Adrenocortical function, steroids

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). 

Woodson, K., Lee, S.L. and Milbrandt, J. (1995) Adrenocortical function and regulation of the steroid 21p-hydroxylase gene in NGFI-B-deficientmice. Molecular and Cellular Biology, 15, 4331-4336. 

Another method that has been used to measure the excretion of adrenal steroids is the determination of formaldehydogenic steroids in the urine. This is no longer considered a reliable method of chemical assay and bears no certain relation to adrenocortical function (Marrian, 1952) nevertheless, it is worth reviewing the results obtained by this method in human scurvy. When ascorbic acid was administered to three patients with scurvy, instead of the expected increase in the excretion of formalde-hydogenic hormones, there was a fall in their excretion lasting several days (Daughaday et al., 1948). 

With the development of knowledge concerning the role of pantothenic acid in intermediary metabolism, the critical importance of this vitamin to adrenocortical function becomes more understandable. When the adrenal cortex is stimulated by stressful situations, its function is to respond rapidly by secreting steroid hormones which initiate and maintain a variety of physiological reactions. Its ability to synthesize these hormones may depend on its capacity to mobilize energy rapidly. Pantothenic acid, as part of coenzyme A, plays a critical role in the oxidative metabolism of both carbohydrate and fatty acids and may also be involved directly in lipid synthesis. Therefore, a deficiency in pantothenic acid can create a situation in which the ability of the adrenocortical cells to secrete steroid hormones is seriously impaired. 

In humans, most steroids function as hormones, chemical messengers that are secreted by endocrine glands and carried through the bloodstream to target tissues. There are two main classes of steroid hormones the sex hormones, which control maturation, tissue growth, and reproduction, and the adrenocortical hormones, which regulate a variety of metabolic processes. 

The natural adrenocortical hormones are steroid molecules produced and released by the adrenal cortex. Both natural and synthetic corticosteroids are used for the diagnosis and treatment of disorders of adrenal function. They are also used—more often and in much larger doses—for treatment of a variety of inflammatory and immunologic disorders. 

Secretion of adrenocortical steroids is controlled by the pituitary release of corticotropin (ACTH). Secretion of the salt-retaining hormone aldosterone is primarily under the influence of angiotensin. Corticotropin has some actions that do not depend on its effect on adrenocortical secretion. However, its pharmacologic value as an anti-inflammatory agent and its use in testing adrenal function depend on its secretory action. Its pharmacology is discussed in Chapter 37 and is reviewed only briefly here. 

Adrenocortical steroid hormones have a vast array of biological functions. Cortisol, the primary human glucocorticoid, regulates the inflammatory response (Newton and Holden, 2007), carbohydrate and lipid metabolism, and stress response (Kassel and Herrlich, 2007). Aldosterone regulates blood pressure by modulating fluid and electrolyte balance (Brizuela et ah, 2006 Foster, 2004). In the adrenal cortex, dehydroepiandrosterone (DHEA), dehy-droepiandrosterone sulfate (DHEA-S), and androstenedione are the androgens produced (Havelock et ah, 2004 Rainey et ah, 2002). 

Agents that inhibit steps in the steroidogenic pathway and thus alter the biosynthesis of adrenocortical steroids are discussed, as are synthetic steroids that inhibit glucocorticoid action. The effects of corticosteroids are numerous and widespread, and include alterations in carbohydrate, protein, and lipid metabolism maintenance of fluid and electrolyte balance and preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system, and the nervous system. 

---