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

`

`
`
`Principles and PractiCe of
`ENDOCRINOLOGY
`
`.
`w
`AND
`METAB OLISM
`
`THIRD EDITION
`
`A v E
`
`DITOR
`Kenneth L. Becker
`
`ASSOCIATE EDITORS
`John P. Bilezikian
`William]. Bremner
`Wellington Hung
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`D. Lynn Loriaux
`Eric S. Nylén
`Robert W. Rebar
`
`Gary L. Robertson
`Richard H. Snider, Jr.
`Leonard Wartofsky
`With 330 Contributors
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`$429 LlPPlNCOTT WILLIAMS 8 WILKINS
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`V A Wolters Kluwer Company
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`Principles and practice of endocrinology and metabolism / editor, Kenneth [ Becker .
`associate editors, John P. Bilezikian
`[et al.].--3rd ed.
`P‘ ,‘ cm.
`Includes bibliographical references and index.
`ISBN 07817-17505
`1. Endocrinology. 2. Endocrine glai'ids-ADiseases. 3. Metabolism--Disorders. l. Becker,
`Kenneth L.
`{DNLM1 l. Endocrine Diseases. 2. Metabolic Diseases. WK 100 P957 2000]
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`

`CORTICOSTEROID ACTION
`
`PERRIN C. WHITE
`
`GENERAL MECHANISMS OF ACTION
`
`71 4
`
`PART V: THE ADRENAL GLANDS
`
`
`
`C H A P T E R 7 3
`
`
`33. Barrett PQ, Bollag WB, lsales CM, et al. Role of calcium in angiotensin II-
`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 )8, Carr BR, Sasano H, et al. Adrenarche results from development of a
`3beta-hydroxysteroid dehydrogenase-deficient adrenal reticularis. J Clin
`Endocrinol Metab 1998; 8323695.
`36. Rosner W. The functions of corticosteroidvbinding globulin and sex hor-
`mone—binding 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 GL. Determinants of steroid hormone bioavailability. Biochem
`Soc Trans 1997; 25:577.
`38a. Emptoz~Bonneton A, Cousin P, Seguehik, et a]. 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 I’hysiol
`1987; 252213365.
`
`heat shock protein (HSP) 90 and one molecule each of HSP 70
`and HSP 56 (immunophilin).7 Binding of ligand changes the
`conformation of the receptor and, thus, has several effects. HSP
`90 is associated with the unliganded glucocorticmd 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 .Sig'nal
`located in a ”hinge” between the DNA and S'teI‘Old-bli‘ICllng
`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.ti Firstcthe gluco'corticmd-
`receptor complex can stimulate transcription by binding to
`specific glucocorticoid-responsive elements (GREs)
`in the. 5
`flanking region of glucocortic01d—responSive genes. GREs, like
`other specific hormone response elements, are often imperfect
`palindromes (in a palindrome, the two complementary strands
`of a DNA molecule, when ”read” in opposrte directions, have
`the identical sequence). Most often, CRT/Ssuare variants of ‘the
`sequence GGTACAnnnTGTTCT, 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, rnarked variations in
`sequence can be tolerated in one half-Site. Thus, monomeric glu-
`cocorticoid receptors can also bind DNA» but the blnding can
`apparently be stabilized by interactions Wlth other bound recep-
`The steroid hormones, vitamin D, retinoic acid, and the thyroid
`tor molecules or other transcription factors. Thus, binding of the
`hormones all share a similar mechanism of action}!2 These hor-
`monomeric receptor to one half—site markedly increases the abil-
`mones diffuse through the target cell membrane and interact
`ity of a second monomer to bind to the other half-Site.
`with a specific receptor protein for each hormone. The activated
`The interaction of the glucocortiCOid receptor and DNA has
`hormone-receptor complex binds to specific DNA sequences, the
`been studied in detail by x-ray crystallography and nuclear
`hormone-responsive elements (HREs), which are usually located
`magnetic resonance techniques.D The tWO 2th fingers form a
`in the 5' flanking region of each hormone-responsive gene. These
`single domain. Alpha helices adjacent to each finger on the
`complexes may also bind to other transcription factors. The bind-
`carboxy-terminal side are oriented perpendicularly to each
`ing of the hormone-receptor complex to these DNA sequences or
`Other; the first helix fits into the major groove of the DNA helix
`transcription factors leads to selective increases or decreases in
`and makes direct contact with bases. The tips of both fingers
`gene transcription. The altered protein levels that result from this
`contact the phosphate backbone, and the second finger also
`change in transcription rate are responsible for the hormonal
`mediates DNA-dependent dimerization of the receptor.
`.
`.
`response seen in that particular tissue.3
`GREs cannot constitute the only DNA sequences mediating
`At least six classes of steroid receptors exist, corresponding to
`the transcriptional effects of glucocorticmds. GREs are indistin-
`the known bioactivities of the steroid hormones: glucocorticoid,
`guishable in sequence from the elements binding mineralocor-
`mineralocorticoid, progestin, estrogen, androgen, and Vitamin D.
`ticoid, progestin, and androgen receptors, andthese receptors
`Additional “orphan” receptors of incompletely understood func-
`are >90% identical in amino-acid sequence in their DNA-binding
`tion are found that bind related compounds such as andro-
`domains. However, the amino-terminal domains of these recep-
`stanes.i Steroid receptors belong to a larger superfamily of nuclear
`tors are <15% identical in amino-acid sequence, 30d at least
`transcriptional factors that includes the thyroid hormone and ret-
`some interactions with other transcriptional factors are medi-
`inoic acid receptors. All of these receptors share a common struc-
`ated by this domain.‘0
`,
`'d
`)
`..
`ture that includes a cm'boxy-tw'mina/ ligand-binding donmin and a
`As a second type of effect, glucocorhcoi
`irlccepto‘is can
`nzidregion DNA-binding domain. The latter domain contains two
`inhibit or activate transcription by interacting W11“ 0:191 trans-
`”zinc fingers,” each of which consists of a loop of amino acids
`cription factorsf’rgl11 In particular, they calafetg: 31:9 £9,913; <18th-
`stabilized by four cysteine residues chelating a zinc ion.5
`ity by repressing gene transcription. me lfa‘em ym S Th or
`Unliganded steroid hormone receptors shuttle between the
`NF-KB elements in the regulatory reglOHS O 5;: >16 5‘5 e 1
`95C
`cytoplasm and the cell nucleus. Importation into the nucleus is
`AP-l and NF-KB sites bind cFos-cJun or
`L 6-13 {0
`leteroj
`an energy-dependent process. This process requires one or
`dimerS, respectively. The ligand-bOLInd gltllcocoqutifsoig “3381301
`more nuclear localization signal sequences on the receptor,
`monomer and/or dimer interacts With AP- “or
`fK an pie-
`which consist of clusters of basic amino-acid residues located in
`)
`.
`tin their transactivational e fects on he
`vents them from exer
`g
`AP-l and NF—KB serve as intra-
`or near the DNA~binding domain. When not occupied by
`gelrllels they normally reEiZEtseior many growth factors and
`ligand, the various hormone receptors differ in their propensity
`ce uar
`>“rirer ss
`.
`inflammaToLryiyifokiné, respectively. The'pr‘ociound antigrptt/vth
`to be transported to the nucleus. For example, the estrogen
`receptor is predominantly located within the nucleus, whereas
`and antiinflammatory effects of glucocorticoi satrc exfer tct VoIa
`the unoccupied glucocorticoid and mineralocorticoid receptors
`great extent via transrepression Of these trailisclripfog )atc orfbtl n
`are found mainly in the cytosol.6
`addition, glucocorticoid reCePtors may me u a :le {if}; 0
`1e
`The cytosolic glucocorticoid receptor, when not bound to its
`Stat4, StatS, NF-1, Oct-1, SP—l, C/EBB HNF3/ 3“
`P
`tram-
`steroid ligand, forms a heterooligomer with two molecules of
`cription factors.
`T‘hie ma+m=irl51 uir‘sr sF»HHifl\H
`
`

`

`Unlike glucocorticoids, mineralocorticoids do not appear to
`interfere with cFos-cjun or NF-KB binding. This functional dif-
`ference may be localized to the amino-terminal domain of the
`r
`tor.10
`.
`eCTIwo new classes of nuclear proteins that influence the transacti-
`vational activity of nuclear receptors have been identified and col-
`lectively called corqgulntorsfli13 According to their ability to
`potentiate or diminish the activity of nuclear receptors, t ey sire
`respectively called coactivators and compressors. KnownOcoregu 1aCi
`tors are large proteins with many functional domains.
`ne colu
`think of coactivators as bridges between the DNA-bound nuchear
`receptor and components of the transcription macfiunery,31;:
`as
`ancillary factors of DNA polymerase II, that stab dd? an
`en?
`stimulate the activity of the initiation complex. In a
`ition, coac l;
`vators have enzymatic activities that promote transprirgiplrx Sue _
`as histone acetyl-transferase actiVity, which loosens t ie
`(iu
`ble helix from the nucleosome and allows the polymerase compflex
`to exert its activity.” On the other hand, corepressors prexgientt. 1e
`nuclear receptor from binding to DNA and/fl: ttransaé 1:11:1ng
`their target genes and have enzymatic actiVities
`afllmpethe titer-
`cription, such as histone deacetylase, which streigg tens1 te
`actions of the DNA with the _nucleosome.
`oreguda ors arc;
`expressed in a tissue-specific fashion and have VaI‘i-lltlfig 6955:2353;
`specificity for particular nuclear receptors. Spmte o Slecsh ps AP-1
`serve as coregulators of other transcription ac ors,
`c
`,
`NF-KB and the Stats, and hence serve as cross-POints between dif—
`'
`'
`‘
`the cell.
`ferent SI ynal transduction systems in
`.
`_
`.
`Sevezrjal factors regulate tissue-speCific effects of steroids at
`several levels both before and after thebreceptfrfigfoihggél
`ously, hormone receptors are WIdEIY .Ciltf riot
`Inge effect};
`expressed, and a particular class of sterOi as o e: e tor Of
`on cells that do not express the corr?SPOI;S;“Ogr :ieccrgase the
`physiologic importance, enzymes may mgrtehus modulate their
`affinity of steroids for their receptors an 'd
`tor has identi-
`activity. For example, the mineralocortiCOi
`recep et cortisol is a
`cal affinities in vitro for cortisol and aldosteronirn}; ma
`result
`weak mineralocorticoid in Vivo. Th1? dlscfiegr Znasey which
`from the action of ughydroxystefmd cle y t 2in "ind, for the
`converts cortisol t0 cortisone- C01fltls’oneblstmie foréhe enz me
`receptor whereas aldosterone.151 1.10m suhs ra 2 me allowsycor;
`PharmacologiC or genetic inhibition ofit
`is ent01s arid
`roduce
`P
`tisol to occupy renal mineralocorticgi
`recep
`sod‘ibikr‘n retencfipfr;23:11? Eépgiréinfig; Share bioactivities because
`of theifhelaeility to bind to the Stmefeceptoi’i ifitieriitgeifl‘ii‘s‘fiy
`d'
`A ebiologic effects in different
`is ‘
`-
`1 Y
`exert
`ivcrsl
`onses is determined by the different genes hat
`2:33;;32;$135 the hormone in different tissues. Glucocorti—
`coids for example, have primarily GRE-mediated metabolic
`.
`-
`’— F-KB—mediated antiinflamma-
`effects in liver and mainly anti Ne.”
`-
`' 1 1 m hoid tissu'
`'
`.
`.
`tor¥npfg§§§§§i$lthz acIiniis resulting from the binding of sterOids
`‘
`ffects might be mediated
`,
`‘
`‘
`'d rece tors, some e
`.
`tp1 nuchaitlbtfrgiechanigns. Such effects often take place With
`biggie :qpfdity (milliseconds to minutes) and/or have been
`documented not to require protein syntheSis, a sme qua non of
`the transcriptional effects mediated by nuclear-hormone recep-
`o ‘.
`t rs These effects have been most extensively documented for
`.
`-
`r
`terone, and aldosterone; they
`mm giggnn inning ginnin
`:13}?le CO igiigcellular calcium levels, nitric_fox1de;na)i;dntey::::1e
`kiliEZes}; Thus far, however, no Sterfild-sep:3112;: and 54-)
`P
`tors have been isolated or cloned. (A 80 S
`
`ACTIONS OF THE GLUCOCORTICOIDS
`
`' gl. The term glucocorti-
`‘
`'
`'
`‘ are essential fOi surViva
`.
`-
`'
`'
`Glgcocpitfcgdfiie glucose—regulating properties of these hor-
`mone: etrlfowever the glucocorticoids have multiple effects that
`m
`~_
`,
`Thip .-..-.-.+n_..:—.In.
`
`Ch. 73: Corticosteroid Action
`
`71 5
`
`TABLE 73-1.
`Major Glucocorticoid ActionsE“
`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 marrowzneu-
`trophilia
`
`Block PMN diapedesis, chemotaxis, and phagocytosis
`Deplete circulating lymphocytes:lymphocytopenia affecting T cells more
`than B cells
`
`Decrease antibody formation from B lymphocytes
`Deplete circulating monocyteszmonocytopenia
`Deplete circulating eosinophils:eosinopenia
`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
`
`I’MN, polymorphonucleocytes; TSH, thyrotropin.
`—_—————-—_———\
`
`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, deveIOpment
`I
`bone metabolism, and central nervous system (CNS) activity.
`In stress situations, glucocorticoid secretion can increase up
`to almost 10-fold.18119 This increase is believed to enhanCe Sur-
`vival by increasing cardiac contractility, cardiac output, senSi-
`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, Proteol _
`sis, and lipolysis. Persons with unrecognized adrenal lnSuffi_
`g-._ _—.._:—,.I
`
`

`

`71 6
`
`PART V: THE ADRENAL GLANDS
`
`ciency are at risk of life-threatening adrenal crisis if subjected to
`stress without glucocorticoid replacement.20
`
`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.“22
`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).23 This may
`involve effects on adipocyte differentiation.“
`
`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
`muscle, the type II white glycolytic fibers are more affected
`than the type I fibers. Cardiac muscle and the diaphragm are
`almost entirely spared from this catabolic effect.
`
`IMMUNOLOGIC EFFECTS
`
`synthesis and the actions of bradykinin. They also block hista-
`mine and proinflammatory cytokine (tumor necrosis factor (X,
`interleukin-1, and interleukin-6) secretion and effects.23 These
`actions inhibit vasoactive agents and diminish the inflamma-
`tory process. Glucocorticoids may cause lyniphtmyttmmim with
`a relative T—cell depletion, monocytopenia, and eosmopenia.
`They do so at least in part by inducmg cell cycle arrest in the G1
`phase and by activating the apoptosts pathway through gluco-
`.
`.
`.
`x
`.2,
`corticoid receptor—mediated effects.
`’
`.
`.
`In contrast, glucocorticoids increase Circulating polymor~
`phonuclear cell counts, mostly by preventing their egress from
`the circulation. Generally, glucocorticmds decrease diapedeSIS,
`chemotaxis, 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 mayvbe'mediated by
`changes in levels of the cytokine migration inhibitory factor
`(MIF) from macrophages and T cells. Whereas‘physiologic lev-
`els of glucocorticoids promote release of lei, pharmacologic
`doses inhibit MIF secretion.”
`‘
`_
`_
`.
`'
`The suppressive effect of glucocorticoids is primarily exerted
`on T helper 1 cells and hence on cellular immunity, whereas the
`T helper 2 cells are spared, which effectively leads to a predomi-
`nantly humoral immune response.”’:-” Indeed, glucocorticmds
`enhance secondary anamnestic antibody responses, whereas
`they inhibit primary antibody responses. I’harmacologic doses
`of glucocorticoids may also decrease the size of the immuno-
`logic tissues (i.e., the spleen, thymus, and lymph nodes). _
`In summary, high levels of glucocorticmds decrease inflam-
`matory and cellular immune responses and increase suscepti-
`bility to certain bacterial, viral, fungal, and parasitic infections.
`
`EFFECTS ON SKIN
`
`Glucocorticoids inhibit fibroblasts, which leads to increased
`bruising and poor wound healing through cutaneous atrophy.
`This effect explains the thinning of the skin Fthat
`is seen in
`patients with Cushing syndrome-’ (SGe ChaP- 73) lmmunosup-
`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). This 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, howevercgenerally does
`not fall below normal because of the secondary increase in par-
`athYroid hormone secretion.
`.
`.
`The most significant effect of ‘long-term glucoggpcoul
`excess on calcium and bone metabolism is osteoporoSis; Glu-
`cocorticoids inhibit osteoblastic activity by decreasmg the num-
`ber and activity of osteoblasts.“ Glucocorticoids also decrease
`osteoclastic activity, but to a lesser extent, (leading to low bone
`turnover with an overall negative balance. Ilie tendency of glu-
`cocorticoids to lower serum calcrum and phosphate levels
`causes secondary hyperparathyroidism. Iogetfhbei, these actions
`decrease bone accretion and cause a net loss 0
`one mineral.
`
`CIRCULATORY AND RENAL EFFECTS
`
`Glucocorticoids play a profound role in immune regulation.”18
`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 immunosuppression that predisposes to
`infection. Glucocorticoids inhibit eicosanoid and glycolipid
`
`the
`(II:
`Glucocorticoids have a positiV'C inotropli I'anLlenlvel
`heart,
`increasing the left ventricular wor.
`fmtjx; 31 (31"?)ng
`they have a permissive effect on the actllol‘li IO eil 111% 31g“; at? A
`norepineplirine on both the heart and t icio ooc tvcis’c s.1
`‘11]
`1!:
`absence of glucocorticoids, decreased 9‘“ 1339”] pu ‘an‘c 5’ IOC, .
`may develop; in states of glucocorticoid efic‘tés’ aypuftcpsuni 15
`frequently observed. This may be due to activation 0 t ic min-
`This material W‘ESCG‘DIEH
`
`

`

`eralocorticoid receptor (see later) that occurs when renal 11B-
`hydroxysteroid dehydrogenase is saturated by excesswe levels
`of glucocorticoids.
`
`CENTRAL NERVOUS SYSTEM EFFECTS
`
`Glucocorticoids readily penetrate the blood—brain barrier and
`have direct effects on brain metabolism. They decrease'CNS
`edema and are commonly used in therapy for increased intra-
`cranial pressure. Paradoxically, they also may contribute to the
`development of pseudotumor cerebrl (increased .intracranial
`pressure in the absence of a structural leSion)‘ Their ‘3“er on
`mood and behavior are well recognized. They stimulate appe-
`tite and cause insomnia with a reduction in rapld eye VFW?"
`ment sleep. An increase in irritability and emotlonal lablllty 15
`seen, with an impairment of memory and ability to concentrate.
`Libido is decreased—an effect that may be secondary to b.0t1} a
`direct glucocorticoid effect on behavior and glucocortlcold-
`induced inhibition of the reproduCthC system.
`.
`Glucocorticoid excess and deficiency may both be assocmted
`with clinical depression. Furthermore} glllcqufihwld Exceis
`may produce a psychosis in some patient? .
`1
`ftto mo er)a e
`glucocorticoid excess for a limited period 0 ftime 0 En ctauses a
`feeling of euphoria or well-being. There rife? patienls 1:23]:
`object to a decrease in glucocorticmd dosgge. aien :rwiiiinexia
`primary psychiatric disorders, such as
`elm-65533111“ attern (if
`nervosa, may have abolition of the norma ego .
`tpc 'd r0~
`glucocorticoid secretion and an increase}n I: ucocor 1901‘. p f
`duction. These abnormalities are revers1ble With remission o
`the Psychiatric illness and (havglbe‘gnzgifprred to as states 0f
`-
`'
`r ~ ndrome see
`c
`-
`.'
`pseéfifcigiililclgfdiffects in brain are mediated largely through
`interactions with two closely related receptors/H 5226:1319:
`referred to as type I and type 1.1 receptors’ iiie lypee 1 feceptor i:
`the conventional glucocorticmdreceptor.
`i: typt 1
`up“.
`1
`identical to the mineralocorticoid receptor, 1“ It “1:11.91 lcat
`affinities for both glucocorticoids and minera ocor icfoli1C:11:f1nos_
`areas of the brain in which it is expressedeCTlsgr: we‘nasewcgge
`Comitant expression of llfi-hydroxysteroi ,1 e izortiéjoid‘s to inac-
`later and Chap. 72); this enzyme oXIdlZQS to ticiissues The t
`‘e I
`tive compounds in mineralocorticmd‘ttalriitels in the limbicy}:
`5—
`receptor, which is expressed at 111811930 (f3 1d hi ,her affinit
`if“
`tem (i.e., the hippocampus ,3— has a
`- O
`b
`1
`t
`y .
`.
`.
`.
`)
`t
`e II receptor. Thus, g ucocortic01d
`glucocorticmds than the VP
`(1'
`ted
`redomimntl
`effects in the limbic sYStem may bel me1 13nd “a actiVifetli:
`through the type I receptor at normal evel S ‘
`seenyu‘nder‘ stre ‘
`type II receptor mainly at elevated 16.3Ve 57:1St1nd in some
`55:
`conditions.3233 These receptOrs hm]? dl“\mréytfnth‘e t
`e I rec Cises
`opposing effects. For example, acuvation (:13 to g: neuroetlrjizr‘s
`reduces sensitivity 0f hippocainpel neufrothe t
`e II rece 115—.
`mitter serotonin whereas aqtlyfltlonlol.
`>311?“ us to self (:rs
`increases it.“ Increased senSitiVity ofiieflll’g‘ E 1 $1 d
`O 0'
`.
`,
`lain the euphoria assOCiate Wit 1 181. oses of
`1““ may hclp exp
`1
`s manner, glucocortiCOids sup-
`glucocorticoids. In an ana ogou
`.-
`, 1
`(CRH) -
`tl
`,
`..
`ilease of corticotroPln‘releasmfi.101;mone
`1
`11:1 K
`giggiiéi h
`othalamus but stimulate it in tie centra nuc eus of
`YP
`1
`t>ral bed nucleus of the stria terminalis,
`c
`the amygdala mad ta {:11- and anxiety states?”
`a 1a 8
`‘L
`t
`.
`l '
`Whlgiitalddiitignljlglucocorticoids and 9“?” sgegoiflsrnay hall/De £101.}
`-
`)
`,
`dulating activ1ties O
`0 1 {amino U yric
`genomic cffccts by mo
`.
`-t1te (NMDA) receptors?"
`acid (GABA) and N_methyl-D-aspal ‘
`
`GROWTH
`
`coids inhibit linear growth and skeletal
`.
`.
`.
`.
`.
`,)
`‘ss
`rluCOcorti
`K
`(
`Eqfigfidnén children-37 T1115 results primarily fiom the direct
`.
`.
`.
`71 cocorticoids on the epiphyses. This effect
`mhlbltory eff: (igdilated by decreasing levels of insulin-like
`may 1th Ifitter—I (IGF-I)“ and by increasing levels of IGF-
`€313;ng p‘rotein-l (lGFBI’-1), which inhibits somatic growth by
`
`Ch. 73: Corticosteroid Action
`
`71 7
`
`decreasing circulating levels of free IGF-I.3S 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 function?“0
`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 production.“ The glucocorticoids also have
`direct
`inhibitory effects on the gonad, and they lead to a
`decrease in libido.42 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 Spe—
`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 aldosterone increases myocardial fibrosis.44
`Such receptors are also found in the brain (see earlier); although
`they are occupied predominantly by glucocorticoids in SOIne
`regions of the brain, aldosterone has distinct effects in increas-
`ing salt hunger and blood pressu