JANSSEN EXHIBIT 2087
`
`Wockhardt v. Janssen lPR2016-01582
`
`JANSSEN EXHIBIT 2087
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`
`
`Principles and Practice of
`ENDOCRINOLOGY
`
`
`
`AND
`METAB OLISM
`
`THIRD EDITION
`
`L V E
`
`DITOR
`Kenneth L. Becker
`
`ASSOCIATE EDITORS
`John P. Bilezikian
`William]. Bremner
`Wellington Hung
`C. Ronald Kahn
`
`D. Lynn Loriaux
`Eric S. Nylén
`Robert W. Rebar
`
`Gary L. Robertson
`Richard H. Snider, Jr.
`Leonard Wartofsky
`With 330 Contributors
`
`LlPl3lNCOTT WILLIAMS 8 \X/ILKINS
`
`' A Wolters Kluwer Company
`Philadelphia - Baltimore - New York - London
`Buenos Aires - Hong Kong - Sydney - Tokyo
`
`
`
`

`

`.»lci;ii1'sitioizs Editor: Lisa i\IcAllister
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`Pmductimi Editor: Shannon Garza, Silverchair Science + C()[11[nu11iCati()n5
`J‘.Imziifizctiniiifq i\lii2z:Iggci': Colin \\/arnocl-;
`Cover [)esi;qiii*2': Joan Greenfield
`Coni;Ios‘i!or: Silverchair Science «- Communications
`Printer: World Color/Rand McNally
`
`79 200'] by LII’I’INCOTT WILLIAMS & WILKINS
`530 Walnut Street
`Philadelphia, PA 19106 USA
`LWW.c0m
`
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`owner, except for brief quotations embodied in critical articles and reviews. Materials
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`ernment employees are not covered by the abovevmentioned copyright.
`
`Printed in the USA
`
`
`Library of Congress Cataloging-in-Publication Data
`
`Principles and practice of endocrinology and metabolism / editor, Kenneth L. Becker;
`associate editors, John I’. Bile’/.ikian
`[et al.].--3rd ed.
`p. ;cm.
`lncludes bibliographical references and index.
`ISBN 0-7817-1750-7
`1. Endocrinology. 2. Lndocrine glands——Diseases. 3. Metabolisin--Disorders. l. Becker,
`Kenneth L.
`1. L’ndocrine Diseases. 2. Metabolic Diseases. WK 100 P957 2000]
`{l).\Jl-;\l:
`l{Cr'>~}t% .l’(>7 2000
`h l ti.4——clc2 l
`
`00-022095
`
`
`Care has been tal-;en to confirm the accuracy of the information presented and to
`describe generally accepted practices. However, the authors, editors, and publisher are
`not rysptjllhlblt’ for errors or omissions or for any consequences from application of the
`mformatioii in this bool; and make no warranty, expressed or implied, with respect to
`the currency, completeness, or accuracy of the contents of the publication. Application
`of this information in a particular situation remains the professional responsibility of
`the practitioner.
`The authors, editors, and publisher have exerted every effort to ensure that drug
`selection and dosage set forth in this text are in accordance with current recoininenda—
`tions and practice at the time of publication. However, in view of ongoing research,
`changes in government regulations, and the constant flow of information relating to
`drug therapy and drug reactions, the reader is urged to check the package insert for each
`drug for any change in indications and dosage and for added warnings and precautions.
`This is particularly important when the recommended agent is a new or infrequentlv
`employed drug.
`'
`Some drugs and medical devices presented in this publication have Food and Drug
`Administration (FDA) clearance for limited use in restricted research settings. It is the
`responsibility of health care providers to ascertain the l’l)A status of each drug or device
`planned for use in their clinical practice.
`
`1098765-1321
`
`

`

`714
`
`PART V: THE ADRENAL GLANDS
`
`33. Barrett PQ, Bollag WB, lsales CM, et al. Role of calcium in angiotensin ll-
`mediated aldosterone secretion. Endocr Rev 1989; 10:496.
`3-1. McKenna T], Fearon U, Clarke D, Cunningham SK. A critical review of the
`origin and control of adrenal androgens. Baillieres Clin Obstet Gynaecol
`1997; 11:229.
`35. Cell JS, Carr BR, Sasano H, et al. Adrenarche results from development of a
`3beta-hydroxysteroid dehydrogenase—deficient adrenal reticularis. I Clin
`Endocrinol Metab 1998; 8323695.
`36. Rosner W. The functions of corticosteroidvbinding globulin and sex hor-
`mone—bindirig globulin: recent advances. Endocr Rev 1990; 11:80.
`37. Hammond CL. Molecular properties of corticosteroid binding globulin
`and the sex—steroid binding proteins. Endocr Rev 1990; 11:65.
`38. Hammond CL. Determinants of steroid hormone bioavailability. Biochem
`Soc Trans 1997; 25:577.
`38a. Emptoz~Bonneton A, Cousin P, Seguehik, et al. Novel human corticoster-
`oid~binding globulin variant with low cortisol-binding affinity.
`J Clin
`Endocrinol Metab 2000; 85:361.
`39. Brownie AC. The metabolism of adrenal cortical steroids. In: James VH, ed.
`The adrenal gland, 2nd ed. New York: Raven Press, 19921209.
`40. Morris D}, Brem AS. Metabolic derivatives of aldosterone. Am J Physiol
`1987; 252213365.
`
`
`
`C H A P T E R 7 3
`
`
`CORTICOSTEROID ACTION
`
`PERRIN C. WHITE
`
`GENERAL MECHANISMS OF ACTION
`
`The steroid hormones, vitamin D, retinoic acid, and the thyroid
`hormones all share a similar mechanism of action.“ These hor-
`mones diffuse through the target cell membrane and interact
`with a specific receptor protein for each hormone. The activated
`hormone-receptor complex binds to specific DNA sequences, the
`hormone-responsive elements (HRES), which are usually located
`in the 5' flanking region of each hormone-responsive gene. These
`complexes may also bind to other transcription factors. The bind-
`ing of the hormone-receptor complex to these DNA sequences or
`transcription factors leads to selective increases or decreases in
`gene transcription. The altered protein levels that result from this
`change in transcription rate are responsible for the hormonal
`response seen in that particular tissue.3
`At least six classes of steroid receptors exist, corresponding to
`the known bioactivities of the steroid hormones: glucocorticoid,
`mineralocorticoid, progestin, estrogen, androgen, and vitamin D.
`Additional ”orphan” receptors of incompletely understood func-
`tion are found that bind related compounds such as andro-
`stanes.4 Steroid receptors belong to a larger superfamily of nuclear
`transcriptional factors that includes the thyroid hormone and ret-
`inoic acid receptors. All of these receptors share a common struc-
`ture that includes a cm'b0x_i/—tcrmiiizi/ ffglllltf-bflldfllg do/izaiiz and a
`nzidregioiz DN/l—bz'iidz'iig donzniii. The latter domain contains two
`”zinc fingers,” each of which consists of a loop of amino acids
`stabilized by four cysteine residues chelating a zinc ion.5
`Unliganded steroid hormone receptors shuttle between the
`cytoplasm and the cell nucleus. Importation into the nucleus is
`an energy—dependent process. This process requires one or
`more nuclear localization signal sequences on the receptor,
`which consist of clusters of basic amino-acid residues located in
`or near the DNA~binding domain. When not occupied by
`ligand, the various hormone receptors differ in their propensity
`to be transported to the nucleus. For example, the estrogen
`receptor is predominantly located within the nucleus, whereas
`the unoccupied glucocorticoid and mineralocorticoid receptors
`are found mainly in the cytosolf’
`The cytosolic glucocorticoid receptor, when not bound to its
`steroid ligand, forms a heterooligomer with two molecules of
`
`heat shock protein (HSP) 90 and one molecule each of HSI’ 70
`and HSP 56 (immunophilin).7 Binding of ligand changes the
`conformation of the receptor and, thus, has several effects. H31’
`90 is associated with the unliganded glucocorticoid receptor at
`the ligand-binding domain and dissociates from the receptor
`complex after glucocorticoid binds to the receptor. A dimeriza-
`tion region that overlaps
`the steroid-binding. domain is
`exposed, promoting dimerization of the occupied receptor.
`Finally,
`a hormone-dependent nuclear
`localization ‘signal
`located in a “hinge” between the DNA and steroid-binding
`domains is activated, which leads to increased importation of
`occupied receptors into the nucleus. The occupied receptors are
`then able to bind DNA and / or other transcription factors and
`modulate transcription of various genes.” .
`_
`Glucocorticoids affect transcription of a wide variety of genes
`through several different mechanisms.“ First,'the glucocorticoid-
`receptor complex can stimulate transcription by binding to
`specific glucocorticoid-responsive elements (GRE5)
`111 1119. 5
`flanking region of glucocorticoid—responsive genes. GREs, like
`other specific hormone response elements, are often imperfect
`palindromes (in a palindrome, the two complementary strands
`of a DNA mo1een1e, when ”read” in opposite directions, have
`the identical sequence). Most often, GREs are variants of ‘the
`sequence GGTAC/\nnnTGTTCT, where ”n” is any nucleotide.
`The existence of two ”half-sites" separated by three nucleotides
`suggests that glucocorticoid receptors interact with GREs as
`dimers, with one monomer binding to each half-site. However,
`many GRES Consist of isolated half-sites or half-sites with vari-
`able spacing between them. Moreover, marked variations in
`sequence can be tolerated in one half—site. Thus, monomeric glu-
`cocorticoid receptors can also bind DNA, but 1119 19111511118 9311
`apparently be stabilized by interactions with other bound F9991?‘
`tor molecules or other transcription factors. Thus, binding of the
`monomeric receptor to one half-site markedly increases the abil-
`ity of a second monomer to bind to the other half-site-
`The interaction of the glucocorticoid receptor and DNA has
`been studied in detail by x-rax crysta110z;r;ip11y_ and nuclear
`magnetic resonance techniques.’ The 1W0 Z1119 11118915 101111 ‘"1
`single domain. Alpha helices adjacent to each finger on the
`carboxy-terminal side are oriented P91p911‘11C111‘111Y 10 93911
`other; the first helix fits into the ma]01 81°°V_9 01 1119 DN/1f11911X
`and makes direct contact with bases. The t1‘P5 01 110111 11118915
`contact the phosphate backbone,
`£11191 1119159901191 1111891 31150
`mediates DNA-dependent dimerization 0 tie receP101-
`.
`.
`GRES cannot constitute the only
`5911119111395 1119111911118
`the transcriptional effects of gluCOCOI‘lZ1CO1C]:l)S:. gREs are indistin-
`guishable in sequence from the elements.
`in mg mineialocor-
`fieoid, progestinl and androgen receptors, andthese receptors
`are >90% identical in amino-acid se5l11e11Ce "1 the” DNA'bmdmg
`domains. However, the amino—termirial 61011131115 01 111959 19C9P'
`tors are <15"/o identical in amino-acid 59111191199 31111 <11 19351
`some interactions with other transcr1P11°11‘11 factors are med“
`ated by this domain.”
`.
`.d
`)
`_V
`As a second type of effect, glucocorticoi
`irlcceptois can
`inhibit or activate transcription 13)’ 111191actmg W111? 0: ml 11935"
`cription factors.”/11 In particular, 1119)’ Ca1:fi1'_‘:tl:1C11abe
`1(1)’;
`11)’ bl’ 191319551118 89119 11‘111SCr1Pt1On- me fcsome ):enes The =
`NF-KB elements in the reg111‘1101Y 195510115 O R)1A1° 50
`59
`AI’-1 and NF—i<B sites bind cFos-ClU11101
`1 t. ‘P. 1
`“*1"f°'.
`dimers, respectively. The ligand-bound g UCOCOF 1C01< fecep 01
`monomer and/ or dimer infemc
`vents them from exerting their tIr)a1 md NRKB Serve as hum-
`genes they normally regulate. A '
`‘
`‘
`V
`c
`C y growth factors and
`cellular messenger systems for min
`f
`d
`t‘,
`H
`inflammatory eytokines, respectively. The pro oun 111 igrow i
`or
`‘odul1}t)e effects of the
`819<119X19111V1a traY151'9P1eSS1On of these
`addition, glucocorticoid receptors ma)’ 111:IF3
`‘ d HNF4 tr n__
`Stat4, Stat5, NF-1, Oct-1, sP—1, C/E311 11
`' ‘"11
`‘1 5
`cription factors.
`
`
`
`

`

`Unlike glucocorticoids, mineralocorticoidsl dofnot tappelaa
`interfere with cFos—c]un or NF—1<B binding. Tiis unc iona
`h
`ference may be localized to the amino-terminal domain of t e
`receptor.”
`_
`_
`._
`Two new classes of nuclear proteins that)mfl11%nCE3tit—fli1eedtre;7rI11CS1ac<?(§_
`vational activity of nuclear receptors have eeni elrli.
`bih
`t
`lectively Called core5"WrS'12'13 Accordmg r0 r err
`9* th rY 0
`potentiate or diminish the activity of nucl:g:Sr:E:g:>;S,COr:yL$1e
`respectively C“11ed.C0”CtziW0rS and Corilimsal domains One ciuld
`tors are large proteins with many func oat: DNA_bOL-md nuclear
`think of coactivators as bridges between tie)“ rmchine
`such as
`receptor and Components of the tmnsclrllpthat stacbilize rarfid hence
`ancillary factors of DNA pglyrrlerase
`,
`fex Ihaddition coacti-
`Srimulate the aCtiV1ty.0fthl7) rnltlatlorlcololilriote transcriptioh such
`Vators have enzymani actwmis
`vxlilliich loosens the DNA, dou-
`as histone acetyl-trans erase ac iv
`,
`_
`t
`1
`lex
`
`(Ii?/or transqcfivqfin
`to exert its activity.” On the other an A
`th t.
`gde (rm?
`nuclear receptor from bmdlng to DN . Q?
`6 1111
`c
`,
`'
`'
`their target genes and have enzyrlnatlcvrihtildlli lslreiigtlienls the inter-
`cription, such as histone deacettiy aseideosome Coregulators are
`actions Of. the ' DNA
`ftasehigrtl and have Varying degrees of
`expressed in a tissue-speci 1C
`e tors some of these proteins
`specificity for P€1I‘l‘1Cul£lIi;1’it:Cl:3iI;":¢::C§pfiO'n hctors Such as AP_1
`)
`e
`c
`.
`1
`i
`I
`c
`1S\r}3§:vr}3aS C(:jrrt31gu1Satt(lIss’l)I1Cl)l11€nCe serve as cross-points between dif-
`-K an
`ie
`3 I t
`( .
`,
`-
`t
`s in the cell.
`_
`fer?“ 518113; rr‘:n5d::;3?;:zStgirlie-specific effects of steroids at
`evera
`ac ors
`c
`'_
`‘
`th rece tor. Most obvi
`several levels both beft(())rr:
`ly ebut got ubiquitously
`0us1y' hgrmoge mi-etijcular class of steroid fails to have effects
`expresse I ar‘
`a pa
`ondin rece tor. Of
`V
`on Cells that do not express t1e1serrCi:yri3rSiIc3rease<)gr decrgase the
`h siologic importance, 9I_1ZYrr‘
`d lat
`their
`Pffy .t
`f
`t
`.dS for then‘ receptors and thus mo u
`e
`3 1r“ Y 0 3 erol
`-
`id rece tor has identi-
`t’
`activity. For example, the rniéislrgnogzhlggteroneget Cortisol is a
`cal affinities in vitro fordcor lvivo This discrepancy may result
`weak mineralocorticoi hindrox éteroid dehydrogenasel which
`from the action of 11l3'_ Y e gornsone is not a ligand for the
`converts cofitisol to1:l‘:§t1eSr(:)Ihe is not a substrate for the enzyme.
`reCeP‘f0f, W erea-5 3
`.
`.
`.
`.
`.
`f n’
`nz me allows cor-
`.
`b t on 0 t
`is e
`Y
`Pharmacologic or g<e1n;:;tiirc1eipfl:)CiOirfiCoid receptors and produce
`.
`.
`on.
`tisol to occupy rem
`‘
`.
`15
`sodlum retentlofn Emil Eggféilltilay share bioactivities because
`Whereai. Cllfioegifld to the Same receptor, a given steroid may
`of tl'1te:§'al‘)1 1:YbiO10giC effects in different tissues. The diversity
`exer
`1V€1‘S’
`V
`.
`-
`d b the different genes that
`Ofh°rm°m1tie§p(illseingliieclinllingiifelent tissues. Glucocorti—
`are regulate
`y
`9
`-
`'
`RE-mediated metabolic
`C0idS, f0F 9X3mPdle'
`§[1;lt}2B§mediated antiinflarnma-
`effects in liver an m‘
`_‘
`r°rY Properties in lYmp.hO1d
`from the binding of steroids
`In addition tothe actionsr
`some effects might be mediated
`r0 nuclear Sterold recrlgtors/Such effects often take place with
`through other mechanisnis. ds to minutes) and/or have been
`extreme 1‘€1PidirY (m11h5°.C°“1.0tem synthesis, a sine qua non of
`documentgd {lot to requtlrerrlgediated by nuclear-hormone recep-
`the l:1~;\nSCI'lplZlO1‘lal effec:
`1 most extensively documented for
`tors. These effects liaveD eeim yesterone, and aldosterone; they
`1,25—dihydroxyvitamin d3» Pssiean rers Systems including protein
`appear to involve secon lrirtfm 163613, nitric OxiC16, and tyrosine
`kinase C, intracellular ca c no Ster0id_speCinC membrane temp-
`kimsesfl Tlmsfarll cfrvilroiied (Also see Chaps. 4 and 54.)
`tors have been iso a
`'
`
`16
`
`.
`
`AC-I-IONS OF THE GLUCOCORTICOIDS
`-
`.
`~
`'
`1ucocorti—
`tial for survival. The term g
`~
`-
`.
`'
`rties of these hor-
`G1UC0C01'“C°‘ds are ersen
`— gulating prope
`V
`,
`cold refers to the glucose re
`lucocorticoids have multiple effects that
`mones. However, the 8
`
`Ch. 73: Corticosteroid Action
`
`71 5
`
`TABLE 73-1.
`Major Glucocorticoid Actions
`METABOLIC EFFECTS
`
`Carbohydrate
`Increase blood sugar
`Increase gluconeogenesis in liver and kidney
`Increase hepatic glycogenesis
`Increase cellular resistance to insulin; decrease glucose uptake in tissues
`Lipid
`Increase lipolysis
`Protein
`
`Increase proteolysis
`IMMUNOLOGIC EFFECTS (PHARMACOLOGIC LEVELS)
`Stabilize lysosomal membranes
`Block bradykinin, histamine, interleukin-1 and interleukin-2, plasminogen-
`activating factor
`Decrease vascular permeability
`Increase polymorphonuclear (PMN) cell release from bone marrow:neu—
`trophilia
`
`Block PMN diapedesis, chemotaxis, and phagocytosis
`Deplete circulating lymphocyteszlymphocytopenia affecting T cells more
`than B cells
`
`Decrease antibody formation from B lymphocytes
`Deplete circulating monocyteszmonocytopenia
`Deplete circulating eosinophilszeosinopenia
`Decrease thymic and lymphoid tissue mass
`Impair delayed hypersensitivity reaction
`Decrease resistance to bacterial, fungal, viral, and parasitic infections
`CONNECTIVE TISSUE EFFECTS
`Decrease collagen formation
`Impair granulation tissue formation and wound healing
`CALCIUM AND BONE EFFECTS
`Decrease serum calcium
`
`Accelerate osteoporosis
`CIRCULATORY EFFECTS
`
`Increase cardiac output
`Increase response to catecholamines
`RENAL EFFECTS
`
`Increase renal blood flow and glomerular filtration rate
`Increase free water clearance
`Inhibit vasopressin
`CENTRAL NERVOUS SYSTEM EFFECTS
`Increase mood lability
`Cause euphoria
`Produce psychosis
`Decrease libido
`
`Blunt thyrotropin and gonadotropin activity
`EYE EFFECTS
`
`May induce posterior subcapsular cataracts
`GROWTH AND DEVELOPMENTAL EFFECTS
`
`Inhibit skeletal growth (pharinacologic doses)
`Mature surfactant, hepatic, and gastrointestinal systems
`
`PMN, polymorphonucleocytes; TSH, fl1)'T0”0Pr“‘
`
`
`include an important role in carbohydrate, lipid, and protein
`metabolism (Table 73-1). They also regulate immune, Circula-
`tory, and renal function. They influence growth, developm nt
`bone metabolism, and central nervous system (CNS) activity.
`In stress situations, glucocorticoid secretion can increase up
`to almost 10—fold.r3'1° This increase is believed to enhance Sun
`vival by increasing cardiac contractility, cardiac output, senSt_
`tivity to the pressor effects of the catecholamines and other
`pressor hormones, work capacity of the skeletal muscles, and
`capacity to mobilize energy through gluconeogenesis, pr0teoly—
`sis, and lipolysis. Persons with unrecognized adrenal insuffi_
`
`
`
`

`

`71 6
`
`PART V: THE ADRENAL GLANDS
`
`ciency are at risk of life-threatening adrenal crisis if subjected to
`stress without glucocorticoid replacement?"
`
`CARBOHYDRATE METABOLISM
`
`The daily secretion rate of cortisol varies little in the absence of
`stress. Cortisol interacts in a permissive fashion with many
`other hormones, including insulin, glucagon, catecholamines,
`and growth hormone, to achieve full homeostasis. For example,
`glucocorticoids are essential for normal epinephrine- or glucagon-
`stimulated lipolysis, gluconeogenesis, and glycogenolysis.2"23
`Excess cortisol increases hepatic glycogen and glucose produc-
`tion and decreases glucose uptake and utilization in the periph-
`eral tissues. These effects combine to cause hyperglycemia. This
`may lead to overt diabetes in persons who have a decreased
`capacity to produce insulin. By contrast, glucocorticoid defi-
`ciency decreases glucose production and hepatic glycogen con-
`tent and may cause hypoglycemia. However, serum glucose
`levels may be normal in the chronically ill patient with Addison
`disease because of a compensatory decrease in insulin secretion.
`The primary action of the glucocorticoids on carbohydrate
`metabolism is to increase glucose production by increasing
`hepatic gluconeogenesis. Gluconeogenesis uses
`substrates
`derived from glycolysis, proteolysis, and lipolysis. Lactate is
`derived from glycolysis in muscle. Alanine is the primary sub-
`strate derived from proteolysis; fatty acids and glycerol are
`derived from lipolysis. In addition to inducing gluconeogenic
`enzymes, glucocorticoids stimulate glycolysis, proteolysis, and
`lipolysis, thus providing more substrate for gluconeogenesis.
`Glucocorticoids also increase cellular
`resistance to insulin,
`thereby decreasing entry of glucose into the cell. This inhibition
`of glucose uptake occurs in adipocytes, muscle cells, and fibro-
`blasts. (Also see Chaps. 75 and 139.)
`In addition to opposing insulin action, glucocorticoids may
`work in parallel with insulin to protect against long-term star-
`vation by stimulating glycogen deposition and production in
`liver. Both hormones stimulate glycogen synthetase activity
`and decrease glycogen breakdown.
`
`LIPID METABOLISM
`
`Glucocorticoids increase free fatty acid levels by enhancing lipol-
`ysis, decreasing cellular glucose uptake, and decreasing glycerol
`production, which is necessary for reesterification of fatty acids.
`This increase in lipolysis is also stimulated through the permis-
`sive enhancement of the lipolytic action of other factors such as
`epinephrine. This action affects adipocytes differently according
`to their anatomic locations. In the patient with glucocorticoid
`excess, fat is lost in the extremities, but it is increased in the trunk
`(centripetal obesity), neck, and face (moon facies).33 This may
`involve effects on adipocyte differentiation.3"
`
`PROTEIN METABOLISM
`
`The glucocorticoids generally exert a catabolic/antianabolic
`effect on protein metabolism. This proteolysis in fat, skeletal
`muscle, bone, and lymphoid and connective tissue increases
`amino-acid substrates that can be used in gluconeogenesis. In
`rfiuscle, the type II white glycolytic fibers are more affected
`t an the type I fibers. Cardiac muscle and the diaphragm are
`almost entirely spared from this catabolic effect.
`
`IMMUNOLOGIC EFFECTS
`
`Glucocorticoids play a profound role in immune regiilation.l"«l3
`At high concentrations,
`they inhibit most immunologic and
`inflammatory responses. Although these effects may have ben-
`eficial aspects, they may also be detrimental to the host by
`inducing a state of immiinosuppression that predisposes to
`infection. Glucocorticoids inhibit eicosanoid and glycolipid
`
`synthesis and the actions of bradykinin. They also block hista-
`mine and proinflammatory cytokine (tumor necrosis factor 0!,
`interleukin-1, and interleukin-6) secretion and effects?’ These
`actions inhibit vasoactive agents and diminish the inflamma-
`tory process. Glucocorticoids may cause lyirnpliocytopienia with
`a relative T-cell depletion, monocytopenia, and eosinopenia.
`They do so at least in part by inducing cell cycle arrest in the G,
`phase and by activating the apoptosis pathway through gluco-
`corticoid receptor—mediated effects.-‘E’
`V
`.
`In contrast, glucocorticoids increase circulating polymor~
`phonuclear cell counts, mostly by preventing their egress from
`the circulation. Generally, glucocorticoids decrease diapedesis,
`chemotaxig, and phagocytosis of polymorphonuclear cells.
`Thus, the mobility of these cells is altered such that they do not
`arrive at
`the site of inflammation to mount an appropriate
`immune response. Some of these effects inayvbemediated by
`changes in levels of the cytokine migration inhibitory ‘factor
`(MIF) from macrophages and 'I' cells. Wliereaspliysiologic lev-
`els of glucocorticoids promote release of l\/III‘, pliarinacologic
`doses inhibit MIF secretion.”
`'
`_
`_
`.
`_
`The suppressive effect of glucocorticoids is primarily exerted
`on T helper 1 cells and hence on cellular iniinunity, whereas the
`T helper 2 cells are spared, which effectively leads to a predomi-
`nanny hurrroral immune response.“"«-“ Indeed, glucocorticoids
`enhance secondary anamnestic antibody responses, whereas
`they inhibit primary antibody responses. Pharmacologic doses
`of glucocorticoids may also decrease the size of the immuno-
`logic tissues (ie., the spleen, thymus, and lyfI'1Pl1 n0d05)- _
`In summary, high levels of glucocorticoids decrease inflam-
`matory and cellular immune responses and increase suscepti-
`bility to certain bacterial, viral, fungal, and parasitic infections.
`
`EFFECTS ON SKIN
`
`Clucocorticoids inhibit fibroblasts, which leads to increased
`bruising and poor wound healing through cutaiieous atrophy.
`This effect explains the thinning of the skin Fthat
`IS seen in
`patients with Cushing syndrome” (509 C-Ilill-T 73)~ 1fY_1mUI10SU}_>-
`pressive effects of glucocorticoids makes them effective for skin
`conditions such as psoriasis.
`
`EFFECTS ON BONE AND CALCIUM
`
`Glucocorticoids have the overall effect of decreasing serum cal-
`cium and have been used in emergency therapy for _certain
`types of hypercalcemia (see Chap.’ 59). Ihis hypocalceiniceffect
`probably results from a decrease in the intestinal absorption of
`calcium and a decrease in the renal reabsorption of calcium and
`phosphorus. The serum calcium level, l10WCV9rr_89“9mII_}’ ‘I005
`not fall below normal because of the secondary increase in par-
`athyroid hormone secretion.
`_
`_
`The most significant effect of ‘long-term gliicocoroticoid
`excess on calcium and bone metabolism is osteOP(_’1'0515-’ GIN‘
`cocorticoids inhibit osteoblastic activ1lY bl’ EICCTCQSIII8 the m”“'
`ber and activity of osteoblasts;"“ Glucocorticoids also decrease
`osteoclastic activity, but to a lesser extent, (l‘Ci1Cl11‘f-I I0 10W Imlle
`turnover with rm Overall negative balance. Ihe tendency of glu-
`cocorticoids to lower serum calcium and PIIOSPIWIG Ie"9I5
`causes secnndqry ]1yperpilI‘ZlIll)/1”()l(.IlSrn_ -fogetlier, these actions
`‘
`‘
`.
`.
`.
`.
`'
`r
`decrease bone accretion and cause a net loss of bone mineral.
`
`CIRCULATORY AND RENAL EFFECTS
`
`e inotropic influence on the
`.
`Glucocorticoids have a pOSiliV
`cular work index.
`lvloreover,
`I
`'
`‘
`.
`-
`~
`tions ofewine ahrine ’ind
`heart’ Increaging the Ieft Vcnm
`l
`l
`they have a permissive effect on the ac
`he blood vessels. In the
`.
`,
`.
`norepinephrine on both the heart and t
`_
`.
`.
`,
`r15e(,I cardiac output and shock
`absence of glucocorticoids, CILCVU
`,
`.
`.
`-ticoid excess, hypertension is
`.
`r
`_
`,
`.
`,
`_
`may develop; in states of glucocol
`t.
`t.
`r H
`.
`freclllently Observed. This may be due to ac iva ion 0
`it min
`
`This rriaterial wascarpieéd
`
`

`

`eralocorticoid receptor (see later) that occurs when renal 11B-
`hydroxysteroid dehydrogenase is saturated by excessive levels
`of glucocorticoids.
`
`CENTRAL NERVOUS SYSTEM EFFECTS
`
`Glucocorticoids readily penetrate ll1€'blO0Cl—bI‘£11I1 barrier ancsl
`have direct effects on brain metabolism. They decreas1e'CtN
`edema and are commonly used in therapy for increase
`in r1a-
`cranial pressure. Paradoxically, they also ‘may coigltri pte to tiel
`development of pseudotumor cerebri
`(increasrlel
`.1f11%Zf1C1':t1\1€l
`pressure in the absence of a structural lesion).
`_ie1r le ec 5 On
`mood and behavior are well recognized The)’ Stlfgu ate ‘"*PPe'
`tite and cause insomnia witlra rec_luCt10§ In 1’<:_P1
`ment sleep. An increase in irritability aicil Eff}? 13113011;entgte
`seen, with an impairment of memory an ba ‘1 1 31mg“
`to botch
`Libido is decreased—an effect that may e segio Ylilcymomcoidc
`direct glucocorticoid effect on behaviortflfl
`in
`.
`-
`_
`_
`(
`induced inhibition of the reprodL}C_t1VL 5Y5 enigoth be qssochted
`Glucocorticoid excess and deficiency Inalylcocorticgid excess
`.'
`'
`‘.
`<
`with clinical depression. Fiirtlierinortei fts Mild to modemte
`ma)’ Pmduce 5‘ Psychoas Ii‘ S.0me pg-1' lit
`ft’
`ften causes 1
`glucocorticoid excess for a limited peiio o
`ime o
`.
`c
`c
`feeling of euphoria or wel1—beir18- Therefme’ patlenlts lmay
`.
`-
`'
`'
`*
`e. P”1l:l€I’1lSW1O iive
`ob}ect to a decrease in glucocorticoid dosag
`c
`.
`c
`_
`.
`.
`-
`d‘
`d )rS such as depression or anorexia
`primary psydllamc blS1(i)trioii of the normal circadian pattern of
`x
`o
`.
`.
`-
`nervosa’ {nay ‘ave a-
`‘
`rease in ’lLlCOC01‘t1C01d pro-
`glucocorticoid secretion and an inc
`ls
`_
`_
`_
`uc ion.
`iese t
`c
`d
`t’
`Tl
`abnormalities are reversible with remission of
`.
`.
`-
`..
`referred to as states of
`the Psychiatric illness and (liav<E1l3::)11201)
`‘
`‘
`-
`‘vs ndrome see
`We
`-
`.~
`pseudo Cush-H E7 yff; t~ in brain are mediated largely through
`.
`.
`o
`I
`Glucocorticoid e cc s
`hted receptors
`sometimes
`J
`.
`interactions with two closely re c tors The type H receptor is
`referred to as type I and type lldrccisptor The type I receptor is
`,
`'
`ocorticoi
`rt
`-
`,
`_
`,
`ihe Cgnvmtloml 8-lucr-11()COrllC0lCl receptor, but it has identical
`lde-nil-Cal to the mme ‘
`t" oids and mineralocorticoids in most
`affinities for both glucocor ic
`H k f
`_
`'
`'
`1‘ 1 itis ex ressed becauseo ac o con
`areas of the brain in w iic i
`P
`,
`d
`,
`.
`15
`. n of Hg hydroxysteroid dehy rogenase
`(see
`,t
`comi ant expressio
`-
`'
`.
`.
`-
`-d
`_
`-_
`dizes ’lLiCOCOI'llCOl s to inac-
`,
`,
`later and Chap. 72)» this ené1Ytnc id hrtéet tissues The type I
`'ier1 ocor
`c
`_
`'
`.
`,
`~
`~
`'
`“VG compounds. 1“ mu \‘
`1
`‘ vhest levels in the limbic SYS-
`V
`__
`.
`.
`_
`(
`reCePt01'r Which 15 expreswd ‘ll my
`10 fold hi ther iffinit
`for
`tem (ie the hippocampU5),3 1135 3
`5
`.
`.
`.,_
`‘
`1 )
`t
`e II receptor. Thus, glucocorticoid
`8luC0C0mCmd5 than “C yp
`b
`diated
`redomimntl
`V
`nqay
`6 1118
`c
`13
`¢
`y
`_
`.
`-
`effects in the limbic system
`.
`)
`3
`‘
`l
`(.c(.
`tor at normal levels and may activate the
`C
`-
`)
`_)
`through the typc rqinip qt elevated levels as seen under stress
`tYPL ‘ll reccipztpfifilrncge reycepmrs have divergent and in some cases
`.'
`‘
`‘
`c
`I
`Comlltlonsxw 11:21 example activation of the type I receptors
`0PP°5“‘8 eff°_’C,tS.'t of hippocampal neurons to the neurotrans-
`reduces S€1151l1/V1};/hereqs
`activation of the type II receptors
`'
`, .
`L
`,
`-mmu Seioslmm -ased sensitivity of the hippocampus to seroto-
`increases It.’
`Incrliin the euphoria associated with high doses of
`nm may help exp C
`‘ manner glucocorticoids suP'
`-
`~
`I
`an analogous
`I
`'
`7lLlC0C()I‘llC()1Cl5.
`I1 c
`.
`-
`la
`f Comcotropin-releasing hormone (CRH) in the
`press. release (E hmus but stimulate it in the central nucleus of
`,
`-
`m“Cr10YhYP"“a‘d 11tem1 bed nucleus of the stria terminalis,
`the amygdala an
`m. and anxiety smtcs},
`where it may mediate fe
`-
`‘
`~
`ther steroids may have non-
`~
`-
`orticoids and o
`.
`_
`In addition, glucoc d 1
`tin Y wtivities of both Y_amm0 butync
`renomic effects by mo u a
`3, c
`, 36
`th l-D-aspartate (NMDA) receptors‘
`27
`acid (GABA) and N-me
`y
`
`GROWTH
`
`coids inhibit linear growth and skeletal
`In excess, glL1COCOI‘lIl
`.
`.
`tl
`t
`,
`.
`.
`7,
`37 This results priinari y iom ie
`irec
`maturation in childrLI1-
`.
`.
`.
`,1
`ticoids on the epiphyses. This effect
`mhlbltory e£f‘13jCet(I)rf1§’d:1Ct(,)3Cc10rt;y decreasing levels of insulin-lil<e
`Ff)z1‘(1;t0r_1
`(1(3F-1)3‘ and by increasing levels of lGF-
`lginding protein-1 (IGFBP-1), which inhibits somatic growth by
`
`Ch. 73: corticosteroid Action
`
`71 7
`
`decreasing circulating levels of free IGF-1.33 Also, chronic gluco-
`corticoid excess has been associated with inhibition of growth
`hormone secretion.”
`
`Although excess glucocorticoids clearly impair growth, glu-
`cocorticoids are necessary for normal growth and development.
`In the fetus and neonate, they accelerate the differentiation and
`development of various tissues. Their actions include promot-
`ing the development of the hepatic and gastrointestinal systems
`as well as the production of surfactant in the fetal lung (see
`Chap. 202). Glucocorticoids are routinely given to pregnant
`women at risk for delivery of premature infants in an effort to
`accelerate these maturational processes.
`
`EFFECTS ON OTHER HORMONES
`
`Glucocorticoids have several effects on pituitary fu11CtlOI1.19'40
`They primarily regulate adrenocorticotropic hormone (ACTH)
`secretion through glucocorticoid (type II) receptor—mediated
`effects at the hypothalamic and pituitary levels (see Chap. 72).
`In addition, they affect both thyroid and reproductive function.
`Thyroid Function. Glucocorticoids blunt the thyroid-stim-
`ulating hormone response to thyrotropin-releasing hormone
`stimulation. They decrease the peripheral conversion of thyrox—
`ine (T4) to triiodothyronine (T3) with a concomitant increase in
`reverse T3. A decrease in both thyroid-binding globulin and
`thyroid-binding prealbumin is seen. The sum of these effects is
`usually a low-normal total T4 and free T4 level, without clinical
`manifestations of hypothyroidism.
`Gonadal Function.
`The glucocorticoids inhibit gonado-
`tropin secretion both in the basal state and in response to gona-
`dotropin-releasing hormone. These actions cause a decrease in
`gonadal sex steroid productions“ The glucocorticoids also have
`direct
`inhibitory effects on the gonad, and they lead to a
`decrease in libido.” Together, these actions impair reproductive
`function.
`
`ACTIONS OF THE MINERALOCORTICOIDS
`
`In order of decreasing potency, the mineralocorticoids include
`aldosterone, 11-deoxycorticosterone, 18-oxocortisol, corticoster-
`one, and cortisol. As a class of hormones, they have more spa-
`cific actions than the glucocorticoids. Their major function is to
`maintain intravascular volume by conserving sodium and
`eliminating potassium and hydrogen ions. They exert these
`actions in kidney, gut, and salivary and sweat glands. In addi-
`tion, aldosterone may have distinct effects in other tissues. Min-
`eralocorticoid receptors are found in the heart and vascular
`endothelium,43 and ald