Review of Medical Physiology - William F. Ganong 2002

Endocrine System, Metabolism, and Reproduction
Adrenal Medulla and Adrenal Cortex
Adrenal Cortex - Structure and Biosynthesis of Adrenocortical Hormones

Classification and Structure

Adrenal Cortex Hormones are derivatives of Cholesterol. Like cholesterol, Bile acids, vitamin D, and testicular Steroids, they contain a cyclopentanoperhydrophenanthrene Nucleus (Fig. 20-7). Gonadal and adrenocortical steroids are of three types: C₂₁ steroids, which have a two-carbon side chain at the 17-position; C₁₉ steroids, which possess a keto or hydroxyl group at the 17-position; and C₁₈ steroids, which feature a 17-keto or hydroxyl group but lack a methyl group at the 10-position. The adrenal cortex predominantly secretes C₂₁ and C₁₉ steroids. Most C₁₉ steroids bear a keto group at the 17-position and are therefore referred to as 17-ketosteroids. C₂₁ steroids containing a hydroxyl group at the 17-position alongside an additional side chain are often termed 17-hydroxycorticoids or 17-corticosteroids.

Furthermore, C₁₉ steroids exhibit androgenic activity, whereas C₂₁ steroids are classified according to Selye's terminology into mineralocorticoids and glucocorticoids. All secreted C₂₁ steroids display both gluco- and mineralocorticoid activity. The predominant effect of mineralocorticoids involves The regulation of Na⁺ and K⁺ excretion, whereas glucocorticoids primarily govern glucose and Protein METABOLISM.

Detailed steroid nomenclature and isomerism are extensively covered in specialized literature; however, It is worth noting that the Greek letter Δ denotes a double bond, while groups positioned above the plane of The Nucleus are designated by the Greek letter β and a solid line (–OH), in contrast to groups located below the steroid ring, which are denoted by the letter α and a dashed line (---OH). Consequently, the C₂₁ steroids secreted by the Adrenal Glands possess a Δ⁴-3-ketoconfiguration in the A-ring.

Naturally occurring adrenal steroids most commonly feature 17-hydroxy groups in the α-configuration, while the 3-, 11-, and 21-hydroxy groups are in the β-configuration; the 18-aldehyde configuration in natural aldosterone is the D-form, as L-aldosterone is physiologically inactive.

Secreted Steroids

A wide variety of steroids have been isolated from adrenal Tissues; however, the only steroids secreted in physiologically significant quantities are the mineralocorticoid aldosterone, the glucocorticoids cortisol and corticosterone, and the androgens dehydroepiandrosterone (DHEA) and androstenedione. The structures of these steroids are illustrated in Figs. 20-8 and 20-9. Deoxycorticosterone is a mineralocorticoid normally secreted in amounts comparable to aldosterone (Table 20-1), yet it possesses only about 3% of aldosterone's mineralocorticoid activity. Its impact on Mineral Metabolism is normally negligible, though it can become pronounced in pathological states characterized by increased secretion. The majority of estrogens not produced in the Ovaries are derived from adrenal androstenedione in the Circulation. Almost all dehydroepiandrosterone is secreted as sulfate, whereas most Other Steroids circulate in a free, unconjugated form.

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Fig. 20-7. Principal structures of adrenocortical and gonadal steroids. Letters in the cholesterol formula designate the four main rings, and numbers indicate the carbon positions of substituents within the molecule. Angular methyl groups (positions 18 and 19) are conventionally represented by dashes.

The secretion rate for individual steroids can be determined by administering trace doses of isotope-labeled steroids and measuring the degree of their dilution by unlabeled hormones recovered in the urine. This methodology is widely applied to measure the secretion rates of numerous hormones.

Species Differentiation

Across all species (from amphibians to humans), the principal C₂₁ Steroid Hormones secreted by adrenocortical tissue are aldosterone, cortisol, and corticosterone, although The ratio of cortisol to corticosterone varies. Birds, mice, and rats secrete almost exclusively corticosterone; dogs produce roughly equal amounts of both glucocorticoids; whereas cortisol predominates in cats, sheep, monkeys, and humans. In humans, the cortisol-to-corticosterone ratio is approximately 7:1.

Fig. 20-8. Pathway of hormone Biosynthesis in the zona fasciculata and zona reticularis of the adrenal cortex. Major secretory products are underlined. Enzymes catalyzing the respective reactions are indicated to the left and top of the scheme. In the absence of a specific enzyme, hormone formation is blocked at the points marked by dashed lines.

Synthetic Steroids

Like many naturally occurring compounds, the biological activity of adrenocortical steroids can be enhanced through structural modification. Today, numerous synthetic steroids are known that exhibit several times the potency of cortisol. Table 20-2 outlines the relative glucocorticoid and mineralocorticoid activities of natural and synthetic steroids, including 9α-fluorocortisone, prednisolone, and dexamethasone. Dexamethasone displays the highest potency, which is attributed to its high affinity for glucocorticoid receptors and prolonged half-life (see below). Prednisolone also possesses a relatively long half-life.

Biosynthesis of Steroids

The primary pathways for The biosynthesis of natural Adrenocortical Hormones are illustrated in Figs. 20-8 and 20-9. Cholesterol serves as the precursor for all steroid hormones. A fraction of cholesterol is synthesized from acetate, but the majority is derived from circulating LDL (see Chapter 17). LDL receptors are most abundant in adrenocortical Cells. Cholesterol is esterified and stored in lipid droplets. Cholesterol ester hydrolase catalyzes The formation of free cholesterol from these droplets (Fig. 20-10). Cholesterol is transported into Cell/35.html">Mitochondria with the assistance of the steroidogenic acute regulatory (StAR) protein or sterol carrier Proteins. Inside the mitochondria, it is converted into pregnenolone via a reaction catalyzed by cholesterol desmolase. This enzyme belongs to the mitochondrial cytochrome P450 superfamily, also known as the side-chain Cleavage enzyme, P450scc, or CYP11A. The principles of the updated CYP nomenclature for Cytochromes P450 are detailed in Chapter 17. Table 20-3 lists the various names of enzymes involved in adrenocortical steroid biosynthesis.

Table 20-1. Principal Adrenocortical Hormones in Adult Humans¹

¹ All plasma concentrations were measured under resting conditions, except for DHEAS, for which the morning concentration is given.

Fig. 20-9. Hormone synthesis in the zona glomerulosa. This zone requires 17α-hydroxylase and is unique in its ability to convert corticosterone to aldosterone, because it is the only site where aldosterone synthase and angiotensin II (A II) are normally present.

Pregnenolone diffuses into the smooth Endoplasmic reticulum, where a portion of it undergoes dehydrogenation to form progesterone in a reaction catalyzed by 3β-hydroxysteroid dehydrogenase. This enzyme has a Molecular Weight of 46,000 and is not a cytochrome P450. In the zona fasciculata and zona reticularis, a fraction of pregnenolone and progesterone is hydroxylated in the smooth endoplasmic reticulum to yield 17α-hydroxypregnenolone and 17α-hydroxyprogesterone (see Fig. 20-8). The enzyme catalyzing these reactions is 17α-hydroxylase, another cytochrome P450 also known as P450c17 (CYP17). This same enzyme Functions as a 17,20-lyase, capable of catalyzing the Cleavage of the 17,20-bond to convert 17α-pregnenolone and 17α-progesterone into the C₁₉ steroids dehydroepiandrosterone and androstenedione.

The hydroxylation of progesterone to 11-deoxycorticosterone and of 17α-hydroxyprogesterone to 11-deoxycortisol also occurs in the smooth Endoplasmic reticulum and is catalyzed by the cytochrome 21-hydroxylase, also known as P450c21 or CYP21A2.

11-Deoxycorticosterone and 11-deoxycortisol are transported back into the mitochondria, where they undergo 11-hydroxylation to yield corticosterone and cortisol, respectively. This reaction takes place in the zona fasciculata and zona reticularis, catalyzed by 11ß-hydroxylase, a cytochrome P450 known as P450c11 or CYP11B1.

Fig. 20-10. MECHANISM OF ACTION of ACTH on cortisol-producing cells in the two inner Zones of the adrenal cortex. When ACTH binds to its receptor (R), adenylyl cyclase (AC) is activated via G_s. The resulting increase in cAMP activates protein kinase A, which in turn phosphorylates cholesterol ester hydrolase (CEH), enhancing its activity. Consequently, a larger pool of free cholesterol is generated and converted into pregnenolone within the mitochondria. Note that during subsequent stages of steroid biosynthesis, intermediates shuttle back and forth between the mitochondria and the smooth endoplasmic reticulum (SER). Corticosterone is also synthesized and secreted.

In the zona glomerulosa, the same enzymes catalyze steroid biosynthesis as far as 11-deoxycorticosterone. However, a different enzyme—aldosterone synthase—catalyzes the formation of corticosterone and its subsequent hydroxylation and oxidation to yield aldosterone. Aldosterone synthase, also known as P450C11AS or CYP11B2, shares 95% sequence identity with CYP11B1, and their respective genes are located in the same region of chromosome 8. Nevertheless, aldosterone synthase is normally restricted to the zona glomerulosa. This zone lacks sufficient 17a-hydroxylase activity, which explains why the zona glomerulosa produces aldosterone yet remains incapable of synthesizing 17-hydroxysteroids or Sex Hormones.

Table 20-2. Relative corticosteroid potency compared with cortisol¹

¹ Mean values based on Liver Glycogen deposition or anti-inflammatory assays for glucocorticoid activity, and effects on urinary Na⁺/K⁺ ratios or mineralocorticoid assays in adrenalectomized animals. The last three steroids listed are synthetic and do not occur naturally in the body (data compiled from various sources).

Table 20-3. Nomenclature of adrenal steroidogenic enzymes and their intracellular localization

Note: SER, smooth endoplasmic reticulum.

A significant portion of the dehydroepiandrosterone produced in the two inner zones is converted into dehydroepiandrosterone sulfate by the action of adrenal sulfotransferase. Androsterone is further converted into testosterone and estradiol.

Action of ACTH

ACTH binds to high-affinity receptors on The Plasma Membrane of adrenocortical cells, activating adenylyl cyclase (see Chapter 1) via a G protein. The resulting elevation in intracellular cAMP levels triggers the activation of protein kinase A. Protein kinase A phosphorylates cholesterol ester hydrolase, thereby increasing its activity and accelerating The conversion of cholesterol esters into free cholesterol (see Fig. 20-10). This, in turn, promotes the rapid synthesis of pregnenolone and its derivatives. Over longer time scales, ACTH also upregulates the synthesis of P450 enzymes involved in glucocorticoid production.

Action of Angiotensin II

Angiotensin II binds to receptors in the zona glomerulosa that act through a G protein to stimulate phospholipase C (see Chapter 1). This pathway leads to the activation of protein kinase C, facilitates the conversion of cholesterol to pregnenolone (see Fig. 20-9), and enhances The production of 18-hydroxycorticosterone, which subsequently drives aldosterone synthesis.

Enzyme Deficiencies

The biochemical consequences of blocking any enzyme system in the steroidogenic pathway can be predicted from Figures 20-8 and 20-9. Congenital enzyme defects result in impaired cortisol secretion and congenital adrenal hyperplasia (CAH). The hyperplasia is a direct consequence of increased ACTH secretion driven by the loss of negative feedback. Cholesterol desmolase deficiency is incompatible with extrauterine survival because it halts the placental progesterone synthesis essential for maintaining Pregnancy. Severe congenital lipoid adrenal hyperplasia in newborns stems from loss-of-function Mutations in the Gene encoding the steroidogenic acute regulatory (StAR) protein. This protein is required in the adrenal glands and Gonads—though not in the Placenta—for the normal translocation of cholesterol to the cholesterol desmolase complex situated on the matrix surface of The inner mitochondrial membrane. In its absence, only trace amounts of steroids are synthesized. Consequently, profound ACTH hypersecretion ensues, leading to massive lipid engorgement of the adrenal cortex, a condition designated as congenital lipoid adrenal hyperplasia. Because androgens fail to form, female external genitalia develop regardless of the genetic sex (see Chapter 23). Deficiency of 3ß-hydroxysteroid dehydrogenase, a rare condition as well, results in elevated levels of DHEA. Although DHEA is a weak androgen, it may induce mild masculinization in affected female infants, yet it is insufficient to achieve complete virilization of the external genitalia in genetic males. Hypospadias, a developmental anomaly in which the urethral meatus opens on the ventral aspect of the Penis or within the Perineum/Vagina, is also frequently observed. Complete absence of 17a-hydroxylase underlies a third rare enzymatic defect, caused by mutations in the CYP17 gene on chromosome 10, resulting in a complete failure of sex hormone synthesis and the default development of female external genitalia. However, the biosynthetic pathways for corticosterone and aldosterone remain intact; the resultant overproduction of 11-deoxycorticosterone and other mineralocorticoids leads to Hypertension and hypokalemia. The glucocorticoid activity of corticosterone partially compensates for the cortisol deficiency. Variants of this syndrome can also arise from isolated losses of 17,20-lyase activity, which obstructs sex hormone production while preserving sufficient 17-hydroxylase activity to maintain cortisol synthesis.

Unlike the rare conditions described above, 21ß-hydroxylase and 11ß-hydroxylase deficiencies are relatively common, accounting for 90% to 95% of all cases of congenital adrenal hyperplasia, with modern estimates suggesting that nearly all cases stem from these defects, leaving merely 1% attributable to others. Both enzyme deficiencies lead to virilization because the compensatory surge in ACTH drives the accumulation of precursor steroids into alternative androgen-producing pathways. The classic presentation is the adrenogenital syndrome, which manifests in untreated females (Fig. 20-11). The gene for 21ß-hydroxylase resides on the short arm of chromosome 6, closely linked to the HLA Major Histocompatibility Complex (see Chapter 19), and a spectrum of clinical phenotypes can result from partial or severe 21ß-hydroxylase deficiencies. In many instances, sufficient glucocorticoids and mineralocorticoids are still produced to sustain life. In severe cases, however, the external genitalia of genetic females undergo pronounced masculinization (female pseudohermaphroditism; see Chapter 23), whereas mild cases may elude clinical detection and require laboratory screening. A major subset of patients with 21ß-hydroxylase deficiency suffer from profound renal sodium wasting (salt-wasting congenital virilizing adrenal hyperplasia). The Na⁺ loss can be exacerbated by mineralocorticoid deficiency combined with the antimineralocorticoid effects of certain overproduced precursor steroids. By contrast, 11ß-hydroxylase deficiency presents with virilization coupled with the hypersecretion of 11-deoxycortisol and 11-deoxycorticosterone. Because 11-deoxycorticosterone possesses potent mineralocorticoid activity, affected patients experience marked salt and Water retention leading to moderate-to-severe hypertension (the hypertensive form of congenital virilizing adrenal hyperplasia). Glucocorticoid replacement therapy is indicated in all virilizing forms of congenital adrenal hyperplasia, as it corrects the cortisol deficit and suppresses ACTH hypersecretion (see below), thereby curbing the pathological overproduction of androgens and other steroids. Nevertheless, dosages tailored strictly to restore physiological glucocorticoid levels may fail to fully suppress excessive androgen production due to the inherent bottleneck in the steroidogenic pathway, which continuously shunts endogenous substrates toward androgens. In clinical practice, this challenge is managed either by administering supraphysiological doses of glucocorticoids or by combining standard replacement therapy with pharmacological agents that block the peripheral effects of excess sex hormones.

Fig. 20-11. Classic Clinical Features of the adrenogenital syndrome in a postpubertal female (reproduced with permission from Forsham PH, Di Raimondo VC: Traumatic Medicine and Surgery for the Attorney. Butterworth, 1960).

The expression and activity of the cytochrome P450 enzymes responsible for steroid hormone biosynthesis are critically dependent on steroidogenic factor-1 (SF-1), an orphan nuclear receptor. Mutations in NR5A1 (the gene encoding SF-1) result in the failure of both the adrenal glands and gonads to develop properly, accompanied by additional developmental anomalies at the hypothalamo-pituitary level.