone (TSH) is implicated. Finally, we saw in an earlier section how an inappropriate steroid hormone may be secreted in excessive amounts when specific enzymes in the adrenal steroid biosynthetic pathway are present at inadequate levels. 

An example of a hormone that exerts its effects through a surface receptor-second messenger system is ACTH.36 ACTH is a polypeptide that binds to a surface receptor on adrenal cortex cells. The surface receptor then stimulates the adenylate cyclase enzyme to increase production of cAMP, which acts as a second messenger (the hormone was the first messenger), and increases the activity of other enzymes within the cell to synthesize adrenal steroids such as cortisol. For a more detailed description of surface receptor-second messenger systems, see Chapter 4. 

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. 

CRH activity, by determination of the hypothalamic peptide content - the information obtained by this measurement is usually limited and and will be controlled by the feedback action of pituitary hormone release or inhibition and adrenal steroid secretion... 

Non-heme iron protein, . . . , . Activity for adrenal steroid Physiological function . 1,, . . 11 p-hydroxylation ... 

In the account that follows, the effects of hydrocortisone will be described and then other steroids in so far as they differ. In the context of this chapter adrenal steroid means a substance with hydro-cortisone-like activity. Androgens are described in Chapter 37. 

CAS 53-43-0. CI9I I2/)2. An androgenic steroid, a metabolic product of the adrenal steroid hormones with about one-third of the androgenic activity of androsterone. 

CAS 57-83-0. C2II I, ),. The female sex hormone secreted in the body by the corpus luteum, adrenal cortex, or placenta during pregnancy. It is important in the preparation of the uterus for pregnancy and for the maintenance of pregnancy. It exists in two crystalline forms (a- and (i ) of equal physiological activity. Progesterone is believed to be the precursor of the adrenal steroid hormones. 

Aldosterone and cortisol are not the only adrenal steroids with mineralocorticoid and glucorticoid activities. Corticosterone (4-pregnen-ll S,21-diol-3,20-dione), a glucocorticoid about one-fifth as active as cortisol, has little mineralocorticoid activity relative to aldosterone 11-deoxycorticosterone (DOC) (4-pregnen-21-ol-... 

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