Chapter 4 Companion site for Basic Medical Endocrinology, 4th Edition Author: Dr. Goodman

Chapter 4Companion site for Basic Medical Endocrinology, 4th Edition

Author: Dr. Goodman

Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

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Chemical communication between cells. A: Local. Secretors product, shown as red dots, reaches nearby target cell by diffusion through extracellular fluid (paracrine or autocrine communication). Juxtacrine: Communication by physical contact via signaling molecules in the membrane of one cell activating membrane receptor molecules in an adjacent cell. B: Endocrine. Secretory product reaches distant cells by transport through the circulation. C: Secretory product released from terminals of long cell processes reaches target cells distant from the nerve cell body by diffusion across the synaptic cleft.

FIGURE 4.1


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The principal adrenal steroid hormones.

FIGURE 4.2


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Conversion of cholesterol to pregnenolone, the rate determining reactions in steroid hormone biosynthesis. Carbons 20 and 22 are sequentially oxidized (in either order) followed by oxidative cleavage of the bond between them (green arrow). All three reactions are catalyzed by a single enzyme, cytochrome P450SCC. The principal adrenal steroid hormones.

FIGURE 4.3


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Biosynthesis of adrenal cortical hormones. Reactions shown in the yellow box are unique to the zona glomerulosa. Reactions shown in the blue box are seen in the zonae fasciculata. Reactions shown in the green box are seen in both the zona glomerulosa and reticularis. Reactions shown in the pink box are largely confined to the zona reticularis. Structural changes produced in each reaction are shown in red.

FIGURE 4.4


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The principal estrogens.

FIGURE 4.5


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Stimulation of steroidogenesis by ACTH in zona fasciculata cells. Conversion of cholesterol to pregnenolone requires mobilization of cholesterol from its storage droplet and transfer to the P450scc (side chain cleavage) enzyme on the inner mitochondrial membrane. See text for discussion. ACTH may also increase cholesterol uptake by increasing the number or affinity of low density lipoprotein (LDL) receptors. s = stimulatory subunit of the guanine nucleotide-binding protein. AC = adenylyl cyclase, = subunits of the guanine nucleotide-binding protein. StAR = steroid acute regulatory protein.

FIGURE 4.6


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Average plasma concentrations of cortisol and dehydroepiandrosterone sulfate (DHEAS) throughout life. DHEAS is abundant in fetal plasma (see Chapter 14) and declines precipitously after birth as the fetal zone of the adrenal involutes. DHEAS increases during adrenarche as the zona reticularis increases in mass. Although both the ovaries and testes contribute to circulating DHEAS, the difference in plasma levels between males and females reflects the greater contribution of the testes. Cortisol is secreted by the fetal adrenal cortex only in the latter part of pregnancy. Average adult levels are reached shortly after birth and remain within a constant range throughout life. (Adapted from Rainey, W.E., Carr, B.R., Sasano, H., Suzuki, T., and Mason, J.I. (2002) Dissecting human adrenal androgen production. Trends in Endocrinology and Metabolism 13: 234–239.)

FIGURE 4.7


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Stimulation of aldosterone synthesis by angiotensin II (AII). AII accelerates the conversion of cholesterol to pregnenolone and 11- deoxycorticosterone to aldosterone. q, = subunits of the guanine nucleotide-binding protein. PLC = phospholipase C. DAG = diacylglycerol; IP3 = inositol trisphosphate; PKC = protein kinase C; CAM kinase II = calcium, calmodulin-dependent protein kinase II; StAR = steroid acute regulatory protein.

FIGURE 4.8


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The cortisol-cortisone shuttle. Two enzymes, 11-hydroxysteroid dehydrogenase (HSD I and HSD II) catalyze the oxidation of cortisol to cortisone. HSD I can also catalyze the reaction in the reverse direction converting the inactive cortisone to cortisol.

FIGURE 4.9


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Oxidation of cortisol to cortisone renders the steroid incapable of binding to the mineralocorticoid receptor.

FIGURE 4.10


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Formation of a hemiacetal with the aldehyde on carbon 18 protects the 11 hydroxyl group of aldosterone from oxidation by HSD (11 hydroxysteroid dehydrogenase) II.

FIGURE 4.11


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Pathways of extra-adrenal synthesis of testosterone and estrogens from DHEAS (dehydroepiandrosterone sulfate). Enzyme-catalyzed changes are shown in red.

FIGURE 4.12


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Effects of continuous administration of aldosterone to a normal man. Aldosterone (3–6 mg/day) increased potassium excretion and sodium retention, represented here as a decrease in urinary sodium. The increased retention of sodium, which continued for two weeks, caused fluid retention and hence an increase in body weight. The subject “escaped” from the sodium-retaining effects but continued to excrete increased amounts of potassium for as long as aldosterone was given. (From August, J.T., Nelson, D.H., Thorn, G.W. (1958) Response of normal subjects to large amounts of aldosterone. J. Clin. Invest. 37: 1549–1559.) Pathways of extra-adrenal synthesis of testosterone and estrogens from DHEAS (dehydroepiandrosterone sulfate). Enzyme-catalyzed changes are shown in red.

FIGURE 4.13


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Proposed mechanisms of action of aldosterone in the kidney. A. Sodium enters principal cells in the cortical collecting ducts through epithelial sodium channels (ENaC), and is extruded into the interstitium by the sodium/potassium ATPase. Potassium exits through ROMK (renal outer medullary K) channels in the luminal surface or through basolateral potassium channels. B. After a delay of ~30 minutes aldosterone increases expression of the serum glucocorticoid-induced kinase (SGK) 1. SGK1 increases ENaC in luminal membranes by phosphorylating and inactivating the ubiquitin ligase Nedd4-2 that initiates ENaC retrieval. SGK1 also phosphorylates and increases the activity of ROMK channels. MR = mineralocorticoid receptor; HSD II = 11 hydroxysteroid dehydrogenase II. C. Later effects of aldosterone include increased expression of proteins associated with increased sodium transport. D. In intercalated cells, aldosterone promotes the secretion of protons by a mechanism that bypasses the nucleus and probably involves an aldosterone receptor on the cell surface (AR) acting through some second messenger. Effects of continuous administration of aldosterone to a normal man. Aldosterone (3–6 mg/day) increased potassium excretion and sodium retention, represented here as a decrease in urinary sodium. The increased retention of sodium, which continued for two weeks, caused fluid retention and hence an increase in body weight. The subject “escaped” from the sodium-retaining effects but continued to excrete increased amounts of potassium for as long as aldosterone was given. (From August, J.T., Nelson, D.H., Thorn, G.W. (1958) Response of normal subjects to large amounts of aldosterone. J. Clin. Invest. 37: 1549–1559.) Pathways of extra-adrenal synthesis of testosterone and estrogens from DHEAS (dehydroepiandrosterone sulfate). Enzyme-catalyzed changes are shown in red.

FIG

UR

E 4.1

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Dual negative feedback control of aldosterone secretion. One monitored variable is blood volume, and another is the plasma potassium concentration (see text for details). thways of extra-adrenal synthesis of testosterone and estrogens from DHEAS (dehydroepiandrosterone sulfate). Enzyme-catalyzed changes are shown in red.

FIGURE 4.15


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Principal effects of glucocorticoids on glucose production and the metabolism of body fuels.

FIGURE 4.16


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Synthesis and structures of some arachidonic acid metabolites. R may be choline, inositol, serine, or ethanolamine. PLA2 = phospholipase A2. COX = cyclo-oxygenase. PG = prostaglandin. LT = leukotriene. TX = thromboxane. The designations E2 or F2 refer to substituents on the ring structure of the PG. The designations D4 and E4 refer to glutathione derivatives in thioester linkage at carbon 6 of LT. Principal effects of glucocorticoids on glucose production and the metabolism of body fuels.

FIGURE 4.17


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Effects of interleukin-1(IL-1). PG = prostaglandin. LT = leukotriene.

FIGURE 4.18


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Anti-inflammatory actions of cortisol. Cortisol induces the formation of the inhibitor of nuclear factor B (I-B), which binds to nuclear factor B (NF-B) and prevents it from entering the nucleus and activating target genes. The activated glucocorticoid receptor (GR) also interferes with NF-B binding to its response elements in DNA thus preventing the induction of phospholipase A2 (PLA2), cyclo-oxygenase 2 (COX2), and the inducible nitric oxide synthase (iNOS). By blocking further production of TNF (tumor necrosis factor-) and IL-1 (interleukin-1) glucocorticoids disrupt the positive feedback cycle involving these cytokines. NO = nitric oxide.

FIGURE 4.19


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Cortisol inhibits proliferation of activated T cells by interfering with secretion of cytokines. IL-1 = interleukin-1; IL-2 = interleukinII; IFN- = interferon-.

FIGURE 4.20


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Negative feedback control of glucocorticoid secretion. CRH = corticotrophin-releasing hormone; AVP = arginine vasopressin (+) = stimulates. () = inhibits.

FIGURE 4.21


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Hormonal interactions that regulate ACTH secretion by pituitary corticotrope. Glucocorticoids produce their negative feedback effects by interfering with POMC gene expression and membrane depolarization. CRH = corticotrophin releasing hormone; AVP = arginine vasopressin; AC = adenylyl cyclase; PLC = phospholipase C; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; PKC = protein kinase C; DAG = diacylglycerol; IP3 = inositol trisphosphate; PKA = protein kinase A; CREB = cyclic AMP response element binding protein; ER = endoplasmic reticulum; AP-1 = activator protein-1; GR = glucocorticoid receptor; POMC = proopiomelanocortin; VSCC = voltage sensitive calcium channels.

FIGURE 4.22


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Variations in plasma concentrations of ACTH and cortisol at different times of day. (From Matsukura, S., West, C.D., Ichikawa, Y., Jubiz, W., Harada, G., Tyler, F.H. (1971) A new phenomenon of usefulness in the radioimmunoassay of plasma adrenocorticotropic hormone. J. Lab. Clin. Med. 77: 490–500.)

FIGURE 4.23


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Negative feedback regulation of the hypothalamic-pituitary-adrenal axis by inflammatory cytokines. CRH = corticotrophin releasing hormone.

FIGURE 4.24


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Consequences of a partial block of cortisol production by defects in either 11- or 21-hydroxylase. Pregnenolone is diverted to androgens, which exert no feedback activity on ACTH secretion. The thickness of the arrows connotes relative amounts. Broken arrows indicate impairment is in the inhibitory limb of the feedback system. Administration of glucocorticoids shuts down androgen production by inhibiting ACTH secretion.

FIGURE 4.25


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Biosynthetic sequence for epinephrine E and norepinephrine N in adrenal medullary cells. TH = tyrosine hydroxylase; AAD = aromatic L-amino acid decarboxylase (also called DOPA decarboxylase); DBH = dopamine betahydroxylase; PNMT = phenylethanolamine-N-methyltransferase.

FIGURE 4.26


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Catecholamine degradation. MAO = monoamine oxidase; COMT = catechol-O methyltransferase; AD = alcohol dehydrogenase. AO = aldehyde oxidase; (From Cryer 1987; in Endocrinology and Metabolism, 2nd ed., Felig et al., eds. McGraw Hill, New York.)

FIGURE 4.27


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Changes in blood concentrations of epinephrine and norepinephrine in response to hypoglycemia. Insulin, which produces hypoglycemia, was injected at the time indicated by the arrow. (From Garber, A.J., Bier, D.M., Cryer, P.E., and Pagliara, A.S. (1976) Hypoglycemia in compensated chronic renal insufficiency. Substrate limitation of gluconeogenesis. J. Clin. Invest. 58: 7–15.)

FIGURE 4.28

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Chapter 4 Companion site for Basic Medical Endocrinology, 4th Edition Author: Dr. Goodman