Porth's Essentials of Pathophysiology, 4e

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Endocrine System

U N I T 9

of metabolic conversions before being conjugated and made water soluble. They are then eliminated in either the urine or the bile. Mineralocorticoid Hormones The mineralocorticoids play an essential role in regu- lating potassium and sodium levels and water balance. They are produced in the zona glomerulosa or the outer layer of cells of the adrenal cortex. Aldosterone secre- tion is regulated by the renin-angiotensin mechanism and by blood levels of potassium. Increased levels of aldosterone promote sodium retention by the distal tubules of the kidney while increasing urinary losses of potassium. The influence of aldosterone on fluid and electrolyte balance is discussed in Chapter 8. Glucocorticoid Hormones The glucocorticoid hormones, mainly cortisol, are syn- thesized in the zona fasciculata and the zona reticularis of the adrenal cortex. The blood levels of these hormones are regulated by negative feedback mechanisms of the hypothalamic-pituitary-adrenal (HPA) system (Fig. 32-13). Just as other hormones from the hypothalamus control the release of their target pituitary hormones, corticotropin-releasing hormone (CRH) controls the release of ACTH. In turn, ACTH controls the release of cortisol. Levels of cortisol increase as ACTH levels rise and decrease as ACTH levels fall. There is considerable diurnal variation in ACTH levels, which reach their peak in the early morning (around 6 to 8 am ) and decline as the day progresses. 26 This appears to be due to rhythmic activity in the CNS, which causes bursts of CRH secre- tion and, in turn, ACTH secretion. This diurnal pattern is reversed in people who work during the night and sleep during the day. The rhythm also may be changed by physical and psychological stresses, endogenous depres- sion, and liver disease or other conditions that affect cortisol metabolism. One of the earliest signs of Cushing syndrome, a disorder of glucocorticoid excess, is the loss of diurnal variation in CRH and ACTH secretion. 40,41 The glucocorticoids perform a necessary function in response to stress and are essential for survival. When produced as part of the stress response, these hormones aid in regulating the metabolic functions of the body and in controlling the inflammatory response. The actions of cortisol are summarized in Table 32-2. Many of the anti-inflammatory actions attributed to cortisol result from the administration of pharmacologic levels of the hormone. By far the best-known metabolic effect of cortisol and other glucocorticoids is their ability to stimulate gluconeogenesis (glucose production) by the liver. In the process, body proteins are broken down and their amino acids are mobilized and transported to the liver, where they are used in the production of glucose. In much the same manner that cortisol promotes amino acid mobilization from muscle, it promotes mobiliza- tion of fatty acids from adipose tissue. This increased mobilization of fats by cortisol converts cell metabo- lism from the use of glucose for energy to the use of

Adrenal Cortical Hormones More than 30 hormones are produced by the adrenal cortex. Of these hormones, aldosterone is the principal mineralocorticoid, cortisol (hydrocortisone) is the major glucocorticoid, and androgens are the main sex hor- mones. All of the adrenal cortical hormones have a simi- lar structure in that all are steroids and are synthesized from acetate and cholesterol. Each of the steps involved in the synthesis of the various hormones requires a spe- cific enzyme (Fig. 32-12B). The secretion of both the glucocorticoids and adrenal androgens is controlled by ACTH secreted by the anterior pituitary gland. Cortisol, aldosterone, and the adrenal androgens are secreted in an unbound state and bind to plasma proteins for transport in the circulatory system. Cortisol binds largely to corticosteroid-binding globulin and to a lesser extent to albumin. Aldosterone and androgens circulate mainly bound to albumin. It has been suggested that the pool of protein-bound hormones may extend the dura- tion of their action by delaying metabolic clearance. The main site for metabolism of the adrenal corti- cal hormones is the liver, where they undergo a number

Cortex

Medulla

Cholesterol

Zona glomerulosa Zona fasciculata Zona reticularis

HO

Pregnenolone

A

Progesterone

17-Hydroxy- progesterone

17-Hydroxy- pregnenolone

11-Deoxycorticosterone

Dehydroepiandrosterone

11-Deoxycortisol

Corticosterone

Cortisol

Androstenedione

Aldosterone

B

Site of enzyme action 21-hydroxylase 11- -hydroxylase

FIGURE 32-12. (A) The adrenal gland, showing the medulla and the three layers of the cortex.The outer layer of the cortex (zona glomerulosa) is primarily responsible for mineralocorticoid production, and the middle layer (zona fasciculata) and the inner layer (zona reticularis) produce the glucocorticoids and the adrenal androgens. (B) Predominant biosynthetic pathways of the adrenal cortex. Critical enzymes in the biosynthetic process include 11- β -hydroxylase and 21-hydroxylase. A deficiency in one of these enzymes blocks the synthesis of hormones dependent on that enzyme and routes the precursors into alternative pathways.