(CYP11A1) to delta-5-pregnenolone, the common parent compound for all adrenal cortex steroids.

Pregnenolone is then shunted to the three biosynthetic pathways, each compartmentalized within the

adrenal according to synthetic capabilities within each zone. In the zonae fasciculata and reticularis,

pregnenolone is either converted to progesterone by 3-beta-hydroxysteroid dehydrogenase or is

oxidized at position 17 by 17-alpha hydroxylase (CYP17) to form 17-hydroxypregnenolone. In the zona

fasciculata, progesterone is hydroxylated by CYP17 at position 17 to form 17-hydroxyprogesterone.

Subsequently, 17-hydroxyprogesterone is sequentially hydroxylated at the 21 position by 21-beta

hydroxylase (CYP21A2) and at position 11 by 11-beta hydroxylase (CYP11B1) to form cortisol. In the

zona reticularis, the androgenic steroids dehydroepiandrostenedione (DHEA) and androstenedione are

made from 17-hydroxypregnenolone and 17-hydroxyprogesterone, respectively. Collectively, the

glucocorticoid and androgenic steroids are known as 17-hydroxy corticosteroids and 17-hydroxy

ketosteroids. In the zona glomerulosa, progesterone is not hydroxylated at the 17 position owing to the

lack of enzyme at this location. Instead aldosterone is made from progesterone by a sequential series of

hydroxylation steps at position 21 by CYP21A2, position 11 by CYP11B1, and position 18 by

aldosterone synthase (CYP11B2 and P450c11as). The zona glomerulosa is well suited to aldosterone

biosynthesis because of the relative lack of 17-hydroxylase and the exclusive expression of aldosterone

synthase, required for the conversion of corticosterone to aldosterone.

Figure 77-2. Steroid biosynthetic pathways in the adrenal cortex. Steroids and precursors are shown in square boxes. Enzymes are

shown in stippled boxes. Enzyme gene symbol designations are: CYP11A1, desmolase; CYP17, 17α-hydroxylase (±17,20 lyase*);

3β-HSD, 3β-hydroxysteroid dehydrogenase; CYP21A2, 21-hydroxylase; CYP11B1, 11β-hydroxylase; CYP11B2, Aldosterone synthase.

Inset: Basic steroid ring structure. The four basic carbon rings are designated A, B, C, and D. Individual carbons at sites of

steroidegenic enzyme activity are designated numerically.

Cortisol

Cortisol is the predominant glucocorticoid in humans. Production and release of cortisol is tightly

regulated by a complex feedback relationship between the hypothalamus, corticotrophs of the anterior

pituitary, and cells of the adrenal cortex zonae fasciculata and reticularis. This endocrine system is

called the hypothalamic–pituitary–adrenal (HPA) axis. Communication within the HPA axis is mediated by

synthesis and secretion of corticotrophin-releasing hormone (CRH) by the hypothalamus and ACTH

production by corticotrophs of the anterior pituitary (Fig. 77-3). ACTH is a cleavage product of a

precursor polipeptide, proopiomelanocortin (POMC) that is built of 241-amino-acid residues within

corticotroph cells of the anterior and intermediate lobes of the pituitary. Several derivatives of POMC

are important biologically active substances, including ACTH. Under stimulation of hypothalamic CRH

stimulus, POMC can be cleaved into ACTH and β-lipotropic hormone in the anterior lobe. ACTH acts

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directly on the adrenal to regulate cortisol production by cells within the zonae fasciculata and

reticularis. Feedback loops involving cortisol, hypothalamic CRH, and pituitary ACTH keep the

concentration of cortisol in plasma within a narrow range of 10 to 15 μg/dL. Typical daily production of

cortisol in humans ranges from 10 to 30 mg and can increase to as high as 300 mg per day under

conditions of maximal stress.

In circulation, cortisol is protein bound to transcortin and albumin with a small percentage of free

cortisol available to target tissues. The half-life of cortisol in circulation is 90 minutes. Cortisol is

metabolized in the liver to the inactive metabolites dihydrocortisol and tetrahydrocortisol, which

become conjugated to glucuronidate and excreted in the urine. These urinary metabolites, collectively

known as 17-hydroxycorticosteroids, as well as free cortisol, can be measured in the urine.

Cortisol binds to specific intracellular cytoplasmic receptors, causing translocation of activated

receptor–ligand complexes to the nucleus. Biologic effects result from transcriptional activation of genes

and may be grouped into intermediary metabolism, immunomodulation, and regulation of intravascular

volume (Table 77-1). Important effects of cortisol on intermediary metabolism center on raising blood

glucose directly and indirectly by providing substrate for gluconeogenesis by the liver. These effects

include (a) stimulation of glucagon and inhibition of insulin-stimulated glucose uptake by cells; (b)

decrease in peripheral protein synthesis and increase in proteolysis, thus delivering gluconeogenic

amino acids to the liver; and (c) stimulation of peripheral lipolysis. In effect, cortisol acts anabolically in

vital organs to preserve glucose supply and catabolically in peripheral tissues to mobilize gluconeogenic

substrates. Cortisol also possesses profound anti-inflammatory and immunosuppressive activities.

Impairment of cellular immunity is due to inhibition of interleukin production, impairment of monocyte

and neutrophil chemotaxis despite raised leukocyte counts, and reduction of T-cell activation. Humoral

immunity is inhibited by inhibition of T-cell stimulation of B cells and by direct inhibition of B-cell

proliferation and activation. These immunomodulatory effects may also underlie the impairment of

normal wound healing seen in states of cortisol excess. Cortisol also regulates intravascular volume

through renal retention of sodium and maintains blood pressure through inotropic and chronotropic

effects on the heart as well as by increasing peripheral vascular resistance. In bone, glucocorticoids

promote osteopenia by inhibition of bone formation by osteoblasts.

Figure 77-3. Schematic of hypothalamic–pituitary–adrenal axis for cortisol. Regulatory feedback relationships are designated with

arrows.

Table 77-1 Systemic Effects of Cortisol

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Figure 77-4. Regulatory relationships of renin, the angiotensins, and their sites of production and enzymatic conversion.

Aldosterone

Aldosterone is the principle mineralocorticoid in humans. Aldosterone secretion by the cells of the

adrenal zona glomerulosa is regulated by the renin–angiotensin system and by plasma potassium (Fig.

77-4). Aldosterone is also regulated to a lesser degree by ACTH and plasma sodium concentration.

Juxtaglomerular myoepithelial cells lining afferent arterioles of the kidney sense renal blood flow and

pressure, and they secrete renin in response to decreased perfusion. Renin enzymatically activates

angiotensinogen to the inactive decapeptide precursor, angiotensin I. Angiotensin I is converted to

angiotensin II by angiotensin-converting enzyme in the lung. Angiotensin II has three major effects: (a)

arteriolar vasoconstriction; (b) renal sodium retention; and (c) increased aldosterone biosynthesis, each

of which results in sodium retention and potassium excretion by the kidney. These effects work together

to maintain arterial blood pressure as well as blood volume. Physiologic conditions that stimulate the

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renin–angiotensin cascade and aldosterone release include dehydration, upright posture, and

hemorrhage. Inhibitory factors include volume repletion. Postural changes in renin–angiotensin and

aldosterone are mediated by the sympathetic nervous system.

Under normal circumstances, aldosterone secretion is controlled by total body sodium and potassium

levels. Excess sodium intake suppresses renin activity and leading to decreased aldosterone levels and

increased renal excretion of sodium. Conversely, sodium depletion stimulates the renin–angiotensin

system and aldosterone production, which promotes sodium retention by the kidney. Increased

potassium intake directly decreases renin release and aldosterone production; decreasing potassium

intake increases renin release. Humans with normal sodium intake typically produce 100 to 150 mg of

aldosterone per day.

In circulation, aldosterone is bound to albumin and transcortin with a small percentage of free

aldosterone available to target tissues. The half-life of aldosterone in plasma is 15 minutes. Aldosterone

is metabolized rapidly in the liver and conjugated to glucuronidate, which is excreted in the urine. In

liver failure, metabolism of aldosterone is impaired leading to elevated levels and fluid retention.

Aldosterone is the major regulator of extracellular fluid volume and potassium homeostasis (Table 77-

2). Aldosterone binds to high-affinity aldosterone receptors in target tissues, including cells of the distal

convoluted tubule in the kidney (the major site of action), the salivary glands, and colonic mucosa

(minor sites). Stimulation of these cells results in retention of sodium and excretion of potassium.

Retention of sodium in the kidney leads to passive reabsorption of water and an increase in extracellular

fluid volume. To balance aldosterone-mediated retention of positively charged sodium ions, the kidney

epithelium releases intracellular potassium into the distal convoluted tubule for excretion in the urine.

Hydrogen ion is also released causing acidification of the urine.

Table 77-2 Effects of Aldosterone Secretion

Adrenal Androgens

Adrenal C-19 androgenic steroids, include DHEA and delta-4-androstenedione, are synthesized in cells of

the zona reticularis. These steroids promote secondary sexual characteristics in men and virilization in

women. DHEA is the major adrenal androgen, while androstenedione is relatively minor. Both are

relatively weak androgens and exert their effects on target tissue after local tissue conversion to

testosterone. Unlike gonadal androgens, adrenal androgens are regulated by ACTH, not gonadotropins,

and can therefore be inhibited by glucocorticoid administration.

Adrenal Medulla

2 Catecholamines of the adrenal medulla include epinephrine, norepinephrine, and dopamine. These

vasoactive hormones are synthetic derivatives of the amino acid tyrosine (Fig. 77-5). The biosynthetic

pathway that converts tyrosine to active catecholamines involves four sequential enzymatic reactions:

(a) tyrosine is converted to L-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase; (b) dopa is

converted to dopamine by aromatic-L-amino acid decarboxylase; (c) dopamine is converted to

norepinephrine by dopamine beta hydroxylase; and (d) norepinephrine is converted to epinephrine by

phenylethanolamine-N-methyltransferase (PNMT). Epinephrine is the major (80%) catecholamine stored

in the adrenal medulla, followed by norepinephrine (20%) and dopamine (<1%). Tissue expression of

the enzyme PNMT is limited to cells of either the adrenal medulla or organ of Zuckerkandl, located near

the aortic bifurcation, thus most extraadrenal pheochromocytomas produce norepinephrine, rather than

epinephrine.

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Figure 77-5. Catecholamine biosynthetic and metabolic pathways. Precursors, catecholamines, and metabolites are shown in square

boxes. Enzymes are shown in stippled boxes. Enzyme gene symbol designations are: TH, tyrosine hydroxylase; AADC, aromatic-Lamino acid decarboxylase; DBH, dopamine-β-hydroxylase; PNMT, phenylethanolamine-N-methyltransferase; COMT, catechol-Omethyl-transferase; MAO, monoamine oxidase. VMA, 3-methoxy-4-hydroxy-mandelic acid.

A complex regulatory network governs synthesis and secretion of catecholamines. Factors that

increase catecholamine release include splanchnic nerve stimulation, stress, and glucocorticoids. The

metabolic milieu within the adrenal medulla also greatly influences catecholamine synthesis by

regulating enzymatic activity: glucocorticoids, phospholipids, cyclic adenosine monophosphate,

adenosine triphosphate, protein kinase, and magnesium increase activity of PNMT and decrease

catecholamine negative feedback. Catecholamines are stored and secreted from granules within cells of

the medulla in association with the matrix protein chromogranin. Chromogranin A is measurable in the

blood and their measurement may support the biochemical testing for pheochromocytoma, as well as

other functional neuroendocrine tumors.

Catecholamines act on target tissues through membrane-bound receptors. Pharmacologic distinction

of adrenergic receptors is made based on their relative responsiveness to natural and artificial

bioamines. Alpha-adrenergic receptors show highest affinity for norepinephrine, less for epinephrine,

and least for isoproterenol. Beta-adrenergic receptors are most responsive to isoproterenol and least to

norepinephrine. In addition, specific antagonists recognize each receptor class: alpha-receptors are

antagonized by phentolamine and phenoxybenzamine, and beta-receptors are blocked by propranolol

and related compounds. Beta-adrenergic receptor subtypes include beta-1, which is present in cardiac

muscle, adipose tissue, and small intestine, and beta-2 receptors, which are found in vascular, tracheal,

and uterine smooth muscle, skeletal muscle, and liver. Alpha-adrenergic receptors are similarly

subdivided: alpha-1 receptors mediate vasoconstriction whereas alpha-2 receptors modulate presynaptic

norepinephrine release and platelet aggregation (Table 77-3).

Metabolism of catecholamines occurs through three mechanisms: by specific uptake by sympathetic

neurons, by nonspecific uptake and degradation by peripheral tissues, and by excretion in the urine.

Catecholamines are metabolized in liver and kidney by two enzymes, monoamine oxidase and catecholO-methyltransferase (Fig. 77-5). In these tissues, monoamine oxidase and catechol-O-methyltransferase

convert epinephrine or norepinephrine to normetanephrine, and metanephrine, 3,4-dihydroxy-mandelic

acid, and 3-methoxy-4-hydroxy-mandelic acid. These inactive metabolites are excreted by the kidney

and are measurable in the urine either as free compounds or as conjugates of glucuronide or sulfate.

Table 77-3 Catecholamine Effects

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