Zonaglomerulosa

Angiotensin IIK+

ACTH

Aldosterone

Cortisol,androgens

11-hydroxylase17-hydroxylase

Aldosteronesynthase

Zonafasciculata/reticularis

CHAPTER 28 / Pharmacology of the Adrenal Cortex 491

protects the mineralocorticoid receptor from activation by cortisol in a variety of cell types, including endothelial cells and vascular smooth muscle cells. In contrast, cortisone can be converted back to cortisol (also referred to as hydrocorti-sone ) in the liver by 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD 1, Fig. 28-3A). The interplay between these op-posing reactions determines overall glucocorticoid activity. In addition, as discussed below, the activity of these enzymes is important in glucocorticoid pharmacology.

Physiologic Actions Like other steroid hormones, unbound cortisol diffuses through the plasma membrane into the cytosol of target cells, where the hormone binds to a cytosolic receptor. There are two types of glucocorticoid receptors: the Type I (mineralo-corticoid) and Type II glucocorticoid receptors . The Type I receptor is expressed in the organs of excretion (kidney, colon, salivary glands, sweat glands) and other tissues in-cluding the hippocampus, vasculature, heart, adipose tissue, and peripheral blood cells. The Type II receptor has a broader

overall capacity, whereas albumin has low cortisol affi nity but high overall capacity. Only molecules of cortisol that are unbound to protein (the so-called free fraction ) are bioavail-able, that is, available to diffuse through plasma membranes into cells. Thus, the affi nity and capacity of plasma bind-ing proteins regulate the availability of active hormone and, consequently, hormone activity.

The liver and kidneys are the primary sites of peripheral cortisol metabolism. Through reduction and subsequent con-jugation to glucuronic acid, the liver is responsible for inacti-vating cortisol in the plasma. The conjugation reaction makes cortisol more water soluble, thus enabling renal excretion. Importantly, the liver and kidneys express different isoforms of the enzyme 11 -hydroxysteroid dehydrogenase , a regu-lator of cortisol activity. The two isoforms catalyze opposing reactions. In distal collecting duct cells of the kidney, 11 -hydroxysteroid dehydrogenase type 2 (11 -HSD 2) converts cortisol to the biologically inactive compound cortisone , which (unlike cortisol) does not bind to the mineralocorticoid receptor (see below, Fig. 28-3B). Expression of 11 -HSD 2

ACTH

CholesterolAminoglutethimideKetoconazole (high)

Feedback inhibition

Trilostane

Metyrapone

Ketoconazole

Trilostane

Metyrapone

Pregnenolone

17-hydroxypregnenolone

17-hydroxyprogesterone

11-deoxycortisol

Cortisol

GlucocorticoidsMineralocorticoids Sex steroids

Progesterone

11-deoxycorticosterone

Corticosterone

Aldosterone

Dehydroepiandrosterone

Androstenedione

Testosterone

Anterior pituitary gland

Adrenal gland

Trilostane

17

21

11

1721

11

FIGURE 28-2. Hormone synthesis in the adrenal cortex. The hormones of the adrenal cortex are steroids derived from cholesterol. The rate-limiting step in adrenal hormone biosynthesis is the modifi cation of cholesterol to pregnenolone by side-chain cleavage enzyme. From this step, pregnenolone metabolism can be directed toward the formation of aldosterone, cortisol, or androstenedione. The fl ux of metabolites through each of these pathways depends on the tissue-specifi c expression of enzymes in the different cell types of the cortex and on the relative activity of the different synthetic enzymes. Note that several enzymes are involved in more than one pathway and that defects in these enzymes can affect the synthesis of more than one hormone. For example, a defect in steroid 21-hydroxylase prevents the synthesis of both aldoster-one and cortisol. This overlap of synthetic activities also contributes to the nonselective action of glucocorticoid synthesis inhibitors such as trilostane. Enzymes are shown as numbers: 17, steroid 17 -hydroxylase; 21, steroid 21-hydroxylase; 11, steroid 11 -hydroxylase. Aminoglutethimide and high levels of ketoconazole inhibit side-chain cleavage enzyme. Ketoconazole also inhibits 17, 20-lyase. Trilostane inhibits 3 -hydroxysteroid dehydrogenase. Metyrapone inhibits steroid 11 -hydroxylase.

O

O

H

H

H

O

OHOH

O

HO

H

H

H

O

OHOH

O

O

H

H

H

O

OHOH

O

HO

H

H

H

O

OHOH

CortisoneCortisol(agonist at mineralocorticoid

receptor)(inactive at mineralocorticoid

receptor)

CortisolCortisone

11-HSD 1

A

B

(liver)

11-HSD 2

(kidney)

CHAPTER 28 / Pharmacology of the Adrenal Cortex 493

stores little cortisol, ACTH regulates cortisol production by promoting synthesis of the hormone. ACTH also has a trophic effect on the zona fasciculata and zona reticularis of the adrenal cortex, and hypertrophy of the cortex can occur in response to chronically elevated levels of ACTH.

As in other endocrine axes, the hormone (cortisol) pro-duced by the target organ (adrenal cortex) exerts negative feedback regulation at the level of both the hypothalamus and the anterior pituitary gland. High cortisol levels de-crease both synthesis and release of CRH and ACTH. Be-cause ACTH has important trophic effects on the adrenal cortex, the absence of ACTH leads to atrophy of the cortisol-producing zona fasciculata and the androgen-producing zona reticularis. However, the aldosterone-producing zona glom-erulosa cells continue to function in the absence of ACTH, because angiotensin II and blood potassium continue to stimulate the production of aldosterone.

Pathophysiology Diseases affecting glucocorticoid physiology can be divided into disorders of hormone defi ciency and disorders of hor-mone excess. Addisons disease is the classic example of adrenocortical insuffi ciency, while Cushings syndrome ex-emplifi es cortisol excess.

Adrenal Insuffi ciency Addisons disease is an example of a primary adrenal insuf-fi ciency in which the adrenal cortex is selectively destroyed, most commonly due to a T cell-mediated autoimmune reac-tion but alternatively due to infection, infi ltration, cancer, or hemorrhage. Destruction of the cortex results in decreased synthesis of all classes of adrenocortical hormones. By comparison, secondary adrenal insuffi ciency is caused by hypothalamic or pituitary disorders or by prolonged admin-istration of exogenous glucocorticoids. In secondary adrenal insuffi ciency, the decrease in ACTH levels causes decreased

CRH then travels through the hypothalamicpituitary por-tal system and binds to G protein-coupled receptors on the surface of corticotroph cells in the anterior pituitary gland. CRH binding stimulates the corticotrophs to synthesize proo-piomelanocortin (POMC) , a precursor polypeptide that is cleaved into multiple peptide hormones including ACTH. The neurons in the paraventricular nucleus that respond to stress by synthesizing and secreting CRH can also respond to stress by synthesizing and secreting vasopressin. This vasopressin is released into the hypothalamicpituitary portal system to-gether with CRH, and it synergizes with CRH to increase the release of ACTH by the anterior pituitary gland. Interestingly, the stress-responsive parvocellular neurons that secrete CRH and vasopressin into the hypothalamicpituitary portal system are different from the osmolality-responsive magnocellular neurons that synthesize vasopressin and transport this hor-mone to the posterior pituitary gland (see Chapter 26), even though both types of neurons are located in the paraventricu-lar nucleus of the hypothalamus. Potential crosstalk between the parvocellular and magnocellular systems in the paraven-tricular nucleus is an area of active investigation.

Proteolytic cleavage of POMC yields not only ACTH but also -melanocytestimulating hormone (MSH), lipotropin, and -endorphin. MSH binds to receptors on skin melano-cytes, promoting melanogenesis and thereby increasing skin pigmentation. Because of the similarities between the ACTH and MSH peptide sequences, high concentrations of ACTH can also bind to and activate MSH receptors. This action becomes apparent in primary hypoadrenalism (see below), in which increased ACTH levels result in increased skin pigmentation. The role of lipotropin in human physiology is uncertain but is thought to involve control of lipolysis. -Endorphin is an endogenous opioid that is important for pain modulation and for regulation of reproductive physiology.

Because steroid hormones are able to diffuse freely through cell membranes and because the adrenal gland

FIGURE 28-4. The immuneadrenal axis. Cortisol has profound immunosuppressive effects. Cortisol inhibits the action of several mediators of infl ammation (eicosanoids, serotonin, platelet activating factor [PAF], bradykinin). Cortisol also inhibits the release of a number of cytokines from macrophages, including IL-1 , IL-1 , IL-6, and TNF- . Because these cytokines in turn promote the hypothalamic release of CRH and thereby increase serum cortisol levels, it is hypothesized that the stress-induced increase in cortisol limits the extent of the infl ammatory response.

Pituitarygland

Adrenalgland

HypothalamusCRH

ACTH

Cortisol

Mediators of inflammation(eicosanoids, serotonin,

PAF, bradykinin)

Thermoregulatorycenters

Fever

Immunestimulus

Macrophages

Inflammatorycytokines

(IL-1, IL-1, IL-6, TNF-)