The adrenal cortex consists of 3 zones that vary in both their morphologic and functional features and thus, the steroid hormones they produce (see Figure 6–1).
The products of the adrenal cortex are classified into 3 general categories: glucocorticoids, mineralocorticoids, and androgens (see Figure 6–2) which reflect the primary effects mediated by these hormones. This will become clear when their individual target organ effects are discussed.
Chemistry and Biosynthesis
Steroid hormones share an initial step in their biosynthesis (steroidogenesis), which is the conversion of cholesterol to pregnenolone (Figure 6–3). Cholesterol used for steroid hormone synthesis can be derived from the plasma membrane or from the steroidogenic cytoplasmic pool of cholesteryl-esters. Free cholesterol is generated by the action of the enzyme cholesterol ester hydrolase. Cholesterol is transported from the outer mitochondrial membrane to the inner mitochondrial membrane, followed by the conversion to pregnenolone by P450scc enzyme; an inner mitochondrial membrane present in all steroidogenic cells. This is considered the rate-limiting step in steroid hormone synthesis and requires the STeroid Acute Regulatory (STAR) protein. STAR is critical in mediating cholesterol transfer to the inner mitochondrial membrane and the cholesterol side chain cleavage enzyme system.
Adrenal steroid hormone synthetic pathway. Cholesterol is converted to pregnenolone by the cytochrome P450 side-chain cleavage enzyme. Pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydrogenase or to 17α-OH-pregnenolone by 17α-hydroxylase. Thereafter, 17α-OH-pregnenolone is converted to 17α-OH-progesterone by 3β-hydroxysteroid dehydrogenase, 17α-OH-progesterone is converted to 11-deoxycortisol by the enzyme 21-hydroxylase, and 11-deoxycortisol is converted to cortisol by 11β-hydroxylase. In addition, 17α-OH-progesterone can be converted to androstenedione. Both 17α-OH-pregnenolone and 17α-OH-progesterone can be converted to the androgens dehydroepiandrosterone (DHEA) and androstenedione, respectively. DHEA is converted to androstenedione. Cells in the zona glomerulosa do not have 17α-hydroxylase activity. Therefore, pregnenolone can be converted only into progesterone. The zona glomerulosa possesses aldosterone synthase activity, and this enzyme converts deoxycorticosterone to corticosterone, corticosterone to 18-hydroxycorticosterone, and 18-hydroxycorticosterone to aldosterone, the principal mineralocorticoid produced by the adrenal glands. The line denotes which steps occur outside the adrenal glands.
This conversion of cholesterol to pregnenolone is the first step in a sequence of multiple enzymatic reactions involved in the synthesis of steroid hormones. Because the cells that constitute the different sections of the adrenal cortex have specific enzymatic features, the synthetic pathway of steroid hormones will result in preferential synthesis of glucocorticoids, mineralocorticoids, or androgens, depending on the region.
Glucocorticoid Hormone Synthesis
Cells of the adrenal zona fasciculata and zona reticularis synthesize and secrete the glucocorticoids cortisol or corticosterone through the following pathway (see Figure 6–3). Pregnenolone exits the mitochondria and is converted to either progesterone or 17α-OH-pregnenolone. Conversion of pregnenolone to progesterone is mediated by 3β-hydroxysteroid dehydrogenase. Progesterone is converted to 11-deoxycorticosterone by 21-hydroxylase; then 11-deoxycorticosterone is converted to corticosterone by 11β-hydroxylase. Conversion of pregnenolone to 17α-OH-pregnenolone is mediated by 17α-hydroxylase; 17α-OH-pregnenolone is converted to 17α-OH-progesterone by 3β-hydroxysteroid dehydrogenase; 17α-OH-progesterone is converted to either 11-deoxycortisol or androstenedione. The enzyme 21-hydroxylase mediates the conversion of 17α-OH-progesterone to 11-deoxycortisol, which is then converted to cortisol by 11β-hydroxylase. Both 17α-OH-pregnenolone and 17α-OH-progesterone can be converted to the androgens DHEA and androstenedione, respectively. DHEA is converted to androstenedione by 3β-hydroxysteroid dehydrogenase.
Mineralocorticoid Hormone Synthesis
The adrenal zona glomerulosa cells preferentially synthesize and secrete the mineralocorticoid aldosterone. The cells of the zona glomerulosa do not have 17α-hydroxylase activity. Therefore, pregnenolone can be converted only to progesterone. The zona glomerulosa possesses aldosterone synthase activity, and this enzyme converts 11-deoxycorticosterone to corticosterone, corticosterone to 18-hydroxycorticosterone, and 18-hydroxycorticosterone to aldosterone, the principal mineralocorticoid produced by the adrenal glands.
Adrenal Androgen Hormone Synthesis
The initial steps in the biosynthesis of DHEA from cholesterol are similar to those involved in glucocorticoid and mineralocorticoid hormone synthesis. The product of these initial enzymatic conversions, pregnenolone, undergoes 17α-hydroxylation by microsomal P450c17 and conversion to DHEA. 17α-pregnenolone can also be converted to 17α-OH-progesterone, which in turn can be converted to androstenedione in the zona fasciculata.
Regulation of Adrenal Cortex Hormone Synthesis
As already mentioned, the initial steps in the biosynthetic pathways of steroid hormones are identical regardless of the steroid hormone synthesized. The production of the hormones can be regulated acutely and chronically. Acute regulation results in the rapid production of steroids in response to immediate need and occurs within minutes of the stimulus. The biosynthesis of glucocorticoids to combat stressful situations and the rapid synthesis of aldosterone to rapidly regulate blood pressure are examples of this type of regulation. Chronic stimulation, such as that which occurs during prolonged starvation and chronic disease, involves the synthesis of enzymes involved in steroidogenesis to enhance the synthetic capacity of the cells. Although both glucocorticoids and mineralocorticoids are released in response to stressful conditions, the conditions under which they are stimulated differ, and the cellular mechanisms responsible for stimulating their release are different. Thus, the mechanisms involved in the regulation of their release differ and are specifically controlled as described below.
Glucocorticoid Synthesis and Release
The pulsatile release of cortisol is under direct stimulation by adrenocorticotropic hormone (ACTH) released from the anterior pituitary. ACTH, or corticotropin, is synthesized in the anterior pituitary as a large precursor, proopiomelanocortin (POMC). POMC is processed post-translationally into several peptides, including corticotropin, β-lipotropin, and β-endorphin, as presented and discussed in Chapter 3
(see Figure 3–4
). The release of ACTH is pulsatile with approximately 7–15 episodes per day. The stimulation of cortisol release occurs within 15 minutes of the surge in ACTH. An important feature in the release of cortisol is that in addition to being pulsatile, it follows a circadian rhythm that is exquisitely sensitive to environmental and internal factors such as light, sleep, stress, and disease (see Figure 1–8
). Release of cortisol is greatest during the early waking hours, with levels declining as the afternoon progresses. As a result of its pulsatile release, the resulting circulating levels of the hormone vary throughout the day, and this has a direct impact on how cortisol values are interpreted according to the timing of blood sample collection.
ACTH stimulates cortisol release by binding to a Gαs protein–coupled plasma membrane melanocortin 2 receptor on adrenocortical cells, resulting in activation of adenylate cyclase, an increase in cyclic adenosine monophosphate, and activation of protein kinase A (see Figure 3–4). Protein kinase A phosphorylates the enzyme cholesteryl-ester hydrolase, increasing its enzymatic activity; leading to increased cholesterol availability for hormone synthesis. In addition, ACTH activates and increases the synthesis of STAR, the enzyme involved in the transport of cholesterol into the inner mitochondrial membrane. Therefore, ACTH stimulates the 2 initial and rate-limiting steps in steroid hormone synthesis.
The release of ACTH from the anterior pituitary is regulated by the hypothalamic peptide corticotropin-releasing hormone (CRH) discussed in Chapter 3. Cortisol inhibits the biosynthesis and secretion of CRH and ACTH in a classic example of negative feedback regulation by hormones. This closely regulated circuit is referred to as the hypothalamic-pituitary-adrenal (HPA) axis (Figure 6–4).
Hypothalamic-pituitary-adrenal axis. Corticotropin-releasing factor (CRF), produced by the hypothalamus and released in the median eminence, stimulates the synthesis and processing of proopiomelanocortin, with resulting release of proopiomelanocortin peptides that include adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH binds to the melanocortin-2 receptor in the adrenal gland and stimulates the cholesterol-derived synthesis of adrenal steroid hormones. Glucocorticoids released into the systemic circulation exert negative feedback inhibition of corticotropin-releasing factor (CRF) and ACTH release from the hypothalamus and pituitary, respectively, in a classic example of negative feedback hormone regulation. This closely regulated circuit is referred to as the hypothalamic-pituitary-adrenal (HPA) axis.
Metabolism of Glucocorticoids
Because of their lipophilic nature, free cortisol molecules are mostly insoluble in water. Therefore, cortisol is usually found in biologic fluids either in a conjugated form (eg, as sulfate or glucuronide derivatives) or bound to carrier proteins (noncovalent, reversible binding). The majority of cortisol is bound to glucocorticoid-binding α2-globulin (transcortin or cortisol-binding globulin [CBG]), a specific carrier of cortisol. Normal levels of CBG average 3–4 mg/dL and are saturated with cortisol levels of 28 μg/dL. The hepatic synthesis of CBG is stimulated by estrogen and decreased by hepatic disease (cirrhosis). Approximately 20%–50% of bound cortisol is bound nonspecifically to plasma albumin. A small amount (<10%) of total plasma cortisol circulates unbound and is referred to as the free fraction. This is considered to represent the biologically active fraction of the hormone that is directly available for action.
As discussed in Chapter 1, the major role of plasma-binding proteins is to act as a “buffer” or reservoir for active hormones. Protein-bound steroids are released into the plasma in free form as soon as the free hormone concentration decreases. Plasma-binding proteins also protect the hormone from peripheral metabolism (notably by liver enzymes) and increase the half-life of biologically active forms. The half-life of cortisol is 70–90 minutes.
Because of their lipophilic nature, steroid hormones diffuse easily through cell membranes and therefore have a large volume of distribution. In their target tissues, steroid hormones are concentrated by an uptake mechanism that relies on their binding to intracellular receptors.
The liver and kidney are the 2 major sites of hormone inactivation and elimination. Several pathways are involved in this process, including reduction, oxidation, hydroxylation, and conjugation, to form the sulfate and glucuronide derivatives of the steroid hormones. These processes occur in the liver through phase I and phase II biotransformation reactions, leading to generation of a more water-soluble compound for easier excretion. Inactivation of cortisol to cortisone and to tetrahydrocortisol and tetrahydrocortisone is followed by conjugation and renal excretion. These metabolites are referred to as 17-hydroxycorticosteroids, and their determination in 24-hour urine collections is used to assess the status of adrenal steroid production.
Localized tissue metabolism contributes to modulation of the physiologic effects of glucocorticoids by the isoforms of the enzyme 11β-hydroxysteroid dehydrogenase. Corticosteroid 11β-hydroxysteroid dehydrogenase type I is a low-affinity nicotinamide adenine dinucleotide phosphate–dependent reductase that converts cortisone back to its active form, cortisol. This enzyme is expressed in liver, adipose tissue, lung, skeletal muscle, vascular smooth muscle, gonads, and the central nervous system. The high expression of this enzyme, particularly in adipose tissue has gained recent attention, as it is thought to contribute to the pathophysiology of metabolic syndrome (see Chapter 10).
The conversion of cortisol to cortisone, its less active metabolite, is mediated by the enzyme 11β-hydroxysteroid dehydrogenase type II. This high-affinity nicotinamide adenine dinucleotide–dependent dehydrogenase is expressed primarily in the distal convoluted tubules and collecting ducts of the kidney, where it contributes to specificity of mineralocorticoid hormone effects. As discussed below, conversion of cortisol to cortisone is critical in preventing excess mineralocorticoid activity resulting from cortisol binding to the mineralocorticoid receptor. Increased expression and activity of 11β-hydroxysteroid dehydrogenase type I amplifies glucocorticoid action within the cell, whereas increased 11β-hydroxysteroid dehydrogenase type II activity decreases glucocorticoid action.
Mineralocorticoid Synthesis and Release
Aldosterone synthesis and release in the adrenal zona glomerulosa is predominantly regulated by angiotensin II and extracellular K+
and, to a lesser extent, by ACTH. Aldosterone is part of the renin-angiotensin-aldosterone
system, which is responsible for preserving circulatory homeostasis in response to a loss of salt and water (eg, with intense and prolonged sweating, vomiting, or diarrhea). The components of the renin-angiotensin-aldosterone system respond quickly to reductions in intravascular volume and renal perfusion. Angiotensin II is the principal stimulator of aldosterone production when intravascular volume is reduced.
Both angiotensin II and K+ stimulate aldosterone release by increasing intracellular Ca2+ concentrations. Angiotensin II receptor-mediated signaling leads to increased intracellular calcium levels, while increased K+ concentrations depolarize the cell leading to Ca2+ influx via voltage-gated L- and T-type Ca2+ channels.
The main physiologic stimulus for aldosterone release is a decrease in the effective intravascular blood volume (Figure 6–5). A decline in blood volume leads to decreased renal perfusion pressure, which is sensed by the juxtaglomerular apparatus (baroreceptor) and triggers the release of renin. Renin release is also regulated by sodium chloride (NaCl) concentration in the macula densa, plasma electrolyte concentrations, angiotensin II levels, and sympathetic tone. Renin catalyzes the conversion of angiotensinogen, a liver-derived protein, to angiotensin I. Circulating angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE), highly expressed in vascular endothelial cells. The increase in circulating angiotensin II produces direct arteriolar vasoconstriction, stimulates adrenocortical cells of the zona glomerulosa to synthesize and release aldosterone, and stimulates arginine vasopressin release from the posterior pituitary (see Chapter 2).
Regulation of aldosterone release by the renin-angiotensin-aldosterone system. A decrease in the effective circulating blood volume triggers the release of renin from the juxtaglomerular apparatus in the kidney. Renin cleaves angiotensinogen, the hepatic precursor of angiotensin peptides, to form angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE), which is bound to the membrane of vascular endothelial cells. Angiotensin II is a potent vasoconstrictor and stimulates the production of aldosterone in the zona glomerulosa of the adrenal cortex. Aldosterone production is also stimulated by potassium, ACTH, norepinephrine, and endothelins. (Modified, with permission, from Weber KT. Mechanisms of disease: aldosterone in congestive heart failure. N Engl J Med. 2001;345:1689. Copyright © Massachusetts Medical Society. All rights reserved.)
Potassium is also a major physiologic stimulus for aldosterone production, illustrating a classic example of hormone regulation by the ion it controls. Aldosterone is critical in maintaining potassium homeostasis by increasing K+ excretion in urine, feces, sweat, and saliva, preventing hyperkalemia during periods of high K+ intake or after K+ release from skeletal muscle during strenuous exercise. In turn, elevations in circulating K+ concentrations stimulate the release of aldosterone from the adrenal cortex.
Metabolism of Mineralocorticoids
The total amount of aldosterone released is markedly less than that of glucocorticoids. Plasma aldosterone levels average 0.006–0.010 μg/dL (in contrast to cortisol levels of 13.5 μg/dL). Secretion can be increased 2- to 6-fold by sodium depletion or by a decrease in the effective circulating blood volume, such as occurs with ascites. Binding of aldosterone to plasma proteins is minimal, resulting in a short plasma half-life of approximately 15–20 minutes. This fact is relevant to mineralocorticoid and glucocorticoid receptor-mediated effects, and their specificity as will be discussed below.
Aldosterone is metabolized in the liver to tetrahydroglucuronide derivative and excreted in the urine. A fraction of aldosterone is metabolized to aldosterone 18-glucuronide, which can be hydrolyzed back to free aldosterone under low pH conditions; thus it is an “acid-labile conjugate.” Approximately 5% of aldosterone is excreted in the acid-labile form; a small fraction of aldosterone appears intact in the urine (1%) and up to 40% is excreted as tetraglucuronide.
Adrenal Androgen Synthesis and Release
The third class of steroid hormones produced by the zona reticularis of the adrenal glands is the adrenal androgens, including DHEA and DHEAS (see Figure 6–3). DHEA is the most abundant circulating hormone in the body and is readily conjugated to its sulfate ester DHEAS. Its production is controlled by ACTH.
Metabolism of Adrenal Androgens
The adrenal androgens are converted into androstenedione and then into potent androgens or estrogens in peripheral tissues. The synthesis of dihydrotestosterone and 17β-estradiol, the most potent androgen and estrogen from DHEA, respectively, involves several enzymes, including 3β-hydroxysteroid dehydrogenase/D5-D4 isomerase, 17β-hydroxysteroid dehydrogenase, and 5β-reductase or aromatase (see Chapters 8 and 9). The importance of the adrenal-derived androgens to the overall production of sex steroid hormones is highlighted by the fact that approximately 50% of total androgens in the prostate of adult men are derived from adrenal steroid precursors.
The control and regulation of the release of adrenal sex steroids are not completely understood. However, it is known that adrenal secretion of DHEA and DHEAS increases in children at the age of 6–8 years, and values of circulating DHEAS peak between the ages of 20 and 30 years. Thereafter, serum levels of DHEA and DHEAS decrease markedly. In fact, at 70 years of age, serum DHEAS levels are at approximately 20% of their peak values and continue to decrease with age. This 70%–95% reduction in the formation of DHEAS by the adrenal glands during the aging process results in a dramatic reduction in the formation of androgens and estrogens in peripheral target tissues. Despite the marked decrease in the release of DHEA as the individual ages, this is not paralleled by a similar decrease in ACTH or cortisol release. The clinical impact of this age-related deficiency in DHEA production is not fully understood but may play an important role in the regulation of immune function and intermediary metabolism, among other aspects of physiology of the aging process.
Steroid Hormone Target Organ Cellular Effects
The physiologic effects of steroid hormones can be divided into genomic and nongenomic effects. Most of the physiologic effects of glucocorticoid and mineralocorticoid hormones are mediated through binding to intracellular receptors that operate as ligand-activated transcription factors to regulate gene expression. Binding of steroid hormones to their specific receptors leads to conformational changes in the receptor, leading to their ability to act as a ligand-dependent transcription factors. The steroid-receptor complex binds to hormone-responsive elements on the chromatin and thereby regulates gene transcription, resulting in the synthesis or repression of proteins, which are ultimately responsible for the physiologic effects of the hormones.
Steroid hormones can also exert their physiologic effects through nongenomic actions. A nongenomic action is any mechanism that does not directly involve gene transcription, such as the rapid steroid effects on the electrical activity of nerve cells or the interaction of steroid hormones with the receptor for γ-aminobutyric acid. In contrast to the genomic effects, nongenomic effects require the continued presence of the hormone and occur more quickly because they do not require the synthesis of proteins. Some of the nongenomic effects may be mediated by specific receptors located on the cell membrane. The nature of these receptors and the signal transduction mechanisms involved are not completely understood and are still under investigation.
Steroid Hormone Receptors
Mineralocorticoid and glucocorticoid receptors share 57% homology in the ligand-binding domain and 94% homology in the DNA-binding domain, and are classified in 2 types of receptors: type I and type II. Type I receptors are expressed predominantly in the kidney, are specific for mineralocorticoids, but have a high affinity for glucocorticoids. Type II receptors are expressed in virtually all cells and are specific for glucocorticoids.
As already mentioned, plasma concentrations of glucocorticoid hormones are much higher (100- to 1000-fold) than those of aldosterone. The higher concentration of glucocorticoids coupled with the high affinity of the mineralocorticoid receptor for glucocorticoids raises the issue of ligand-receptor specificity and resulting physiologic action. Given the high levels of circulating glucocorticoids (cortisol), one might predict permanent maximal occupancy of the mineralocorticoid receptor by cortisol, leading to sustained maximal sodium reabsorption and precluding any regulatory role of aldosterone. However, several factors are in place to enhance the specificity of the mineralocorticoid receptor for aldosterone (Figure 6–6
). First, glucocorticoids circulate bound to CBG and albumin, allowing only a small fraction of the unbound hormone to freely cross cell membranes. Second, aldosterone target cells possess enzymatic activity of 11β-hydroxysteroid dehydrogenase type II
. This enzyme converts cortisol into its inactive form (cortisone) which has significantly less affinity for the mineralocorticoid receptor (see Figure 6–6
). Third, the mineralocorticoid receptor discriminates between aldosterone and glucocorticoids. Aldosterone dissociates from the mineralocorticoid receptor 5 times more slowly than do the glucocorticoids, despite their similar affinity constants. In other words, aldosterone is less easily displaced from the mineralocorticoid receptor than is cortisol. Together, these mechanisms ensure that under normal conditions, mineralocorticoid action is restricted to aldosterone. However, it is important to keep in mind that when production and release of glucocorticoids is excessive, or when the conversion of cortisol to its inactive metabolite cortisone is impaired; the higher circulating and tissue cortisol levels may lead to binding and stimulation of mineralocorticoid receptors.
Steroid hormone receptors. Mineralocorticoids (MC) (aldosterone) and glucocorticoid (GC) (cortisol) hormones bind to intracellular receptors that share 57% homology in the ligand-binding domain and 94% homology in the DNA-binding domain. Cortisol binds the mineralocorticoid (MR) receptor with high affinity. Once GC and MC bind to intracellular receptors, these dimerize prior to nuclear translocation and binding to DNA GC- or MC-responsive elements increasing or suppressing transcription of specific genes. Cortisol binds with high affinity to the MR and can produce MC-like effects (sodium retention). Cortisol conversion to cortisone (CS) decreases the affinity for the receptor shown in the figure by the ill fit of CS with the MR. Decreased activity of the 11β-HSD2 leads to decreased conversion of cortisol to cortisone and increased MC activity. GR, Glucocorticoid receptor; GRE, glucocorticoid responsive element; H, hormone; HR, hormone–receptor; HRE, Hormone responsive element; HSD, hydroxysteroid dehydrogenase; HSD2, hydroxysteroid dehydrogenase type II; MRE, mineralocorticoid responsive element; NAD, nicotinamide adenine dinucleotide; NADP(H), nicotinamide adenine dinucleotide phosphate; R, receptor.
Specific Effects of Adrenal Cortex Hormones
Cortisol, the principal glucocorticoid exerts multisystemic effects because virtually all cells express glucocorticoid receptors. Glucocorticoids as their name imply play an important role in regulation of glucose homeostasis. Glucocorticoids affect intermediary metabolism, stimulate proteolysis and gluconeogenesis, inhibit muscle protein synthesis, and increase fatty acid mobilization. Their hallmark effect is to increase blood glucose concentrations, hence the name “glucocorticoids.” In the liver, glucocorticoids increase the expression of gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase, tyrosine aminotransferase, and glucose-6-phosphatase. In muscle, glucocorticoids interfere with glucose transporter 4 translocation to the plasma membrane (see Chapter 7
). In bone and cartilage, glucocorticoids decrease insulin-like growth factor 1, insulin-like growth factor-binding protein 1, and growth hormone expression and action, and affect thyroid hormone interactions. Excessive glucocorticoid levels result in osteoporosis and impair skeletal growth and bone formation by inhibiting osteoblasts and collagen synthesis. Particularly at high circulating levels, glucocorticoids are catabolic and result in loss of lean body mass including bone and skeletal muscle. Glucocorticoids modulate the immune response by increasing antiinflammatory cytokine synthesis and decreasing proinflammatory cytokine synthesis, exerting an overall anti-inflammatory effect. Their anti-inflammatory effects have been exploited by the use of synthetic analogs of glucocorticoids, such as prednisone, for the treatment of chronic inflammatory diseases. In the vasculature, glucocorticoids modulate reactivity to vasoactive substances, like angiotensin II and norepinephrine. This interaction becomes evident in patients with glucocorticoid deficiency and manifests as hypotension and decreased sensitivity to vasoconstrictor administration. In the central nervous system, they modulate perception and emotion and may produce marked changes in behavior. This should be kept in mind when administering synthetic analogs, particularly in elderly patients. Some of the main physiologic effects of glucocorticoids are summarized in Table 6–1
Table 6–1. Physiologic Effects of Glucocorticoids ||Download (.pdf)
Table 6–1. Physiologic Effects of Glucocorticoids
- Degrades muscle protein and increases nitrogen excretion
- Increases gluconeogenesis and plasma glucose levels
- Increases hepatic glycogen synthesis
- Decreases glucose utilization (anti-insulin action)
- Decreases amino acid utilization
- Increases fat mobilization
- Redistributes fat
- Permissive effects on glucagon and catecholamine effects
- Maintains vascular integrity and reactivity
- Maintains responsiveness to catecholamine pressor effects
- Maintains fluid volume
- Increases antiinflammatory cytokine production Decreases proinflammatory cytokine production
- Decreases inflammation by inhibiting prostaglandin and leukotriene production
- Inhibits bradykinin and serotonin inflammatory effects
- Decreases circulating eosinophil, basophil, and lymphocyte counts (redistribution effect)
- Impairs cell-mediated immunity
- Increases neutrophil, platelet, and red blood cell counts
|Central nervous system|
- Modulates perception and emotion
- Decreases CRH and ACTH release
The principal physiologic function of aldosterone is to regulate mineral (sodium and potassium) balance; specifically renal potassium excretion and sodium reabsorption, hence the name “mineralocorticoid.” Aldosterone receptors are expressed in the distal nephron including the distal convoluted tubule and the collecting duct. Within the collecting duct, the principal cells express significantly more mineralocorticoid receptors than do the intercalated cells. Thus, the most relevant physiologic effects of aldosterone are mediated by its binding to the mineralocorticoid receptor in the principal cells of the distal tubule and the collecting duct of the nephron (Figure 6–7
). Aldosterone-induced activation of preexisting proteins and stimulation of new proteins mediate an increase in transepithelial sodium transport. The specific effects of aldosterone are to increase the synthesis of Na+
channels in the apical membrane, increase the synthesis and activity of Na+
-adenosine triphosphatase (ATPase) in the basolateral membrane (which pulls cytosolic Na+
to the interstitium in exchange for K+
transport into the cell), and increase the expression of H+
-ATPase in the apical membrane and the Cl–
exchanger in the basolateral membrane of intercalated cells. Intercalated cells express carbonic anhydrase and contribute to the acidification of urine and alkalinization of plasma. Thus, aldosterone increases sodium entry at the apical membrane of the cells of the distal nephron through the amiloride-sensitive epithelial Na+
channel. The Na+
-ATPase, located in the basolateral membrane of the cells, maintains the intracellular sodium concentration by extruding the reabsorbed sodium toward the extracellular and blood compartments creating an electrochemical gradient that facilitates the transfer of intracellular K+
from tubular cells into the urine. The increase in Na+
reabsorption leads to increased water reabsorption. When most of the filtered Na+
is reabsorbed in the proximal tubule, only a small amount of sodium reaches the distal tubule (the site of aldosterone regulation). In this case, no net Na+
reabsorption occurs even in the presence of elevated levels of aldosterone. As a result, potassium excretion is minimal. In fact, only 2% of filtered sodium is under regulation by aldosterone. The role of aldosterone in regulation of sodium transport is a major factor determining total-body Na+
levels and thus long-term blood pressure regulation (see Chapter 10
Aldosterone renal physiologic effects. Aldosterone diffuses across the plasma membrane and binds to its cytosolic receptor. The receptor-hormone complex is translocated to the nucleus where it interacts with the promoter region of target genes, activating or repressing their transcriptional activity producing an increase in transepithelial Na+ transport. Aldosterone increases Na+ entry at the apical membrane of the cells of the distal nephron through the amiloride-sensitive epithelial Na+ channel (ENaC). Aldosterone promotes potassium excretion through its effects on Na+/K+-adenosine triphosphatase (ATPase) and epithelial Na+ and K+ channels in collecting-duct cells. Additional effects of aldosterone on intercalated cells leads to increased activation of the H-ATPase and Cl/HCO3 exchanger. A, aldosterone; AM, apical membrane; BM, basolateral membrane; ENaC: epithelial sodium channel.
Mineralocorticoid receptors are not as widely expressed as those for glucocorticoids. Classic aldosterone-sensitive tissues include epithelia with high electrical resistance, such as the distal parts of the nephron, the surface epithelium of the distal colon, and the salivary and sweat gland ducts. More recently, other cells that express mineralocorticoid receptor have been identified, such as epidermal keratinocytes, neurons of the central nervous system, cardiac myocytes, and endothelial and smooth muscle cells of the vasculature (large vessels). Therefore, additional effects of aldosterone include increased sodium reabsorption in salivary and sweat glands, increased K+ excretion from the colon, and a positive inotropic effect on the heart.
Recent studies indicate that aldosterone may be synthesized in tissues other than the adrenal cortex. Aldosterone synthase activity, messenger RNA, and aldosterone production has been demonstrated in endothelial and vascular smooth muscle cells in the heart and blood vessels. The physiologic importance of locally produced aldosterone (paracrine effects) is not yet clear, but some clinician scientists have proposed that it may contribute to tissue repair after myocardial infarction as well as promote cardiac hypertrophy and fibrosis. In the brain, aldosterone affects neural regulation of blood pressure, salt appetite, volume regulation, and sympathetic outflow. Extra-adrenal sites of aldosterone production, release, and action have become prevalent areas of targeted pharmacologic manipulation.
The physiologic effects of DHEA and DHEAS are not completely understood. However, their importance is evident in congenital adrenal hyperplasia associated with deficiencies of either 21-hydroxylase or 11β-hydroxylase, in which pregnenolone is shunted to the androgen biosynthetic pathway as discussed later in this chapter. In females adrenal androgens may contribute to libido. In addition, their contribution to androgen levels in aging males and females is considerable as discussed in Chapters 8 and 9. Current knowledge indicates that low levels of DHEA are associated with cardiovascular disease in men and with an increased risk of premenopausal breast and ovarian cancer in women. In contrast, high levels of DHEA might increase the risk of postmenopausal breast cancer. Exogenous administration of DHEA to the elderly increases several hormone levels, including insulin-like growth factor 1, testosterone, dihydrotestosterone, and estradiol. However, the clinical benefit of these changes and the side effects of long-term use remain to be clearly defined. Furthermore, the specific mechanisms through which DHEA exerts its actions are not completely understood.
Diseases of Overproduction and Undersecretion of Glucocorticoids
Abnormalities in Steroid Hormone Biosynthesis
Any deficiency in the pathway of enzymatic events leading to the synthesis of glucocorticoids, mineralocorticoids, and androgens causes serious pathology. The key enzymes involved in steroid hormone synthesis and the consequences of their deficiency are described in Table 6–2. The severity of enzyme deficiency manifestations ranges from death in utero as in the case of congenital deficiency of cholesterol side chain cleavage enzyme (P450scc, also known as 20,22 desmolase), to abnormalities that become evident in adult life and that are not life-threatening. An enzymatic defect of 21-hydroxylase accounts for 95% of the genetic abnormalities in adrenal steroid hormone synthesis (see Figure 6–8). This enzyme converts progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone to 11-deoxycortisol. The second most frequent abnormality in glucocorticoid synthesis is deficiency of the enzyme 11β-hydroxylase, which converts 11-deoxycortisol to cortisol.
Table 6–2. Key Enzymes Involved in Steroid Hormone Synthesis and Metabolism ||Download (.pdf)
Table 6–2. Key Enzymes Involved in Steroid Hormone Synthesis and Metabolism
|Enzyme and relevance||Physiologic function||Consequence of deficiency|
|Accounts for 95% of genetic abnormalities in adrenal steroid hormone synthesis||Converts progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone to 11-deoxycortisol|
- Decreased cortisol and aldosterone
- Hypoglycemia because of low cortisol
- Loss of sodium because of mineralocorticoid deficiency
- Virilization because of excess androgen production
|Second most frequent abnormality in adrenal steroid hormone synthesis||Converts 11-deoxycorticosterone to corticosterone; 11-deoxycortisol to cortisol|
- Excess 11-deoxycortisol and 11-deoxycorticosterone Excess mineralocorticoid activity
- Hypoglycemia because of low cortisol
- Salt and water retention
|11β-Hydroxysteroid dehydrogenase type II|
|Inhibited by glycyrrhetinic acid, a compound of licorice||Converts cortisol into corticosterone, which has less affinity for the mineralocorticoid receptor||Decrease in glucocorticoid inactivation in mineralocorticoid-sensitive cells leading to excess mineralocorticoid activity|
Alterations in steroid hormone synthesis. A. Deficiency of 21-hydroxylase accounts for 95% of genetic abnormalities in adrenal steroid hormone synthesis. This enzyme converts progesterone to deoxycorticosterone and 17-hydroxyprogesterone to 11-deoxycortisol. Thus, more pregnenolone is shunted to the DHEA-androstenedione pathway (more androgen synthesis), resulting in virilization (presence of masculine traits). In addition, aldosterone deficiency leads to sodium wasting. B. Deficiency of 11β-hydroxylase is the second most frequent abnormality in glucocorticoid synthesis. 11β-hydroxylase is the enzyme that converts deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. Its deficiency results in excess 11-deoxycortisol and 11-deoxycorticosterone production. Both metabolites have active mineralocorticoid activity. The resulting excess in mineralocorticoid-like activity leads to salt and water retention and may cause hypertension. Metabolites in dark boxes are produced in excess. Dotted lines indicate pathways affected by enzymatic abnormalities.
Deficiencies in these enzymes result in impaired cortisol synthesis, lack of negative feedback inhibition of the release of ACTH, resulting in elevated ACTH levels, and greater stimulation of cholesterol conversion to pregnenolone (initial step shared by adrenal steroid hormone synthesis). The ACTH-mediated increase in steroidogenesis produces increased synthesis of the intermediate metabolites (before the enzymatic step that is deficient). Their buildup leads to a shunting to the alternate enzymatic pathways. Thus, more pregnenolone is shunted to the DHEA-androstenedione pathway and more intermediate metabolites are converted to androgens, with their excess resulting in virilization (presence of masculine traits). Additional consequences of 21-hydroxylase deficiency include hyponatremia resulting from mineralocorticoid deficiency and hypoglycemia resulting from deficient cortisol synthesis. In contrast, patients with 11β-hydroxylase deficiency produce excess 11-deoxycortisol and 11-deoxycorticosterone, both intermediate metabolites with mineralocorticoid activity. Because of the resulting excess in mineralocorticoid-like activity, patients with this deficiency retain salt and water and may present with hypertension. These individuals may also manifest with hypoglycemia because they lack cortisol and with increased virilization because of shunted intermediaries to adrenal androgen synthesis. The sustained elevation of ACTH levels caused by lack of cortisol-mediated negative feedback leads to growth (hyperplasia) of the adrenal gland.
Glucocorticoid excess can be caused by overproduction by an adrenal tumor, overstimulation of adrenal glucocorticoid synthesis by ACTH produced by a pituitary tumor or an ectopic tumor, or the iatrogenic (induced by a physician’s prescription) administration of excess synthetic glucocorticoids. The clinical manifestation of glucocorticoid excess, known as Cushing syndrome, can be separated into 2 categories depending on its etiology.
ACTH-dependent Cushing syndrome is characterized by elevated glucocorticoid levels caused by excess stimulation by ACTH produced by pituitary or ectopic (extrapituitary tissue) tumors. The most frequent source of ectopically produced ACTH is small cell lung carcinoma. Ectopic secretion of ACTH is usually not suppressed by exogenously administered glucocorticoids (dexamethasone), and this feature is helpful in its differential diagnosis. The name “Cushing disease” is reserved for Cushing syndrome caused by excess secretion of ACTH by pituitary tumors and is the most common form of the syndrome.
In ACTH-independent Cushing syndrome, excess cortisol production is caused by abnormal adrenocortical glucocorticoid production regardless of ACTH stimulation. In fact, the elevated circulating cortisol levels suppress CRH and ACTH levels in plasma.
Clinically, the most common presentation of glucocorticoid excess is weight gain, which is usually central but may be general in distribution; thickening of the facial features, giving the typical round face or “moon face”; an enlarged dorsocervical fat pad, or “buffalo hump”; and increased fat that bulges above the supraclavicular fossae. Hypertension, glucose intolerance, decreased or absent menstrual flow in premenopausal women, decreased libido in men, and spontaneous bruising are frequent concomitant findings. Muscle wasting and weakness are manifested by difficulty in climbing stairs or rising from a low chair. In children and young adolescents, glucocorticoid excess causes stunted linear growth and excessive weight gain. Depression and insomnia often accompany the other symptoms. Older patients and those with chronic Cushing syndrome tend to have thinning of the skin and osteoporosis, with low back pain and vertebral collapse caused by increased bone turnover leading to osteoporosis.
Glucocorticoid deficiency is less common than diseases caused by excess production of glucocorticoids. Glucocorticoid deficiency can result from adrenal dysfunction (primary deficiency) or from lack of ACTH stimulation of adrenal glucocorticoid production (secondary deficiency). Exogenous administration of synthetic analogs of glucocorticoids in the chronic treatment of some diseases suppresses CRH and ACTH (Figure 6-4). Therefore, the sudden discontinuation of treatment may be manifested as an acute case of adrenal insufficiency, a medical emergency. Thus, it is important to carefully taper the withdrawal of glucocorticoid treatment allowing CRH and ACTH production rhythms to be restored and the endogenous synthesis of cortisol to be normalized.
Most cases of ACTH deficiency involve deficiencies of other pituitary hormones. Because aldosterone is mainly under the regulation of angiotensin II and K+, individuals may not necessarily manifest with simultaneous mineralocorticoid deficiency when impaired ACTH release is the causative factor. Glucocorticoid deficiency caused by adrenal hypofunction is known as Addison disease, which can be the result of autoimmune destruction of the adrenal gland or inborn errors of steroid hormone synthesis (described earlier).
Diseases of Overproduction and Undersecretion of Mineralocorticoids
Excess aldosterone can be classified as primary, secondary, tertiary, or pseudohyperaldosteronism.
Primary hyperaldosteronism, also known as Conn syndrome, is a condition in which autonomous benign tumors of the adrenal glands hypersecrete aldosterone. The excess aldosterone leads to hypertension because of Na+ and H2O retention and hypokalemia because of excess K+ secretion. The release of renin is suppressed.
Secondary hyperaldosteronism is the result of excess aldosterone production in response to increased renin-angiotensin system activity. A decrease in the effective arterial blood volume resulting from other pathologic states, such as ascites or heart failure, leads to continuous stimulation of the renin-angiotensin system which in turn leads to stimulation of aldosterone release.
Tertiary hyperaldosteronism can be caused by rare genetic disorders such as Bartter or Gitelman syndromes. Bartter and Gitelman syndromes result from mutations in ion transporters in the kidney resulting in excess sodium loss. In addition, they may be associated with increased renal prostaglandin E2 production. To compensate for the loss of NaCl in the urine and contracted circulating volume and aided by the excess prostaglandin E2 production; the kidney increases renin release, which in turn stimulates angiotensin II production and aldosterone release.
Pseudohyperaldosteronism is the excess mineralocorticoid activity caused by mineralocorticoid receptor activation by substances other than aldosterone. This condition is known as the syndrome of apparent mineralocorticoid excess. Several factors have been associated with this syndrome:
- Congenital adrenal hyperplasia (11β-hydroxylase deficiency and 17α-hydroxylase deficiency) leading to excess production of 11-deoxycortisone (an active mineralocorticoid).
- Deficiency of 11β-hydroxysteroid dehydrogenase type II, which leads to insufficient conversion of cortisol to its inactive metabolite cortisone in the principal cells of the distal tubule. An example of this alteration occurs with excess consumption of licorice. Glycyrrhetinic acid, a compound of licorice, inhibits the activity of 11β-hydroxysteroid dehydrogenase. Inhibition of this enzyme results in a decrease in the inactivation of glucocorticoids in mineralocorticoid-sensitive cells.
- Primary glucocorticoid resistance, characterized by hypertension, excess androgens, and increased plasma cortisol concentrations.
- Liddle syndrome, caused by activating mutations of the renal epithelial sodium channel (ENaC), leading to salt-sensitive hypertension.
- Mutations in the mineralocorticoid receptor resulting in constitutive mineralocorticoid receptor activity and altered receptor specificity. In this condition, progesterone and other steroids lacking 21-hydroxyl groups become potent agonists of the mineralocorticoid receptor.
In summary, excess mineralocorticoid-like activity can result not only from excess production of aldosterone, but also from other mechanisms, including overproduction of 11-deoxycorticosterone, inadequate conversion of cortisol to cortisone by 11β-hydroxysteroid dehydrogenase type II in target tissues, glucocorticoid receptor deficiency, and constitutive activation of renal sodium channels.
Chronic excess of mineralocorticoids can result in what is known as an escape phenomenon. Although sodium retention increases during the initial phase of mineralocorticoid excess, compensatory mechanisms involved in sodium excretion subsequently go into effect, resulting in new sodium equilibrium in the body maintained by higher sodium excretion. The importance of this escape mechanism is that it limits the volume expansion related to Na+ retention.
Deficient aldosterone activity can be classified as primary, secondary, or pseudohypoaldosteronism.
Primary hypoaldosteronism is the lack of adrenal gland production of aldosterone because of Addison disease (destruction of the adrenal gland because of infection, injury, or autoimmune processes), from genetic disorders affecting the entire gland, or from genetic disorders affecting specific enzymatic conversions required for aldosterone biosynthesis. Two of these genetic diseases, the salt-wasting forms of 21-hydroxylase and 3β-hydroxysteroid dehydrogenase deficiencies, also affect cortisol biosynthesis. In primary aldosterone deficiency, plasma renin activity is elevated, so this condition is also known as hyperreninemic hypoaldosteronism.
Secondary hypoaldosteronism is lack of aldosterone production caused by inadequate stimulation by angiotensin II (hyporeninemic hypoaldosteronism) despite normal adrenal function. This condition is usually associated with renal insufficiency.
Pseudohypoaldosteronism is caused by unresponsiveness to mineralocorticoid hormone action and characterized by severe neonatal salt wasting, hyperkalemia, metabolic acidosis. This inherited disease can be caused by a loss-of-function mutation in the mineralocorticoid receptor or, in the more severe recessive form, to a loss-of-function mutation in the ENaC subunits.
Diseases of Overproduction and Undersecretion of Adrenal Androgens
The most likely cause of excessive androgen secretion is dysregulation of the 17-hydroxylase and 17,20-lyase activities of P450c17, the rate-limiting step in androgen biosynthesis. Congenital adrenal hyperplasia because of 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. As discussed above, impaired cortisol production leads to a lack of negative glucocorticoid feedback resulting in an increase in ACTH release, increased steroid hormone biosynthesis, buildup of cortisol and aldosterone precursors, and increased shunting to the androgen synthetic pathway. The classic form of congenital adrenal hyperplasia presents in infancy and early childhood as signs and symptoms of virilization with or without adrenal insufficiency.
Adrenal Androgen Deficiency
Similar to the deficiencies of glucocorticoids and mineralocorticoids, adrenal androgen deficiency can be primary or secondary to hypopituitarism. Of greater importance is the continuous decrease in adrenal androgen production that is associated with aging and menopause (discussed in Chapters 8 and 9). Pharmacologic treatment with oral glucocorticoids results in ACTH suppression, which in turn results in reduced adrenal androgen production.