Walter L. Miller
EMBRYOLOGY AND ANATOMY
The cells of the adrenal cortex are of mesodermal origin, in contrast to the neuroectodermal cells of the adrenal medulla. Human embryonic adrenogonadal progenitor cells first appear at around the fourth week of gestation. By the end of the eighth week, the rudimentary adrenal has become encapsulated and is associated with the upper pole of the kidney.
The fetal adrenal cortex consists of an outer “definitive” zone, the principal site of glucocorticoid and mineralocorticoid synthesis, and a much larger “fetal” zone that makes androgenic precursors (dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS]), which the placenta converts to estriol throughout pregnancy. At birth, the adrenals weigh 8 to 9 g, about the same size of adult adrenals, and represent approximately 0.4% of total body weight. The fetal adrenal zone involutes rapidly following birth and has disappeared by 6 to 12 months of postnatal life.
The adrenal cortex consists of three morphologically distinct zones: the glomerulosa, immediately below the capsule; the fasciculata, in the middle; and the reticularis, next to the medulla. After birth, the large fetal zone begins to involute and disappears by about 6 to 12 months of age. The definitive zone simultaneously enlarges, but the glomerulosa and fasciculate are not fully differentiated until about 3 years of age, and the reticularis may not be fully differentiated until adolescence.
STEROID HORMONE SYNTHESIS
The adrenal cortex produces three types of steroid hormones. Mineralocorticoids (aldosterone) regulate renal sodium retention, regulating electrolyte balance, intravascular volume, and blood pressure. Glucocorticoids (cortisol) are named for their carbohydrate-mobilizing activity, but regulate a wide variety of bodily functions. Adrenal androgens serve no known physiologic role, but mediate some secondary sexual characteristics in women (eg, pubic and axillary hair), and their overproduction may result in virilism.1 The principal pathways of human adrenal steroid hormone synthesis are shown in Figure 531-1.
All steroid hormones are derivatives of pregnenolone. Pregnenolone and its derivatives that contain 21 carbon atoms are often termed C21 steroids. Each carbon atom is numbered, indicating the location at which the various steroidogenic reactions occur (eg, 21-hydroxylation, 11-hydroxylation). Unambiguous chemical terminology has been formulated to describe the structure of all steroid hormones, but this terminology is quite cumbersome (eg, cortisol is 11β, 17α, 21-trihydroxy-pregn-4-ene-3, 20-dione, and dexamethasone is 9α-fluoro-11β, 17α, 21-trihydroxy- prena-1, 4-diene-3, 20-dione). Therefore, we use only the standard “trivial names.”
Most steroidogenic enzymes are members of the cytochrome P450 group of oxidases. Five P450 enzymes are involved in adrenal steroidogenesis (Fig. 531-1). Mitochondrial P450scc is the cholesterol side-chain cleavage enzyme catalyzing the series of reactions formerly termed 20,22 desmolase. Two distinct isozymes of P450c11, P450c11β, and P450c11AS, also found in mitochondria, catalyze 11b-hydroxylase, 18-hydroxylase, and 18-methyl oxidase activities. P450c17, found in the endoplasmic reticulum, catalyzes both 17α-hydroxylase and 17,20-lyase activities, and P450c21 catalyzes the 21-hydroxylation of both glucocorticoids and mineralocorticoids. In the gonads and elsewhere, P450aro in the endoplasmic reticulum catalyzes aromatization of androgens to estrogens.
FIGURE 531-1. Principal pathways of human adrenal steroid hormone synthesis. Reaction 1: Mitochondrial cytochrome P450scc mediates 20α-hydroxylation, 22-hydroxylation, and scission of the C20–22 carbon bond. Reaction 2: 3βHSD mediates 3β-hydroxysteroid dehydrogenase and isomerase activities, converting Δ5 steroids to Δ4 steroids. Reaction 3: P450c17 catalyzes the 17α-hydroxylation of pregnenolone to 17OH-pregnenolone and of progesterone to 17OH-progesterone. Because P450c17 has both 17a-hydroxylase activity and 17,20-lyase activity, it is the branch point in steroid hormone synthesis. Neither activity of P450c17 is present in the adrenal zona glomerulosa; hence, pregnenolone is converted to mineralocorticoids. In the zona fasciculata, the 17a-hydroxylase activity is present, but 17,20-lyase activity is not; hence, pregnenolone is converted to glucocorticoids. In the zona reticularis, both activities are present so that pregnenolone is converted to sex steroids. Reaction 4: The 17,20-lyase activity of P450c17 converts 17OH-pregnenolone to DHEA; only insignificant amounts of 17OH-progesterone are converted to Δ4 androstenedione by human P450c17, although this reaction occurs in other species. Reaction 5: P450c21 catalyzes the 21-hydroxylation of progesterone to DOC and of 17OH-progesterone to 11-deoxycortisol. 21-Hydroxylase deficiency causes more than 90% of all cases of congenital adrenal hyperplasia.37–39 Reaction 6: DOC is converted to corticosterone by the 11-hydroxylase activity of P450c11AS in the zona glomerulosa and by P450c11β in the zona fasciculata. Reaction 7: 11-Deoxycortisol undergoes 11β-hydroxylation by P450c11β to produce cortisol in the zona fasciculata. Patients with disorders in P450c11b have classical 11b-hydroxylase deficiency, but can still produce aldosterone. Reactions 8 and 9: The 18-hydroxylase and 18-methyl oxidase activities of P450c11AS convert corticosterone to 18OH-corticosterone and aldosterone, respectively, in the zona glomerulosa. Patients with disorders in P450c11AS have rare forms of aldosterone deficiency (so-called corticosterone methyl oxidase deficiency), while retaining the ability to produce cortisol. Reactions 10 and 11 are found principally in the testes and ovaries. Reaction 10: 17βHSD-III converts DHEA to androstenediol and androstenedione to testosterone, while 17βHSD-I converts estrone to estradiol. Reaction 11: Testosterone may be converted to estradiol and androstenedione may be converted to estrone by P450aro. Aromatase expression in extraglandular tissues, especially fat, can convert adrenal androgens to estrogens. Aromatase in the epiphyses of growing bone converts testosterone to estradiol; the tall stature, delayed epiphyseal maturation and osteopenia of males with aromatase deficiency, and their rapid reversal with estrogen replacement, indicate that estrogen, not androgen, is responsible for epiphyseal maturation in males.
Whereas steroidogenic reactions catalyzed by P450 enzymes are due to the action of a single form of P450, each reaction catalyzed by hydroxysteroid dehydrogenases can be catalyzed by multiple isozymes. Members of this family include the 3β-hydroxysteroid dehydrogenases, the two 11β-hydroxysteroid dehydrogenases, and a series of 17β-hydroxysteroid dehydrogenases; the 5α-reductases are unrelated to this family. The dehydrogenases oxidize hydroxysteroids to ketosteroids, and the reductases reduce ketosteroids to hydroxysteroids.
Conversion of cholesterol to pregnenolone in mitochondria is the first rate-limiting and hormonally regulated step in steroidogenesis.2-5 Corticotropin (ACTH) regulates steroidogenic capacity (chronic regulation) by inducing the transcription of genes for steroidogenic enzymes. However, in the adrenal, the acute increases in steroid production triggered by angiotensin II (for aldosterone), ACTH (for cortisol), and luteinizing hormone (LH; for sex steroids) are mediated by the steroidogenic acute regulatory protein, StAR. Activation of StAR leads to a rapid flux of cholesterol from the outer to inner mitochondrial membrane, allowing cholesterol access to the P450scc enzyme, such that it enters into the appropriate synthetic pathway.11-13 The central role of StAR in steroidogenesis was proven by finding that mutations of StAR caused congenital lipoid adrenal hyperplasia.14,15
A single microsomal enzyme, 3β-hydroxysteroid dehydrogenase (3bHSD), converts pregnenolone to progesterone, 17α-hydroxypregnenolone to 17α-hydroxyprogesterone, dehydroepiandrosterone (DHEA) to androstenedione, and androstenediol to testosterone. Pregnenolone and progesterone may undergo 17α-hydroxylation to 17α-hydroxypregnenolone and 17α-hydroxyprogesterone (17OHP), respectively. 17α-Hydroxyprogesterone may also undergo cleavage of the C17,20 carbon bond to yield DHEA; however, very little 17OHP is converted to androstenedione because the human P450c17 enzyme catalyzes this reaction at only 3% of the rate for conversion of 17α-hydroxypregnenolone to DHEA.16-27 These reactions are mediated by P450c17, which is bound to smooth endoplasmic reticulum, where it accepts electrons from P450 oxidoreductase. Because P450c17 has both 17α-hydroxylase activity and 17,20-lyase activity, it is the branch point in steroid hormone synthesis. Neither activity of P450c17 is present in the adrenal zona glomerulosa; hence, pregnenolone is converted to mineralocorticoids. In the zona fasciculata, the 17α-hydroxylase activity is present, but 17,20 lyase activity is not; hence, pregnenolone is converted to glucocorticoids. In the zona reticularis, both activities are present so that pregnenolone is converted to sex steroids. Further details are provided in Figure 531-1.
REGULATION OF CORTISOL SECRETION
Cortisol is mainly secreted in response to corticotropin (ACTH) produced by the pituitary, and secretion of ACTH is stimulated primarily by corticotropin-releasing factor (CRF) from the hypothalamus. Vasopressin is cosecreted with CRF in response to stress, and both CRF and vasopressin stimulate the synthesis and release of ACTH, but by different mechanisms.99 ACTH is a 39-amino acid peptide derived from proopiomelanocortin (POMC), a 241-amino acid protein. POMC undergoes a series of proteolytic cleavages, yielding several biologically active peptides (eFig. 531.1 ).100,101 Only the first 20 to 24 amino acids of ACTH are needed for its full biologic activity, and synthetic ACTH 1–24 is widely used in diagnostic tests of adrenal function.
ACTH acts through the melanocortin 2 receptor (MC2R) in the adrenal cortex. ACTH elicits both acute and long-term effects. ACTH phosphorylates StAR, which facilitates transport of cholesterol into mitochondria, constituting the “acute” effect of ACTH on steroidogenesis. The long-term “chronic” effects of ACTH are mediated by stimulating the accumulation of the steroidogenic enzymes and their mRNAs and by stimulating the transcription of their genes.102-109 ACTH also stimulates the biosynthesis of low-density lipoprotein (LDL) receptors and the uptake of LDL, which provides most of the cholesterol used for steroidogenesis.104
Plasma concentrations of ACTH and cortisol tend to be high in the morning and low in the evening. Peak ACTH levels are usually seen at 4 to 6 am, and peak cortisol levels follow at about 8 am. Both ACTH and cortisol are released episodically in pulses every 30 to 120 minutes throughout the day, but the frequency and amplitude of these is much greater in the morning. At least four factors play a role in this diurnal rhythm: intrinsic rhythmicity of synthesis and secretion of CRF by the hypothalamus, light/dark cycles, feeding cycles, and inherent rhythmicity in the adrenal. The diurnal rhythms of ACTH and cortisol begin to be established at 6 to 12 months and may not be well established until after 3 years of age.120
Physical stress (eg, major surgery, severe trauma, blood loss, high fever, serious illness) can increase the secretion of both ACTH and cortisol, but minor surgery and minor illnesses (eg, upper respiratory infections) have little effect on ACTH and cortisol secretion.121,122 Most psychoactive drugs, such as anticonvulsants, neurotransmitters, and antidepressants, do not affect the diurnal rhythm of ACTH and cortisol, although cyproheptadine (a serotonin antagonist) effectively suppresses ACTH release. The hypothalamic-pituitary-adrenal axis is a classic example of an endocrine feedback system. ACTH increases cortisol production, and cortisol decreases production of ACTH.103,124
REGULATION OF MINERALOCORTICOID SECRETION
Aldosterone secretion is primarily controlled by the renin-angiotensin system. Renin is a serine protease synthesized primarily by the juxtaglomerular cells of the kidney. Low blood pressure, upright posture, sodium depletion, vasodilators, kallikrein, opiates, and b-adrenergic stimulation promote release of renin. Renin proteolytically cleaves the 10 amino-terminal amino acids of angiotensinogen, a glycoprotein in the circulation, to yield inactive angiotensin I. Converting enzyme, found primarily in the lungs and blood vessels, cleaves off the two carboxy-terminal amino acids of angiotensin I to produce angiotensin II, which binds to membrane receptors in the zona glomerulosa to stimulate aldosterone production. Angiotensin-converting enzyme can be inhibited by captopril and related agents.
Angiotensin II directly stimulates arteriolar vasoconstriction within a few seconds, and stimulates synthesis and secretion of aldosterone within minutes. Increased plasma potassium is a powerful, direct stimulator of aldosterone synthesis and release.126,127 Aldosterone causes renal sodium retention and potassium loss, with a consequent increase in intravascular volume and blood pressure. Expansion of the blood volume provides the negative feedback for regulation of renin and aldosterone secretion. Ammonium ion, hyponatremia, dopamine antagonists, and some other agents can also stimulate secretion of aldosterone, and atrial natriuretic factor is a potent physiologic inhibitor of aldosterone secretion.130
REGULATION OF ADRENAL ANDROGEN SECRETION
Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione, which are almost exclusively secreted by the adrenal zona reticularis, are generally referred to as adrenal androgens because they can be peripherally converted to testosterone. However, these steroids have little, if any, capacity to bind to and activate androgen receptors; hence, they are only androgen precursors, not true androgens. The fetal adrenal secretes large amounts of DHEA and DHEAS, and these steroids are abundant in the newborn, but their concentrations fall rapidly as the fetal zone of the adrenal involutes following birth. After the first year of life, the adrenals of young children secrete very small amounts of DHEA, DHEAS, and androstenedione until the onset of adrenarche, usually around ages 7 to 8 years, preceding the onset of puberty by about 2 years. Adrenarche is discussed further in Chapter 540.
CIRCULATING STEROIDS AND THEIR DISPOSAL
Most circulating steroids are bound to plasma proteins, including corticosteroid-binding globulin (CBG; also termed transcortin), albumin, and a1 acid glycoprotein.131-148 CBG has a very high affinity for cortisol, but a relatively low binding capacity; albumin has a low affinity and high capacity; and α1 acid glycoprotein is intermediate for both variables. The result is that about 90% of circulating cortisol is bound to CBG, and a little more is bound to other proteins. These steroid-binding proteins are not transport proteins because the biologically important steroids are water soluble in physiologically effective concentrations, and absence of CBG does not cause a detectable physiologic disorder. However, these plasma proteins act as a reservoir for steroids, ensuring that peripheral tissues are bathed in approximately equal concentrations of cortisol. This greatly diminishes the physiologic effect of the diurnal variation in cortisol secretion. Most synthetic glucocorticoids used clinically bind poorly to CBG and albumin, partially accounting for their increased potencies, which are also associated with increased receptor-binding affinities. Aldosterone is not bound by plasma proteins; hence, changes in plasma protein concentration do not affect plasma aldosterone concentrations but greatly influence plasma cortisol concentrations. Estradiol and testosterone bind strongly to sex steroid-binding globulin and also bind weakly to albumin.
Only about 1% of circulating plasma cortisol and aldosterone are excreted unchanged in the urine; the remainder is metabolized by the liver, principally by adding hydroxyl groups and sulfate or glucuronide moieties, rendering the steroid more soluble and readily excretable by the kidney.