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HORMONES | Adrenal Hormones
HORMONES/Adrenal Hormones
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HORMONES Contents Adrenal Hormones Thyroid Hormones Gut Hormones Pancreatic Hormones Pituitary Hormones Steroid Hormones
Adrenal Hormones L N Parker, University of California, Long Beach, CA, USA Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Background and History 0001
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Hormones secreted by both parts of the adrenal gland, the cortex and medulla, affect metabolism of proteins, carbohydrates, fat, minerals, and water. The human adrenal glands are paired structures located at the superior pole of each kidney. They are compound glands, composed of an outer cortex and an inner medulla. The cortex secretes three classes of steroid hormones. In humans, the main examples of these hormones are cortisol, a glucocorticoid; dehydroepiandrosterone (DHEA), an androgen; and aldosterone, a mineralocorticoid. The adrenal medulla secretes nonsteroidal hormones with a catechol nucleus, among them epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine. Norepinephrine and epinephrine are primarily involved in the biological alarm mechanism of the sympathoadrenal system. The embryological development of the adrenal cortex and medulla are different, as are their control mechanisms and functions, and in some nonhuman vertebrates, including fish, are located apart from each other. The adrenal glands were described in the sixteenth century by Eustachius, although their functions remained unknown for approximately three centuries. In the nineteenth century, histological studies revealed three zones in the adrenal cortex, and an inner medullary zone which stained differently from the cortex in the fetal and adult adrenal gland. The functions of the adrenal glands were then gradually elucidated. In 1855, Thomas Addison described a group of patients with anemia, pigmented skin, gastrointestinal symptoms, and marked weakness, who were found at autopsy to have atrophied adrenal
glands. Their condition of adrenal failure still bears his name, Addison’s disease. At approximately the same time, the physiologists Claude Bernard and Charles Brown-Se´ quard popularized the concept of internal secretions by glands, and showed by adrenalectomies in animals that the adrenal glands are essential for life. The next clues about the role of the adrenal glands were discovered beginning at the turn of the twentieth century, when a substance with vasopressor activity was isolated from the adrenal medulla, purified and named adrenaline, or epinephrine. In retrospect, epinephrine thereby became the first hormone with a known chemical structure. Shortly thereafter, it was hypothesized that the adrenal glands controlled salt balance as well as blood pressure when it was found that sodium salts could prolong the life of adrenalectomized animals. A generation later, by the use of lipid, rather than aqueous extracts, steroid hormones were sequentially discovered and purified after it was observed that crude lipid extracts of adrenal glands could keep adrenalectomized animals alive indefinitely. The first adrenal steroid hormone synthesized was deoxycorticosterone (DOC), a weak mineralocorticoid, in 1937. The first glucocorticoid synthesized was cortisone in 1949, and by 1955 the main mineralocorticoid in humans, aldosterone, had been characterized and synthesized. Experiments soon demonstrated adrenocortical control by the pituitary gland, and in turn hypothalamic control of adrenocorticotropin (ACTH) was demonstrated conclusively by the characterization and synthesis of corticotropin-releasing hormone (CRH) in 1981. More recent research has focused on many aspects of adrenal gland function, such as hormone synthesis, hormone receptors, and mechanisms of intracellular action. Clinical research has shown the clinical usefulness of epinephrine and related substances in the treatment of asthma, glucocorticoids in the treatment of inflammatory and other conditions, and mineralocorticoids and related substances in the management of autonomic insufficiency.
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3132 HORMONES/Adrenal Hormones
Structure of the Adrenal Glands and Hormones Secreted Adrenal Cortex 0005
The location of the human adrenal glands and the structures surrounding them are shown in Figure 1. The weight range of each adrenal gland is approximately 3.5–5 g, and the cortex comprises about 90% of the gland volume. Chronically increased ACTH secretion causes adrenal weight to increase. The adrenal glands, normally adjacent to the kidneys, are surrounded by fat, and can be separated from the kidney in obesity. Occasionally, accessory adrenal tissue is found in the connective tissue near the main glands, most commonly in locations such as in the retroperitoneal celiac plexus, in the hilum of the spleen, near the ovaries or broad ligament, in the scrotum or in the liver. Embryologically, the adrenal cortex is derived from mesenchymal cells adjacent to the urogenital ridge. The fetal adrenal can be recognized by 2 months of gestation, at which time it is invaded by neuroectodermal cells which will form the medulla. By the second trimester, there is a thin outer definitive zone, which will later form the adult adrenal cortex, but the inner fetal zone comprises most of the adrenal mass. After birth, the fetal zone, which secretes mostly DHEA sulfate (DHEAS), rapidly involutes by 2 months of age, and disappears by 1 year.
Adrenal glands
Esophagus (cut)
Kidney
By 1 year of age, three zones can be identified by light microscopy in the definitive adrenal cortex, as shown in Figure 2. The outer zone, the zona glomerulosa, is relatively thin, and consists of cells which secrete aldosterone. The middle zone, the zona fasciculata, is usually the thickest layer of the adrenal cortex, and has a columnar structure. Its cells are relatively clear, since they are large and have a high lipid content. The inner zone, the zona reticularis, surrounds the medulla. Its cells are relatively darkstaining and compact in appearance, and often contain lipofuscin pigment granules. Both the zona fasciculata and the zona reticularis produce cortisol and androgens, but in the human, the zona reticularis has sulfotransferase activity, and produces DHEAS. Chronically increased ACTH concentrations result in lipid depletion from the zona fasciculata and an increase in the width of the zona reticularis. Adrenal Medulla
The adrenal medulla is part of the sympathetic nervous system, which arises from cells of the neural crest during embryonic development. Storage granules which stain brown with chromic acid due to oxidation of catecholamines to melanin give the cells which contain them the name chromaffin or pheochrome cells. These cells are also found on both sides of the aorta, and comprise the paraganglia. The largest collection of these cells is found near the inferior mesenteric artery, where the cells fuse to form a fetal structure called the organ of Zuckerkandl, which undergoes involution within the first year of life. The remainder of the chromaffin cells in the paraganglia and adrenal medulla persist during adult life and secrete norepinephrine, epinephrine, and dopamine. In the adrenal medulla, the cells are arranged in an irregular network with a rich blood supply, and are in contact with sympathetic ganglia. The cells of the adrenal medulla are innervated by preganglionic
Connective tissue capsule
Cortex
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Zona glomerulosa Zona fasciculata
Zona reticularis
Inferior vena cava Aorta fig0001
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Figure 1 Location and surrounding structures of the human adrenal glands. Reproduced from Gaudin A and Jones K (1989) Human Anatomy and Physiology. San Diego: Harcourt Brace Jovanovich, with permission.
Medulla Figure 2 Histology of the human adrenal gland. Reproduced from Gaudin A and Jones K (1989) Human Anatomy and Physiology, San Diega: Harcourt Brace Jovanovich, with permission.
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HORMONES/Adrenal Hormones
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fibers of the sympathetic nervous system. Most of the blood supply of the adrenal glands enters through the cortex and drains into the medulla, except for some vessels which supply the medulla directly.
Physiological Effects of Adrenal Gland Hormones
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As in the case of other steroid hormones, glucocorticoids exert their effects on target cells by interacting with soluble cytosolic receptor proteins, after mostly passive diffusion into cells. The glucocorticoid receptor is a single-chain polypeptide with a molecular weight of 94 kDa which binds glucocorticoids with a high affinity. After binding glucocorticoids at the COOH-terminus, the DNA-binding region in midmolecule binds to the nucleus. The glucocorticoid receptor is a member of a family of DNA-binding proteins which act as regulators of gene transcription, including receptors for all types of steroid hormones, the thyroid hormone receptor, and the retinoic acid receptor. The hormone-binding domain of these receptors is well conserved, but the most distinctive feature is the highly conserved central DNA-binding domain. This is the zinc-finger domain, a series of finger-like loop structures of amino acids anchored at the base by a zinc ion chelated between two pairs of cysteine and histidine residues (Figure 3), which interact with coils of the DNA double helix. Glucocorticoid receptor complexes interact with specific glucocorticoid response elements, usually located near the promoter region of target genes. Glucocorticoids are named for their effect of increasing hepatic glucose production by several mechanisms. They increase activity of hepatic gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, in the latter case by gene transcription. Glucocorticoids also activate glycogen synthase and inactivate the glycogenmobilizing enzyme glycogen phosphorylase, with a net increase in hepatic glycogen synthesis. Finally, glucocorticoids decrease peripheral glucose utilization in part by decreasing adipocyte glucose transporter mRNA levels. With respect to protein and fat metabolism, glucocorticoids stimulate catabolism of nonhepatic proteins with a resultant release of glucogenic amino acids, largely from skeletal muscle, and an increased uptake into liver for gluconeogenesis. In adipose tissue, glucocorticoids stimulate lipolysis and subsequent release of glycerol and free fatty acids, while enhancing the rate of fat oxidation. Pharmacological amounts of glucocorticoids cause osteopenia on
H
His
C
Zn Cys
Zn H
His C
(a)
(b)
Figure 3 Two postulated models (a, b) of zinc-finger structures in the DNA-binding region of the glucocorticoid receptor. Reproduced from Evans R and Hollenberg S (1988) Zinc Fingers. Cell 52: 1. Cambridge, MA: Cell Press, with permission.
a chronic basis, by inhibiting osteoblast function, thereby decreasing new bone formation, and by decreasing intestinal calcium absorption. Cortisol is a major stress hormone and is secreted in so many different forms of stress that an increase in cortisol secretion is often considered to be part of the definition of a stressful stimulus. It has been speculated that cortisol functions to aid survival in stress by improving the metabolic milieu by means of the energy-producing and biosynthetic pathways described above. The inflammatory process is common in stress caused by illness or injury, and cortisol may also help to minimize damage to the body resulting from excessive inflammation by stimulating mechanisms such as lysosomal membrane stabilization, which prevents release of proteolytic enzymes, and reduction in capillary permeability to avoid leakage of plasma and blood cells into an inflamed area. Among the mechanisms by which cortisol performs these functions is the inhibition of the action of histamine, and the synthesis of prostaglandins. Cortisol inhibits the accumulation of neutrophils at sites of inflammation. Cortisol also has numerous other effects, such as maintenance of normal cardiac output and renal blood flow, and modification of immunological responses. One mechanism for the modification of immunological responses is the promotion of lymphocyte apoptosis. Adrenal androgens such as DHEAS circulate at high concentrations in young adults, and in the case of DHEAS, the concentration is much greater than that of cortisol. However, their functions are not as clearly elucidated. There is evidence that these steroids have a hepatic receptor, and that they may prevent osteoporosis, facilitate the birth process by
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3134 HORMONES/Adrenal Hormones
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causing cervical softening, modify immunological processes, mediate female libido, and serve as precursors for the more potent sex steroids. In animal studies these steroids have been shown to protect against obesity, diabetes, and certain types of infections and tumors. There is DHEAS in the human brain, and it has been shown to be synthesized in rat brain, but its function in the nervous system of either species is not known. Aldosterone and other mineralocorticoids maintain normal sodium and potassium concentrations and intravascular volume by regulating electrolyte transport across epithelial surfaces. The specific renal type I mineralocorticoid receptor is unrelated to the glucocorticoid receptor at the amino-terminus, but partially homologous at the steroid-binding COOH-terminus, and highly homologous at the DNA-binding zinc-finger domain. Cortisol displaces aldosterone from this receptor, but in vivo is converted locally to cortisone by the microsomal 11-b hydroxysteroid dehydrogenase enzyme, and cortisone has relatively little affinity for the mineralocorticoid receptor. After binding to the mineralocorticoid receptor, mineralocorticoids induce protein synthesis and subsequent activation of a sodium pump, which transports sodium across cell membranes. In the kidney, sodium is absorbed, and potassium and hydrogen ions are secreted. Under the influence of aldosterone, sodium is therefore conserved, and potassium and hydrogen ions are excreted into the urine. Aldosterone has similar effects in sweat glands, salivary glands, and in the intestinal lumen. Adrenal Medulla
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Catecholamines exert their effects via two classes of receptors, a and b. Adrenergic receptors interact with catecholamines on the extracellular side of the plasma membrane, and with G proteins within the cell membrane. Adrenergic receptors are part of a large family of membrane-associated proteins which includes muscarinic acetylcholine receptors. Regions of these proteins show considerable homology with each other, especially the membrane-spanning domains. As with other receptors which are coupled to G proteins, there are seven hydrophobic membranespanning domains connected by three extracellular and cytoplasmic loops. Stimulation of the a class of receptors by norepinephrine results in a variety of actions, such as vasoconstriction and blood pressure elevation, pupillary dilatation, and bladder sphincter contraction. Epinephrine also stimulates a receptors. However, in addition, epinephrine also stimulates the b types of receptors, which result in actions such as vasodilatation, acceleration of the heart rate,
bronchodilatation, glycogenolysis, and lipolysis. These actions are part of the physiological response to stressful stimuli, and complement those of cortisol. Dopamine is a weak agonist of both the a and b classes of receptors, but in addition, there are several classes of dopaminergic receptors in the central nervous system and peripheral tissues. In liver, catecholamines promote glucose output by activating glycogenolysis, accelerating gluconeogenesis, and inhibiting glycogen synthesis. Stimulation of adrenergic receptors by catecholamines increases activity of adrenyl cyclase and conversion of glycogen phosphorylase from the inactive to the active form, while there is a simultaneous increase of amino acid uptake by the liver, which increases substrate availability for gluconeogenesis. In adipose tissue, catecholamines also stimulate lipolysis by increasing activity of hormone-sensitive lipase, and the cleavage of triglycerides into fatty acids and glycerol for increased gluconeogenesis and energy availability.
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Synthesis and Control of Adrenal Gland Hormones Adrenal Cortex
The adrenal cortex produces cortisol in response to ACTH secreted by the pituitary gland. The secretion of ACTH occurs in response to decreased circulating concentrations of cortisol, as part of a negativefeedback system, and in response to stressors of many types, including surgery, hemorrhage, thermal injury, and hypoglycemia. In addition, there is a circadian rhythm of pulsatile ACTH and cortisol secretion which in humans results in increased secretion towards the end of the sleep period, and therefore higher levels of circulating cortisol in the morning. ACTH is a 39-amino-acid peptide derived from a larger molecule, 241-amino-acid proopiomelanocortin (POMC). The first 24 amino acids of ACTH are constant and bioactive in many species. POMC secretion is under the control of neurotransmitters and hypothalamic CRH, as shown in Figure 4. POMC undergoes extensive posttranslational processing, producing many peptides, including ACTH, as shown in Figure 5. There is evidence from animal experiments that non-ACTH POMC peptides may synergize with ACTH in control of corticosteroid secretion. Concentrations of CRH, a 41-amino-acid peptide, are high in the hypophysical portal system. The mechanism of action of ACTH involves many steps, including initial binding to an adrenal cell surface receptor, which ACTH upregulates, thereby increasing the steroidogenic response to ACTH stimulation. ACTH binding activates adenyl cyclase
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HORMONES/Adrenal Hormones
(−) (−)
(−)
(+) (−)
(+)
CRH pit. (−)
(−)
ACTH Cortisol
Adrenal cortex
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Figure 4 Cortisol feedback loop in the hypothalamic–pituitary– adrenal system. CRH, corticotropin-releasing hormone; pit, pituitary gland; ACTH, adrenocorticotropic hormone. Cortisol negative feedback shown by dashed lines. Reproduced from Darlington D and Dallman M (1990) Feedback Control in Endocrine Systems. Principles and Practice of Endocrinology and Metabolism. Philadelphia: JB Lippincott, with permission.
which increases cyclic 30 ,50 -monophosphate (cAMP) concentrations, which in turn activate cAMPdependent protein kinase and phosphorylation of a number of proteins in the presence of extracellular calcium. There is an increase in activity of cholesterol ester hydrolase, which produces free cholesterol for the rate-limiting conversion of cholesterol to pregnenolone. Intracellular delivery of cholesterol to the inner mitochondrial membrane is facilitated by the 30-kDa steroidogenic acute regulatory protein, induced by cAMP. The conversion of cholesterol to pregnenolone then proceeds via the mitochondrial side-chain cleavage enzyme. Plasma lipoproteins also provide cholesterol for steroidogenesis. As shown in Figure 6, pregnenolone can be converted to mineralocorticoids, glucocorticoids, or androgens. Many of the microsomal enzymatic steps are controlled by ACTH by regulation of the rate of steroidogenic enzyme synthesis. In contrast to the
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situation in the human, there is little activity of the enzyme 17b-hydroxylase (Figure 6) in rodents, and therefore the main glucocorticoid is corticosterone in this species. Cortisol and ACTH secretion are closely related, and linked by a negative-feedback loop, as described above. Adrenal androgens, such as DHEA, are also secreted in response to acute ACTH stimulation, but their control is more complex since in some situations they are not secreted in parallel with cortisol. These situations include adrenarche, puberty, aging, polycystic ovarian syndrome, stress, serious illness, anorexia nervosa, and starvation. Adrenarche is the process of adrenal gland maturation which occurs before puberty at approximately age 7, and which involves increased secretion of DHEA and DHEAS along with unchanged secretion of cortisol. In contrast, during aging, while basal levels of cortisol are unchanged, levels of DHEAS peak in young adulthood in both sexes, and then decline markedly, as shown in Figure 7. The decrease in concentrations of adrenal androgens in stress, serious illness, anorexia nervosa, and starvation is somewhat similar to the situation in aging, except that it is reversible with recovery. The reason for the dissociation between cortisol and adrenal androgen secretion is not clear, but may involve regulation by a non-ACTH POMCrelated peptide. Aldosterone is produced only by the zona glomerulosa, because it is the only zone with aldosterone synthase activity. The zona glomerulosa does not have 17b-hydroxylase activity, and does not produce cortisol. Although ACTH causes acute stimulation of aldosterone secretion, there are other more important control mechanisms in addition to ACTH. Angiotensin II is the major regulator of aldosterone secretion. Secretion of angiotensin II is controlled by renin, as shown in Figure 8. Renin release is regulated primarily by the sodium concentration of fluid in contact with the renal juxtaglomerular cells, and renal perfusion, as sensed by renal baroreceptors. Increased renin release is stimulated by decreased sodium concentration or renal arteriolar blood pressure. Renin mediates the conversion of hepatic renin substrate (angiotensinogen) to the 10-amino-acid peptide, angiotensin I, which in turn is converted to the 8-amino-acid peptide angiotensin II, a potent vasopressor, by the converting enzyme in lung and other tissues. The 7-amino-acid peptide angiotensin III is also bioactive in stimulation of aldosterone secretion. Angiotensins II and III bind to high-affinity zona glomerulosa cell surface receptors and stimulate aldosterone production from cholesterol by a calciumdependent mechanism involving activation of protein
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3136 HORMONES/Adrenal Hormones β-LPH
16 K fragment
JP
N-POC(1−76)
γ-LPH
ACTH
β-LPH
16 K
N-POC(1−76)
β-endo
JP
γ-LPH
ACTH
β-endo
16 K
N-POC(1−76)
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ACTH
N-POC(1−76)
N-POC(1−76)
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ACTH
ACTH
γ-LPH
β-endo
K = kilodaltons;
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Know maturation products;
MSH (melanocyte-stimulating hormone) structural units;
lys−arg dibasic residues;
O-glycosylation;
Figure 5 Structure and processing of proopiomelanocortin (POMC; POC). ACTH, adrenocorticotropic hormone; LPH, lipotropin; endo, endorphin; JP, joining peptide. Reproduced from Seidah N et al. (1981) The missing fragment of the pro-sequence of human POMC: sequence and evidence for C-terminal amidation. Biochemistry Biophys Research Commun 102: 710, with permission.
kinase C, rather than adenylate cyclase. In addition, aldosterone synthesis may be modified by lipoxygenase pathway metabolites of arachidonic acid. Potassium ion also influences aldosterone secretion by a direct effect on zona glomerulosa cells, and forms the basis for a feedback mechanism to regulate the concentration of extracellular potassium ions. Concentrations of potassium ion have the opposite effect on renin concentrations, but the direct effect on aldosterone secretion is predominant. In addition, as in the case of cortisol and adrenal androgen secretion, there is evidence that an influence on aldosterone secretion may be exerted by non-ACTH POMC-related peptides. Adrenal Medulla 0022
N-glycosylation.
Control of the adrenal medulla is exerted by the sympathetic nervous system. Whereas preganglionic fibers of the parasympathetic branch of the autonomic nervous system emerge from cranial and sacral spinal nerves, those of the sympathetic nervous system emerge from the thoracic and lumbar spinal nerves and innervate many organs, including the adrenal medulla. Preganglionic nerve impulses
are transmitted to postganglionic fibers by liberation of acetylcholine at nerve terminals. This results in secretion of catecholamines by the peripheral sympathetic nervous system and by the adrenal medulla. Norepinephrine is the major secretory product of the peripheral nervous system, and is primarily a neurotransmitter, not a circulating hormone. In the human adrenal medulla, the ratio of epinephrine to norepinephrine secretion is approximately 4:1, and concentrations of epinephrine, a circulating hormone, are sufficient to stimulate adrenergic receptors. Catecholamine biosynthetic pathways are shown in Figure 9. The rate-limiting step in catecholamine biosynthesis is the initial conversion of tyrosine to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (TH), an enzyme which is inhibited by DOPA, dopamine, and norepinephrine. Tyrosine itself is derived from the diet, or converted in the liver from phenylalanine by phenylalanine hydroxylase. The decarboxylation of DOPA to dopamine is catalyzed by aromatic-l-amino acid decarboxylase (AADC). Unlike the other enzymes of catecholamine biosynthesis, AADC is not only found in sympathetic nerve
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HORMONES/Adrenal Hormones CH3
CH3
C
C
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O
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O
O
OH A
D
C
E HO
HO Pregnenolone B
Dehydroepiandrosterone
17α-OH pregnenolone B
CH3 C
−SO 4
OH
Dehydroepiandrosterone sulfate
B CH3
O
O
C
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OH A
O
C
O Progesterone
F
O Androstenedione
17α-OH progesterone
F
CH2OH C
O
CH2OH C
O OH
O
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11-Deoxycorticosterone
11-Deoxycortisol
G
CH2OH C
O
C
HO
O OH
HO
O
CH2OH
O Corticosterone
CH2OH
H
HO
Cortisol
C CHO
O
O Aldosterone fig0006
Figure 6 Human adrenocortical steroidogenic pathways. Enzyme activities: A, 17a-hydroxylase (CYP 17); B, 3b-hydroxysteroid dehydrogenase-isomerase (3b-HSD II); C, C17–20 desmolase (CYP 17); D, steroid sulfotransferase; E, steroid sulfatase; F, 21-hydroxylase (CYP21A2); G, 11b-hydroxylase (CYP11B1); H, aldosterone synthase (CYP11B2). Reproduced from Parker (1989) Adrenal Androgens in Clinical Medicine. San Diego: Academic Press, with permission.
3138 HORMONES/Adrenal Hormones NH2
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CH2CHCOOH
Males DHAS (µg per 100 ml)
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HO
Females Tyrosine hydroxylase
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HO 200
Dihydroxyphenylalanine (DOPA)
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Figure 7 Serum concentrations of dehydroepiandrosterone sulfate (DHAS) in normal subjects 1–73 years of age. Reproduced from Smith M, et al. (1975) A radioimmunoassay for the estimation of serum DHAS in normal and pathological sera. Clinica Chimica Acta 65: 5, with permission.
HO
ECF depletion JUXTAGLOMERULAR Decrease in renal APPARATUS Potassium arterial pressure Increase in Sympathetic nerves renal arterial [Na+] at macula densa pressure or Hypokalemia Stimulate volume Prostaglandins it b i h In 'Long-loop Blood feedback' angiotensinogen ECF Renin expansion 'Short-loop Angiotensin I feedback' Converting enzyme ibit Angiotensin II Inh Arteriolar constriction Renal sodium retention Angiotensinases Angiotensin ADRENAL III GLAND Aldosterone Inactive
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Figure 8 Control of aldosterone secretion by the renin– angiotensin system. ECF, extracellular fluid. Reproduced from Bondy P and Rosenberg L (1980) Metabolic Control and Disease. Philadelphia: WB Saunders, with permission.
endings and the adrenal medulla, but also in nonneuronal tissues, including the kidney, and catalyzes the decarboxylation of other aromatic amino acids in addition to DOPA, including 5-hydroxytryptophan, which is converted to serotonin. Dopamine b-hydroxylase (DBH) catalyzes the hydroxylation of dopamine to form norepinephrine. The enzyme is found in sympathetic nerve endings, and also in adrenal medullary chromaffin granules, which release DBH along with norepinephrine when
CH2CH2NH2 Dopamine
Dopamine β-hydroxylase OH HO HO Phenylethanolamine N -methyl transferase
fig0008
CH2CHCOOH
HO
100
fig0007
NH2
300
0
Tyrosine
CHCH2NH2 Norepinephrine
OH HO HO
CHCH2NHCH3 Epinephrine
Figure 9 Catecholamine biosynthetic pathway of the sympathetic nervous system. Reproduced from Cryer P (1987) Diseases of the sympathochromaffin system. In: Felig P (ed.) Endocrinology and Metabolism. New York: McGraw-Hill, with permission.
stimulated. The major difference between the catecholaminergic pathways of the adrenal medulla and the peripheral nervous system is the presence of the enzyme phenylethanolamine-N-methyl transferase (PNMT) in the medulla. This enzyme, also found in small amounts in the brain, catalyzes the conversion of norepinephrine to epinephrine, using S-adenosylmethionine as a methyl donor. PNMT is inducible by high concentrations of cortisol which are present in the capillary sinusoidal circulation from the adrenal cortex to the medulla. A large percentage of synaptically released catecholamines are inactivated by reuptake into storage granules. Metabolism of circulating catecholamines occurs via two main pathways, mediated by the enzymes catechol-O-methyltransferase (COMT) and by monoamine oxidase (MAO), as shown in Figure 10. The end product of norepinephrine and epinephrine metabolism, after transformation by both enzymes, is 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid). Catecholamines in the liver and gut are also inactivated by sulfate or glucuronide conjugation of the phenolic hydroxyl group.
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HORMONES/Adrenal Hormones
OH
OH
HO
CH
HO
CH
HO
CH2
HO
CH2
HO
CH2
NH2
HO
CH2
NHCH3
Norepinephrine
Epinephrine
AO M
AO
HO
CH
HO
C
M HO
O
COMT
OH Dihydroxymandelic acid OH CH
CH3O HO
Dopamine
OH CH
CH3O
CH2
HO
COMT
CH2
NHCH3
NH2
HO
AO
NH2 T M CO
M
OH
COMT
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CH2 C
AO M
OH CH3O HO
CH2
HO
CH2
O
NH2 3-Methoxytyramine
OH Dihydroxyphenyl acetic acid C O M T
AO
M
CH2
CH3O HO
C
O
OH
Normetanephrine
Metanephrine
CH3O
Homovanillic acid
AO M
CH C
O
OH 3-Methoxy-4-hydroxy mandelic acid fig0010
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Figure 10 Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Reproduced from Goldfien A (1986) The adrenal medulla. In: Greenspan F and Forsham P (eds) Basic and Clinical Endocrinology. Los Altos, CA: Lange Medical Publications, with permission.
The hypothalamus is the main regulator of sympathetic nervous system function. Impulses from the posterior and lateral hypothalamus result in generalized discharge of the sympathetic nervous system, including the adrenal medulla, although they can also be activated separately. The sympathoadrenal system is characterized by speed and integration, in that catechol-mediated events can take place within seconds, and can coordinate vascular, metabolic, and hormonal components. As discussed above, these responses occur to a variety of noxious, threatening, or stressful stimuli. In addition, the sympathetic nervous system is instrumental in maintaining an appropriate circulating volume and cardiac output during changes of posture from supine to upright. These feedback systems are mediated by sensors in the carotid sinuses, aorta, and medulla, which detect changes in circulatory volume and blood pressure. Although of different embryological origins, and operating via different regulatory mechanisms, the hypothalamic–pituitary–adrenocortical system and the sympathoadrenal system complement each
other in the maintenance of homeostasis and a stable metabolic milieu in response to many forms of stress. See also: Amino Acids: Metabolism; Fatty Acids: Metabolism; Renal Function and Disorders: Kidney: Structure and Function; Stress and Nutrition
Further Reading Baxter J and Tyrrell J (1987) The adrenal cortex. In: Felig P (ed.) Endocrinology and Metabolism. New York: McGraw-Hill. DeQuattro V, Myers M and Campese V (1989) Anatomy and biochemistry of the sympathetic nervous system. In: DeGroot L (ed.) Endocrinology. Philadelphia: WB Saunders. Ganong W (1991) Review of Medical Physiology. The Adrenals. Norwalk, CT: Appleton & Lange. Guyton A (1986) The adrenocortical hormones. In: Textbook of Medical Physiology. Philadelphia: WB Saunders.
3140 HORMONES/Thyroid Hormones Hale A and Rees L (1989) ACTH and related peptides. In: DeGroot (ed.) Endocrinology. Philadelphia: WB Saunders. Loriaux DL (1990) The adrenal glands. In: Becker K (ed.) Principles and Practice of Endocrinology and Metabolism. Philadelphia: JB Lippincott. Orth D and Kovacs W (1998) The adrenal cortex. In: Williams Textbook of Endocrinology. Philadelphia: WB Saunders. Parker L (1989) Adrenal androgens: normal physiology. In: Adrenal Androgens in Clinical Medicine. San Diego: Academic Press.
TPO
NADPH Oxidase
Tg
TTF-1 TTF-2 Pax8
Thyroid Hormones J Vanderpas, Faculte´ Me´decine, FUNDP, Namur, Belgium Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Iodinated Thyroid Hormones Thyroid Follicles and their Development 0001
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The thyroid gland displays a peculiar, highly organized architecture characterized by the presence of spheroidal structures – follicles – that are composed of a single layer of epithelial cells (thyroid follicular cells) surrounding a closed cavity (follicular lumen) filled with colloid, a concentrated solution of thyroglobulin (Tg). The follicle has been defined as the morphologic and functional unit of the thyroid. Notably, during intrauterine life, the onset of thyroid function (around 10 weeks in humans) coincides with the appearance of differentiated follicles. It is the follicular organization, together with the polarity of the follicular cells, that allows the several biochemical steps required for thyroid hormone biosynthesis: (1) secretion of a peculiar protein with iodinated amino acids in the follicular lumen as exocrine cells; (2) reabsorption of this peculiar protein, with hydrolysis of its iodinated amino acids; (3) release of iodothyronines into blood by endocrine secretion. The follicle cell divides the follicular lumen (where hormone synthesis begins) and the blood stream, from where iodine has to be uploaded and where hormones will be released at the end of the process. The surface of a polarized thyroid follicular cell is divided into two functionally distinct, but physically contiguous regions: an apical and a basolateral domain. Junctional complexes between cells separate these two domains and prevent the mixing of asymmetrically distributed proteins (Figure 1). The apical domain displays a differentiated tissue-specific organization characterized by the presence of apical
B
TSH-R
NIS
Figure 1 Schematic structural representation of thyroid follicular cell with its polarized architecture. TSH-R, thyroid-stimulating hormone receptor; NIS, Na/I symporter; Tg, thyroglobulin; TPO, thyroperoxidase; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; TTF-1.
microvilli and pseudopods, and by the localization of thyroperoxidase (TPO). Naþ/I symporter (NIS), epidermal growth factor, and thyroid-stimulating hormone (TSH) receptors are located in the basal domain. Thyroid hormone synthesis requires basalto-apical transport of iodide and Tg. Conversely, hormone secretion is based on apical-to-basal transport of Tg and hormones; in addition, a bidirectional ion transport system controls follicular size. The thyroid primordium of the human embryo is first visible at 20 embryonic days, as a midline enodermal thickening in the floor of the primitive pharynx. It migrates caudally to form a transient thyroglossal duct, and reaches its final position at 35 embryonic days. Tg is detectable at 60 embryonic days, and this step corresponds to the occurrence of fetal thyroid hormone biosynthesis. The early stages of folliculogenesis are independent of thyrotropin. At midgestation (18–20 weeks), the hypothalamopituitary–thyroid axis begins to develop, and thyrotropin is absolutely necessary for thyroid growth and function.
fig0001
0004
Biosynthesis of Thyroid Hormones
Figure 2 summarizes the process of thyroid hormone synthesis, which includes active concentration of
0005
3131
HORMONES Contents Adrenal Hormones Thyroid Hormones Gut Hormones Pancreatic Hormones Pituitary Hormones Steroid Hormones
Adrenal Hormones L N Parker, University of California, Long Beach, CA, USA Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Background and History 0001
0002
0003
Hormones secreted by both parts of the adrenal gland, the cortex and medulla, affect metabolism of proteins, carbohydrates, fat, minerals, and water. The human adrenal glands are paired structures located at the superior pole of each kidney. They are compound glands, composed of an outer cortex and an inner medulla. The cortex secretes three classes of steroid hormones. In humans, the main examples of these hormones are cortisol, a glucocorticoid; dehydroepiandrosterone (DHEA), an androgen; and aldosterone, a mineralocorticoid. The adrenal medulla secretes nonsteroidal hormones with a catechol nucleus, among them epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine. Norepinephrine and epinephrine are primarily involved in the biological alarm mechanism of the sympathoadrenal system. The embryological development of the adrenal cortex and medulla are different, as are their control mechanisms and functions, and in some nonhuman vertebrates, including fish, are located apart from each other. The adrenal glands were described in the sixteenth century by Eustachius, although their functions remained unknown for approximately three centuries. In the nineteenth century, histological studies revealed three zones in the adrenal cortex, and an inner medullary zone which stained differently from the cortex in the fetal and adult adrenal gland. The functions of the adrenal glands were then gradually elucidated. In 1855, Thomas Addison described a group of patients with anemia, pigmented skin, gastrointestinal symptoms, and marked weakness, who were found at autopsy to have atrophied adrenal
glands. Their condition of adrenal failure still bears his name, Addison’s disease. At approximately the same time, the physiologists Claude Bernard and Charles Brown-Se´ quard popularized the concept of internal secretions by glands, and showed by adrenalectomies in animals that the adrenal glands are essential for life. The next clues about the role of the adrenal glands were discovered beginning at the turn of the twentieth century, when a substance with vasopressor activity was isolated from the adrenal medulla, purified and named adrenaline, or epinephrine. In retrospect, epinephrine thereby became the first hormone with a known chemical structure. Shortly thereafter, it was hypothesized that the adrenal glands controlled salt balance as well as blood pressure when it was found that sodium salts could prolong the life of adrenalectomized animals. A generation later, by the use of lipid, rather than aqueous extracts, steroid hormones were sequentially discovered and purified after it was observed that crude lipid extracts of adrenal glands could keep adrenalectomized animals alive indefinitely. The first adrenal steroid hormone synthesized was deoxycorticosterone (DOC), a weak mineralocorticoid, in 1937. The first glucocorticoid synthesized was cortisone in 1949, and by 1955 the main mineralocorticoid in humans, aldosterone, had been characterized and synthesized. Experiments soon demonstrated adrenocortical control by the pituitary gland, and in turn hypothalamic control of adrenocorticotropin (ACTH) was demonstrated conclusively by the characterization and synthesis of corticotropin-releasing hormone (CRH) in 1981. More recent research has focused on many aspects of adrenal gland function, such as hormone synthesis, hormone receptors, and mechanisms of intracellular action. Clinical research has shown the clinical usefulness of epinephrine and related substances in the treatment of asthma, glucocorticoids in the treatment of inflammatory and other conditions, and mineralocorticoids and related substances in the management of autonomic insufficiency.
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3132 HORMONES/Adrenal Hormones
Structure of the Adrenal Glands and Hormones Secreted Adrenal Cortex 0005
The location of the human adrenal glands and the structures surrounding them are shown in Figure 1. The weight range of each adrenal gland is approximately 3.5–5 g, and the cortex comprises about 90% of the gland volume. Chronically increased ACTH secretion causes adrenal weight to increase. The adrenal glands, normally adjacent to the kidneys, are surrounded by fat, and can be separated from the kidney in obesity. Occasionally, accessory adrenal tissue is found in the connective tissue near the main glands, most commonly in locations such as in the retroperitoneal celiac plexus, in the hilum of the spleen, near the ovaries or broad ligament, in the scrotum or in the liver. Embryologically, the adrenal cortex is derived from mesenchymal cells adjacent to the urogenital ridge. The fetal adrenal can be recognized by 2 months of gestation, at which time it is invaded by neuroectodermal cells which will form the medulla. By the second trimester, there is a thin outer definitive zone, which will later form the adult adrenal cortex, but the inner fetal zone comprises most of the adrenal mass. After birth, the fetal zone, which secretes mostly DHEA sulfate (DHEAS), rapidly involutes by 2 months of age, and disappears by 1 year.
Adrenal glands
Esophagus (cut)
Kidney
By 1 year of age, three zones can be identified by light microscopy in the definitive adrenal cortex, as shown in Figure 2. The outer zone, the zona glomerulosa, is relatively thin, and consists of cells which secrete aldosterone. The middle zone, the zona fasciculata, is usually the thickest layer of the adrenal cortex, and has a columnar structure. Its cells are relatively clear, since they are large and have a high lipid content. The inner zone, the zona reticularis, surrounds the medulla. Its cells are relatively darkstaining and compact in appearance, and often contain lipofuscin pigment granules. Both the zona fasciculata and the zona reticularis produce cortisol and androgens, but in the human, the zona reticularis has sulfotransferase activity, and produces DHEAS. Chronically increased ACTH concentrations result in lipid depletion from the zona fasciculata and an increase in the width of the zona reticularis. Adrenal Medulla
The adrenal medulla is part of the sympathetic nervous system, which arises from cells of the neural crest during embryonic development. Storage granules which stain brown with chromic acid due to oxidation of catecholamines to melanin give the cells which contain them the name chromaffin or pheochrome cells. These cells are also found on both sides of the aorta, and comprise the paraganglia. The largest collection of these cells is found near the inferior mesenteric artery, where the cells fuse to form a fetal structure called the organ of Zuckerkandl, which undergoes involution within the first year of life. The remainder of the chromaffin cells in the paraganglia and adrenal medulla persist during adult life and secrete norepinephrine, epinephrine, and dopamine. In the adrenal medulla, the cells are arranged in an irregular network with a rich blood supply, and are in contact with sympathetic ganglia. The cells of the adrenal medulla are innervated by preganglionic
Connective tissue capsule
Cortex
0007
Zona glomerulosa Zona fasciculata
Zona reticularis
Inferior vena cava Aorta fig0001
0006
Figure 1 Location and surrounding structures of the human adrenal glands. Reproduced from Gaudin A and Jones K (1989) Human Anatomy and Physiology. San Diego: Harcourt Brace Jovanovich, with permission.
Medulla Figure 2 Histology of the human adrenal gland. Reproduced from Gaudin A and Jones K (1989) Human Anatomy and Physiology, San Diega: Harcourt Brace Jovanovich, with permission.
fig0002
HORMONES/Adrenal Hormones
3133
fibers of the sympathetic nervous system. Most of the blood supply of the adrenal glands enters through the cortex and drains into the medulla, except for some vessels which supply the medulla directly.
Physiological Effects of Adrenal Gland Hormones
Cys
Adrenal Cortex 0008
0009
0010
As in the case of other steroid hormones, glucocorticoids exert their effects on target cells by interacting with soluble cytosolic receptor proteins, after mostly passive diffusion into cells. The glucocorticoid receptor is a single-chain polypeptide with a molecular weight of 94 kDa which binds glucocorticoids with a high affinity. After binding glucocorticoids at the COOH-terminus, the DNA-binding region in midmolecule binds to the nucleus. The glucocorticoid receptor is a member of a family of DNA-binding proteins which act as regulators of gene transcription, including receptors for all types of steroid hormones, the thyroid hormone receptor, and the retinoic acid receptor. The hormone-binding domain of these receptors is well conserved, but the most distinctive feature is the highly conserved central DNA-binding domain. This is the zinc-finger domain, a series of finger-like loop structures of amino acids anchored at the base by a zinc ion chelated between two pairs of cysteine and histidine residues (Figure 3), which interact with coils of the DNA double helix. Glucocorticoid receptor complexes interact with specific glucocorticoid response elements, usually located near the promoter region of target genes. Glucocorticoids are named for their effect of increasing hepatic glucose production by several mechanisms. They increase activity of hepatic gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, in the latter case by gene transcription. Glucocorticoids also activate glycogen synthase and inactivate the glycogenmobilizing enzyme glycogen phosphorylase, with a net increase in hepatic glycogen synthesis. Finally, glucocorticoids decrease peripheral glucose utilization in part by decreasing adipocyte glucose transporter mRNA levels. With respect to protein and fat metabolism, glucocorticoids stimulate catabolism of nonhepatic proteins with a resultant release of glucogenic amino acids, largely from skeletal muscle, and an increased uptake into liver for gluconeogenesis. In adipose tissue, glucocorticoids stimulate lipolysis and subsequent release of glycerol and free fatty acids, while enhancing the rate of fat oxidation. Pharmacological amounts of glucocorticoids cause osteopenia on
H
His
C
Zn Cys
Zn H
His C
(a)
(b)
Figure 3 Two postulated models (a, b) of zinc-finger structures in the DNA-binding region of the glucocorticoid receptor. Reproduced from Evans R and Hollenberg S (1988) Zinc Fingers. Cell 52: 1. Cambridge, MA: Cell Press, with permission.
a chronic basis, by inhibiting osteoblast function, thereby decreasing new bone formation, and by decreasing intestinal calcium absorption. Cortisol is a major stress hormone and is secreted in so many different forms of stress that an increase in cortisol secretion is often considered to be part of the definition of a stressful stimulus. It has been speculated that cortisol functions to aid survival in stress by improving the metabolic milieu by means of the energy-producing and biosynthetic pathways described above. The inflammatory process is common in stress caused by illness or injury, and cortisol may also help to minimize damage to the body resulting from excessive inflammation by stimulating mechanisms such as lysosomal membrane stabilization, which prevents release of proteolytic enzymes, and reduction in capillary permeability to avoid leakage of plasma and blood cells into an inflamed area. Among the mechanisms by which cortisol performs these functions is the inhibition of the action of histamine, and the synthesis of prostaglandins. Cortisol inhibits the accumulation of neutrophils at sites of inflammation. Cortisol also has numerous other effects, such as maintenance of normal cardiac output and renal blood flow, and modification of immunological responses. One mechanism for the modification of immunological responses is the promotion of lymphocyte apoptosis. Adrenal androgens such as DHEAS circulate at high concentrations in young adults, and in the case of DHEAS, the concentration is much greater than that of cortisol. However, their functions are not as clearly elucidated. There is evidence that these steroids have a hepatic receptor, and that they may prevent osteoporosis, facilitate the birth process by
fig0003
0011
0012
3134 HORMONES/Adrenal Hormones
0013
causing cervical softening, modify immunological processes, mediate female libido, and serve as precursors for the more potent sex steroids. In animal studies these steroids have been shown to protect against obesity, diabetes, and certain types of infections and tumors. There is DHEAS in the human brain, and it has been shown to be synthesized in rat brain, but its function in the nervous system of either species is not known. Aldosterone and other mineralocorticoids maintain normal sodium and potassium concentrations and intravascular volume by regulating electrolyte transport across epithelial surfaces. The specific renal type I mineralocorticoid receptor is unrelated to the glucocorticoid receptor at the amino-terminus, but partially homologous at the steroid-binding COOH-terminus, and highly homologous at the DNA-binding zinc-finger domain. Cortisol displaces aldosterone from this receptor, but in vivo is converted locally to cortisone by the microsomal 11-b hydroxysteroid dehydrogenase enzyme, and cortisone has relatively little affinity for the mineralocorticoid receptor. After binding to the mineralocorticoid receptor, mineralocorticoids induce protein synthesis and subsequent activation of a sodium pump, which transports sodium across cell membranes. In the kidney, sodium is absorbed, and potassium and hydrogen ions are secreted. Under the influence of aldosterone, sodium is therefore conserved, and potassium and hydrogen ions are excreted into the urine. Aldosterone has similar effects in sweat glands, salivary glands, and in the intestinal lumen. Adrenal Medulla
0014
Catecholamines exert their effects via two classes of receptors, a and b. Adrenergic receptors interact with catecholamines on the extracellular side of the plasma membrane, and with G proteins within the cell membrane. Adrenergic receptors are part of a large family of membrane-associated proteins which includes muscarinic acetylcholine receptors. Regions of these proteins show considerable homology with each other, especially the membrane-spanning domains. As with other receptors which are coupled to G proteins, there are seven hydrophobic membranespanning domains connected by three extracellular and cytoplasmic loops. Stimulation of the a class of receptors by norepinephrine results in a variety of actions, such as vasoconstriction and blood pressure elevation, pupillary dilatation, and bladder sphincter contraction. Epinephrine also stimulates a receptors. However, in addition, epinephrine also stimulates the b types of receptors, which result in actions such as vasodilatation, acceleration of the heart rate,
bronchodilatation, glycogenolysis, and lipolysis. These actions are part of the physiological response to stressful stimuli, and complement those of cortisol. Dopamine is a weak agonist of both the a and b classes of receptors, but in addition, there are several classes of dopaminergic receptors in the central nervous system and peripheral tissues. In liver, catecholamines promote glucose output by activating glycogenolysis, accelerating gluconeogenesis, and inhibiting glycogen synthesis. Stimulation of adrenergic receptors by catecholamines increases activity of adrenyl cyclase and conversion of glycogen phosphorylase from the inactive to the active form, while there is a simultaneous increase of amino acid uptake by the liver, which increases substrate availability for gluconeogenesis. In adipose tissue, catecholamines also stimulate lipolysis by increasing activity of hormone-sensitive lipase, and the cleavage of triglycerides into fatty acids and glycerol for increased gluconeogenesis and energy availability.
0015
Synthesis and Control of Adrenal Gland Hormones Adrenal Cortex
The adrenal cortex produces cortisol in response to ACTH secreted by the pituitary gland. The secretion of ACTH occurs in response to decreased circulating concentrations of cortisol, as part of a negativefeedback system, and in response to stressors of many types, including surgery, hemorrhage, thermal injury, and hypoglycemia. In addition, there is a circadian rhythm of pulsatile ACTH and cortisol secretion which in humans results in increased secretion towards the end of the sleep period, and therefore higher levels of circulating cortisol in the morning. ACTH is a 39-amino-acid peptide derived from a larger molecule, 241-amino-acid proopiomelanocortin (POMC). The first 24 amino acids of ACTH are constant and bioactive in many species. POMC secretion is under the control of neurotransmitters and hypothalamic CRH, as shown in Figure 4. POMC undergoes extensive posttranslational processing, producing many peptides, including ACTH, as shown in Figure 5. There is evidence from animal experiments that non-ACTH POMC peptides may synergize with ACTH in control of corticosteroid secretion. Concentrations of CRH, a 41-amino-acid peptide, are high in the hypophysical portal system. The mechanism of action of ACTH involves many steps, including initial binding to an adrenal cell surface receptor, which ACTH upregulates, thereby increasing the steroidogenic response to ACTH stimulation. ACTH binding activates adenyl cyclase
0016
0017
HORMONES/Adrenal Hormones
(−) (−)
(−)
(+) (−)
(+)
CRH pit. (−)
(−)
ACTH Cortisol
Adrenal cortex
fig0004
0018
Figure 4 Cortisol feedback loop in the hypothalamic–pituitary– adrenal system. CRH, corticotropin-releasing hormone; pit, pituitary gland; ACTH, adrenocorticotropic hormone. Cortisol negative feedback shown by dashed lines. Reproduced from Darlington D and Dallman M (1990) Feedback Control in Endocrine Systems. Principles and Practice of Endocrinology and Metabolism. Philadelphia: JB Lippincott, with permission.
which increases cyclic 30 ,50 -monophosphate (cAMP) concentrations, which in turn activate cAMPdependent protein kinase and phosphorylation of a number of proteins in the presence of extracellular calcium. There is an increase in activity of cholesterol ester hydrolase, which produces free cholesterol for the rate-limiting conversion of cholesterol to pregnenolone. Intracellular delivery of cholesterol to the inner mitochondrial membrane is facilitated by the 30-kDa steroidogenic acute regulatory protein, induced by cAMP. The conversion of cholesterol to pregnenolone then proceeds via the mitochondrial side-chain cleavage enzyme. Plasma lipoproteins also provide cholesterol for steroidogenesis. As shown in Figure 6, pregnenolone can be converted to mineralocorticoids, glucocorticoids, or androgens. Many of the microsomal enzymatic steps are controlled by ACTH by regulation of the rate of steroidogenic enzyme synthesis. In contrast to the
3135
situation in the human, there is little activity of the enzyme 17b-hydroxylase (Figure 6) in rodents, and therefore the main glucocorticoid is corticosterone in this species. Cortisol and ACTH secretion are closely related, and linked by a negative-feedback loop, as described above. Adrenal androgens, such as DHEA, are also secreted in response to acute ACTH stimulation, but their control is more complex since in some situations they are not secreted in parallel with cortisol. These situations include adrenarche, puberty, aging, polycystic ovarian syndrome, stress, serious illness, anorexia nervosa, and starvation. Adrenarche is the process of adrenal gland maturation which occurs before puberty at approximately age 7, and which involves increased secretion of DHEA and DHEAS along with unchanged secretion of cortisol. In contrast, during aging, while basal levels of cortisol are unchanged, levels of DHEAS peak in young adulthood in both sexes, and then decline markedly, as shown in Figure 7. The decrease in concentrations of adrenal androgens in stress, serious illness, anorexia nervosa, and starvation is somewhat similar to the situation in aging, except that it is reversible with recovery. The reason for the dissociation between cortisol and adrenal androgen secretion is not clear, but may involve regulation by a non-ACTH POMCrelated peptide. Aldosterone is produced only by the zona glomerulosa, because it is the only zone with aldosterone synthase activity. The zona glomerulosa does not have 17b-hydroxylase activity, and does not produce cortisol. Although ACTH causes acute stimulation of aldosterone secretion, there are other more important control mechanisms in addition to ACTH. Angiotensin II is the major regulator of aldosterone secretion. Secretion of angiotensin II is controlled by renin, as shown in Figure 8. Renin release is regulated primarily by the sodium concentration of fluid in contact with the renal juxtaglomerular cells, and renal perfusion, as sensed by renal baroreceptors. Increased renin release is stimulated by decreased sodium concentration or renal arteriolar blood pressure. Renin mediates the conversion of hepatic renin substrate (angiotensinogen) to the 10-amino-acid peptide, angiotensin I, which in turn is converted to the 8-amino-acid peptide angiotensin II, a potent vasopressor, by the converting enzyme in lung and other tissues. The 7-amino-acid peptide angiotensin III is also bioactive in stimulation of aldosterone secretion. Angiotensins II and III bind to high-affinity zona glomerulosa cell surface receptors and stimulate aldosterone production from cholesterol by a calciumdependent mechanism involving activation of protein
0019
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3136 HORMONES/Adrenal Hormones β-LPH
16 K fragment
JP
N-POC(1−76)
γ-LPH
ACTH
β-LPH
16 K
N-POC(1−76)
β-endo
JP
γ-LPH
ACTH
β-endo
16 K
N-POC(1−76)
JP
ACTH
N-POC(1−76)
N-POC(1−76)
JP
JP
ACTH
ACTH
γ-LPH
β-endo
K = kilodaltons;
fig0005
Know maturation products;
MSH (melanocyte-stimulating hormone) structural units;
lys−arg dibasic residues;
O-glycosylation;
Figure 5 Structure and processing of proopiomelanocortin (POMC; POC). ACTH, adrenocorticotropic hormone; LPH, lipotropin; endo, endorphin; JP, joining peptide. Reproduced from Seidah N et al. (1981) The missing fragment of the pro-sequence of human POMC: sequence and evidence for C-terminal amidation. Biochemistry Biophys Research Commun 102: 710, with permission.
kinase C, rather than adenylate cyclase. In addition, aldosterone synthesis may be modified by lipoxygenase pathway metabolites of arachidonic acid. Potassium ion also influences aldosterone secretion by a direct effect on zona glomerulosa cells, and forms the basis for a feedback mechanism to regulate the concentration of extracellular potassium ions. Concentrations of potassium ion have the opposite effect on renin concentrations, but the direct effect on aldosterone secretion is predominant. In addition, as in the case of cortisol and adrenal androgen secretion, there is evidence that an influence on aldosterone secretion may be exerted by non-ACTH POMC-related peptides. Adrenal Medulla 0022
N-glycosylation.
Control of the adrenal medulla is exerted by the sympathetic nervous system. Whereas preganglionic fibers of the parasympathetic branch of the autonomic nervous system emerge from cranial and sacral spinal nerves, those of the sympathetic nervous system emerge from the thoracic and lumbar spinal nerves and innervate many organs, including the adrenal medulla. Preganglionic nerve impulses
are transmitted to postganglionic fibers by liberation of acetylcholine at nerve terminals. This results in secretion of catecholamines by the peripheral sympathetic nervous system and by the adrenal medulla. Norepinephrine is the major secretory product of the peripheral nervous system, and is primarily a neurotransmitter, not a circulating hormone. In the human adrenal medulla, the ratio of epinephrine to norepinephrine secretion is approximately 4:1, and concentrations of epinephrine, a circulating hormone, are sufficient to stimulate adrenergic receptors. Catecholamine biosynthetic pathways are shown in Figure 9. The rate-limiting step in catecholamine biosynthesis is the initial conversion of tyrosine to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (TH), an enzyme which is inhibited by DOPA, dopamine, and norepinephrine. Tyrosine itself is derived from the diet, or converted in the liver from phenylalanine by phenylalanine hydroxylase. The decarboxylation of DOPA to dopamine is catalyzed by aromatic-l-amino acid decarboxylase (AADC). Unlike the other enzymes of catecholamine biosynthesis, AADC is not only found in sympathetic nerve
0023
HORMONES/Adrenal Hormones CH3
CH3
C
C
O
O
3137
O
O
OH A
D
C
E HO
HO Pregnenolone B
Dehydroepiandrosterone
17α-OH pregnenolone B
CH3 C
−SO 4
OH
Dehydroepiandrosterone sulfate
B CH3
O
O
C
O
OH A
O
C
O Progesterone
F
O Androstenedione
17α-OH progesterone
F
CH2OH C
O
CH2OH C
O OH
O
O
11-Deoxycorticosterone
11-Deoxycortisol
G
CH2OH C
O
C
HO
O OH
HO
O
CH2OH
O Corticosterone
CH2OH
H
HO
Cortisol
C CHO
O
O Aldosterone fig0006
Figure 6 Human adrenocortical steroidogenic pathways. Enzyme activities: A, 17a-hydroxylase (CYP 17); B, 3b-hydroxysteroid dehydrogenase-isomerase (3b-HSD II); C, C17–20 desmolase (CYP 17); D, steroid sulfotransferase; E, steroid sulfatase; F, 21-hydroxylase (CYP21A2); G, 11b-hydroxylase (CYP11B1); H, aldosterone synthase (CYP11B2). Reproduced from Parker (1989) Adrenal Androgens in Clinical Medicine. San Diego: Academic Press, with permission.
3138 HORMONES/Adrenal Hormones NH2
600
CH2CHCOOH
Males DHAS (µg per 100 ml)
500
HO
Females Tyrosine hydroxylase
400
HO 200
Dihydroxyphenylalanine (DOPA)
Aromatic L-amino acid decarboxylase 0
10
20
30 40 50 Age (years)
60
70
HO
80
Figure 7 Serum concentrations of dehydroepiandrosterone sulfate (DHAS) in normal subjects 1–73 years of age. Reproduced from Smith M, et al. (1975) A radioimmunoassay for the estimation of serum DHAS in normal and pathological sera. Clinica Chimica Acta 65: 5, with permission.
HO
ECF depletion JUXTAGLOMERULAR Decrease in renal APPARATUS Potassium arterial pressure Increase in Sympathetic nerves renal arterial [Na+] at macula densa pressure or Hypokalemia Stimulate volume Prostaglandins it b i h In 'Long-loop Blood feedback' angiotensinogen ECF Renin expansion 'Short-loop Angiotensin I feedback' Converting enzyme ibit Angiotensin II Inh Arteriolar constriction Renal sodium retention Angiotensinases Angiotensin ADRENAL III GLAND Aldosterone Inactive
0024
Figure 8 Control of aldosterone secretion by the renin– angiotensin system. ECF, extracellular fluid. Reproduced from Bondy P and Rosenberg L (1980) Metabolic Control and Disease. Philadelphia: WB Saunders, with permission.
endings and the adrenal medulla, but also in nonneuronal tissues, including the kidney, and catalyzes the decarboxylation of other aromatic amino acids in addition to DOPA, including 5-hydroxytryptophan, which is converted to serotonin. Dopamine b-hydroxylase (DBH) catalyzes the hydroxylation of dopamine to form norepinephrine. The enzyme is found in sympathetic nerve endings, and also in adrenal medullary chromaffin granules, which release DBH along with norepinephrine when
CH2CH2NH2 Dopamine
Dopamine β-hydroxylase OH HO HO Phenylethanolamine N -methyl transferase
fig0008
CH2CHCOOH
HO
100
fig0007
NH2
300
0
Tyrosine
CHCH2NH2 Norepinephrine
OH HO HO
CHCH2NHCH3 Epinephrine
Figure 9 Catecholamine biosynthetic pathway of the sympathetic nervous system. Reproduced from Cryer P (1987) Diseases of the sympathochromaffin system. In: Felig P (ed.) Endocrinology and Metabolism. New York: McGraw-Hill, with permission.
stimulated. The major difference between the catecholaminergic pathways of the adrenal medulla and the peripheral nervous system is the presence of the enzyme phenylethanolamine-N-methyl transferase (PNMT) in the medulla. This enzyme, also found in small amounts in the brain, catalyzes the conversion of norepinephrine to epinephrine, using S-adenosylmethionine as a methyl donor. PNMT is inducible by high concentrations of cortisol which are present in the capillary sinusoidal circulation from the adrenal cortex to the medulla. A large percentage of synaptically released catecholamines are inactivated by reuptake into storage granules. Metabolism of circulating catecholamines occurs via two main pathways, mediated by the enzymes catechol-O-methyltransferase (COMT) and by monoamine oxidase (MAO), as shown in Figure 10. The end product of norepinephrine and epinephrine metabolism, after transformation by both enzymes, is 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid). Catecholamines in the liver and gut are also inactivated by sulfate or glucuronide conjugation of the phenolic hydroxyl group.
fig0009
0025
HORMONES/Adrenal Hormones
OH
OH
HO
CH
HO
CH
HO
CH2
HO
CH2
HO
CH2
NH2
HO
CH2
NHCH3
Norepinephrine
Epinephrine
AO M
AO
HO
CH
HO
C
M HO
O
COMT
OH Dihydroxymandelic acid OH CH
CH3O HO
Dopamine
OH CH
CH3O
CH2
HO
COMT
CH2
NHCH3
NH2
HO
AO
NH2 T M CO
M
OH
COMT
3139
CH2 C
AO M
OH CH3O HO
CH2
HO
CH2
O
NH2 3-Methoxytyramine
OH Dihydroxyphenyl acetic acid C O M T
AO
M
CH2
CH3O HO
C
O
OH
Normetanephrine
Metanephrine
CH3O
Homovanillic acid
AO M
CH C
O
OH 3-Methoxy-4-hydroxy mandelic acid fig0010
0026
Figure 10 Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Reproduced from Goldfien A (1986) The adrenal medulla. In: Greenspan F and Forsham P (eds) Basic and Clinical Endocrinology. Los Altos, CA: Lange Medical Publications, with permission.
The hypothalamus is the main regulator of sympathetic nervous system function. Impulses from the posterior and lateral hypothalamus result in generalized discharge of the sympathetic nervous system, including the adrenal medulla, although they can also be activated separately. The sympathoadrenal system is characterized by speed and integration, in that catechol-mediated events can take place within seconds, and can coordinate vascular, metabolic, and hormonal components. As discussed above, these responses occur to a variety of noxious, threatening, or stressful stimuli. In addition, the sympathetic nervous system is instrumental in maintaining an appropriate circulating volume and cardiac output during changes of posture from supine to upright. These feedback systems are mediated by sensors in the carotid sinuses, aorta, and medulla, which detect changes in circulatory volume and blood pressure. Although of different embryological origins, and operating via different regulatory mechanisms, the hypothalamic–pituitary–adrenocortical system and the sympathoadrenal system complement each
other in the maintenance of homeostasis and a stable metabolic milieu in response to many forms of stress. See also: Amino Acids: Metabolism; Fatty Acids: Metabolism; Renal Function and Disorders: Kidney: Structure and Function; Stress and Nutrition
Further Reading Baxter J and Tyrrell J (1987) The adrenal cortex. In: Felig P (ed.) Endocrinology and Metabolism. New York: McGraw-Hill. DeQuattro V, Myers M and Campese V (1989) Anatomy and biochemistry of the sympathetic nervous system. In: DeGroot L (ed.) Endocrinology. Philadelphia: WB Saunders. Ganong W (1991) Review of Medical Physiology. The Adrenals. Norwalk, CT: Appleton & Lange. Guyton A (1986) The adrenocortical hormones. In: Textbook of Medical Physiology. Philadelphia: WB Saunders.
3140 HORMONES/Thyroid Hormones Hale A and Rees L (1989) ACTH and related peptides. In: DeGroot (ed.) Endocrinology. Philadelphia: WB Saunders. Loriaux DL (1990) The adrenal glands. In: Becker K (ed.) Principles and Practice of Endocrinology and Metabolism. Philadelphia: JB Lippincott. Orth D and Kovacs W (1998) The adrenal cortex. In: Williams Textbook of Endocrinology. Philadelphia: WB Saunders. Parker L (1989) Adrenal androgens: normal physiology. In: Adrenal Androgens in Clinical Medicine. San Diego: Academic Press.
TPO
NADPH Oxidase
Tg
TTF-1 TTF-2 Pax8
Thyroid Hormones J Vanderpas, Faculte´ Me´decine, FUNDP, Namur, Belgium Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Iodinated Thyroid Hormones Thyroid Follicles and their Development 0001
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The thyroid gland displays a peculiar, highly organized architecture characterized by the presence of spheroidal structures – follicles – that are composed of a single layer of epithelial cells (thyroid follicular cells) surrounding a closed cavity (follicular lumen) filled with colloid, a concentrated solution of thyroglobulin (Tg). The follicle has been defined as the morphologic and functional unit of the thyroid. Notably, during intrauterine life, the onset of thyroid function (around 10 weeks in humans) coincides with the appearance of differentiated follicles. It is the follicular organization, together with the polarity of the follicular cells, that allows the several biochemical steps required for thyroid hormone biosynthesis: (1) secretion of a peculiar protein with iodinated amino acids in the follicular lumen as exocrine cells; (2) reabsorption of this peculiar protein, with hydrolysis of its iodinated amino acids; (3) release of iodothyronines into blood by endocrine secretion. The follicle cell divides the follicular lumen (where hormone synthesis begins) and the blood stream, from where iodine has to be uploaded and where hormones will be released at the end of the process. The surface of a polarized thyroid follicular cell is divided into two functionally distinct, but physically contiguous regions: an apical and a basolateral domain. Junctional complexes between cells separate these two domains and prevent the mixing of asymmetrically distributed proteins (Figure 1). The apical domain displays a differentiated tissue-specific organization characterized by the presence of apical
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NIS
Figure 1 Schematic structural representation of thyroid follicular cell with its polarized architecture. TSH-R, thyroid-stimulating hormone receptor; NIS, Na/I symporter; Tg, thyroglobulin; TPO, thyroperoxidase; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; TTF-1.
microvilli and pseudopods, and by the localization of thyroperoxidase (TPO). Naþ/I symporter (NIS), epidermal growth factor, and thyroid-stimulating hormone (TSH) receptors are located in the basal domain. Thyroid hormone synthesis requires basalto-apical transport of iodide and Tg. Conversely, hormone secretion is based on apical-to-basal transport of Tg and hormones; in addition, a bidirectional ion transport system controls follicular size. The thyroid primordium of the human embryo is first visible at 20 embryonic days, as a midline enodermal thickening in the floor of the primitive pharynx. It migrates caudally to form a transient thyroglossal duct, and reaches its final position at 35 embryonic days. Tg is detectable at 60 embryonic days, and this step corresponds to the occurrence of fetal thyroid hormone biosynthesis. The early stages of folliculogenesis are independent of thyrotropin. At midgestation (18–20 weeks), the hypothalamopituitary–thyroid axis begins to develop, and thyrotropin is absolutely necessary for thyroid growth and function.
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Biosynthesis of Thyroid Hormones
Figure 2 summarizes the process of thyroid hormone synthesis, which includes active concentration of
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