unbound fraction of plasma cortisol rises. Plasma has two cortisol-
`binding systems. One is a high-affinity,
`low-capacity a2-globulin
`termed transcortin orWc~Q_2;t_z'K.smo__l-__l3yghaigi;,r,g_EglQQ14,lig‘_(CBG), and the other
`is a low-affinity, highcapacity protein, albumin. Cortisol binding to
`CEG is reduced in areas of inflammation, thus increasing the local
`concentration of free cortisol. When the concentration of cortisol is
`
`>700 nmol/L (25 /.r.g/dL), part of the excess binds to albumin, and a
`greater proportion than usual circulates unbound._CBGflis~increased in
`high-estrogen states (e.g., pregnancyggral,contraceptive _adnTi}"1istra-
`tion). The rise in CBG is accompanied by a parallel rise in protein-
`bormd cortisol, with the result
`that
`the total plasma cortisol
`concentration is elevated. However, the free cortisol level probably‘
`remains nonnal, and manifestations of glucocorticoid excess are ab-
`sent. Most synthetic glucocorticoid analogues bind less efficiently to
`CBG (~70% binding). This may explain the propensity of some syn-
`thetic analogues to produce cushingoid effects at low doses. Q0_1;zjgj_sg1
`metalgoliies __are, biologically inactive and bind only ‘weakly to circu-
`latiiig 3ra:;aa‘p;at'ang;r ‘
`teiit than cortisol,
`AldOStC[OTl,C is bound to proteins to aTsi‘i"r"'iféill
`and an ultrafiltrate of plasma contains as in/ucli as 50% of circulating
`aldosterone.
`-» .
`..”.~.,,,—1,/.«,r»*-w—x..
`"\_r
`
`
`
`STEROID METABOLISM AND EXCRETION ‘:‘IJi|_CP_C9[CICOIdS §The daily secre-
`tion of cortisol ranges between 40 and 80 ,u.mol ”( I5 and 30 mg; 8-10
`mg/m2), with a pronounced circadian cycle. The plasma concentration
`of cortisol is determined by the rate of secretion, the rate of inactiva-
`tion, and the rate of excretion of free cortisol. The liver is the rrjjor
`
`organ responsible for ste/r9_id inactivatpn. A major enzyme regulating
`cortisol metabolism is 11B-hydroxysteroid dehydrogenase (1lB-
`H_S5). There are two isofoims: ll B—HSD I is primarily expressed in
`the liver and acts as a reductase, converting the inactive cortisone to
`the active glucocorticoid, cortisol;
`the 11B-HSD II isoforrn is ex-
`pressed in a number of tissues and converts cortisol to the inactive
`
`metabolite, cortisone. Mutations in the 11 BHSDI gene ted
`with rapid cortisol turnover, lea mg to activation of the hypothalamic-
`
`pituitary-a rena
`PA) axis an
`cessive a rena an rogen pro ric-
`tion in women. _In animal mo pression of
`11B-HSD 1 increases local glucocorticoid production and is associated
`with central obesity and insulin resistance. The oxidative reaction of
`11B-HSD I
`is
`increased in hyperthyroidism. Mutations
`in the
`IIBHSDZ ene cause the syndrome of ez‘aIoc0r‘tic0id
`
`——.‘7._
`. ‘,\( _-._‘_,.-\
`excess, reflect/ir\i_g‘insufficient inactivation of cortiso ih'Tl‘TewEHi‘E§/,
`, - ‘ - w/\_ «.__..
`____,‘ .,--.
`allowin inappropriate cortisol actix/~a1ti(’)n\6‘fThe mineralocorticoid re-
`ceptor (see below).
`/"T
`T/"T"
`~\
`
`In individuals with normal salt intake, the average
`Mineralocorticoids
`daily secretion of aldosterone ranges between 0.1 and 0.7 time] (50
`and 250 Mg). During a single passage through the liver, >75%'To'f
`c ’aldosterone is normally inactivated by conjugation with
`
`glucuronic acid. However, under certain conditions, such as congestive
`giilure, this rate of inactivation is reduced.
`
`‘Adrenal Androgens The major androgen secreted by the adrenal is de-
`hydroepiandrosterone (DHEA) and its sulfuric acid ester (DHEAS).
`Approximately 15 to 30 mg of these compounds is secreted daily.
`Smaller amounts of androstenedione,
`llB—hydroxyandrostenedione,
`and testosterone are secreted. DHEA is the major precursor of the
`urinary l7-ketosteroids. Two-thirds of the urine l7-ketosteroids in the
`_..,...__.__,.\,_,,\,,,\..\__,,.\,~,..-\_d..,\_,.,_,.x ,_.___
`male are derived from adrenal metabolites, -
`
`
`third comes from testicular androgens. In the female, fimostalT‘1’ifi‘Tfé'
` s are nTtHe adren3IT'\‘~~r“"T/I’
`Steroids diffuse passively through the cell membrane and bind to
`intracellular receptors (Chap. 317). Glucocorticoids and mineralocor-
`:ic?6E1§‘BTH&Tx7iHfi{e‘a:1y equal affinity to the mineralocorticoid receptor
`(MR). However, only glucocorticoids bind to the glucocorticoid re-
`ceptor (GR). After the steroid binds to the receptor, the steroid-receptor
`complex is transported to the nucleus, where it binds to specific sites
`on steroid-regulated genes, altering levels of transcription. Some ac-
`tions of glucocorticoids (e.g., anti-inflammatory effects) are mediated
`
`by GR-mediated inhibition of other transcription factors, such as ac-
`V‘~xA
`
`3 T215 ‘Disorders of tIie,Adrenal Cortex
`
`t in-1 (AP-_lg_)_or niglear factor kappa B (NFKB), which
`
`n tokine_g5:pes. Because
`cortisol binds to the MR with the same affinity as aldosterone, min-
`eralocorticoid specificity is achieved by local metabolism of cortisol
`to the inactive compound cortisone by l l /3-HSD II. The glucocorticoid
`effects of other steroids, such as high-dose progesterone, correlate with
`their relative binding affinities for the GR. Inherited defects in the GR
`cause glucocorticoid resistance states. Individuals with GR defects
`have high levels of cortisol but do not have manifestations of hyper-
`._cortisolism.
`
`ACTH PHYSIOLOGY ACTH and a number of other peptides (lipotropins,
`endorphins, and melanocyte-stimulating hormones) are processed
`from a larger precursor molecule of 31,000 mol wt—proopiomelan-
`ocoitin (POMC) (Chap. 318). POMC is made in a variety of tissues,
`including brain, anterior and posterior pituitary, and lymphocytes. The
`constellation of POMC—derived peptides secreted depends on the tis-
`sue. ACTH, a 39-amino-acid peptide, is synthesized and stored in ba-
`sophilic cells of the anterior pituitary. The N-terminal 18-amino-acid
`fragment of ACTH has full biologic potency, and shorter N-terminal
`fragments have partial biologic activity. Release of ACTH and related
`peptides from the anterior pituitary gland is stimulated by corticotro-
`pin-releasing hormone (CRH), a 41-amino—acid peptide produced in
`the median eminence of the hypothalamus (Fig. 321-3). Urocortin, a
`neuropeptide related to CRH, mimics many of the central effects of
`CRH (e.g., appetite suppression, anxiety), but its role in ACTH reg-
`
`Circadian
`regulation
`
`Stress
`(physical, emotional,
`hypoglycemia)
`
`\
`(4)
`
`
`
`
`Neurotransmitters;
`peptides
`/'
`Hypothalamic corticotropin
`releasing center .
`
`
` (5)
`
`Plasma cortisol
`
`concentration
`
`
`
`
`Epinephrine
`Norepinephrine
`
`The hypothalamic-pituitary-adrenal axis. The main sites for feedback
`FIGURE 321-3
`control bg plasma cortisol are the pituitary gland (1) and the hgpothalamic corticotro-
`pin—releasing center (2). Feedback control bg plasma cortisol also occurs at the locus
`coeruleus/sympathetic sgstem (3) and mag involve higher nerve centers (4) as well.
`There mag also be a short feedback loop involving inhibition of corticotropin-releasing
`hormone (CRH) bg adrenocorticotropic hormone (ACTH) (5). Hgpothalamic neurotrans-
`mitters influence CRH release; serotoninergic and cholinergic sgstems stimulate the
`secretion of CRH and ACTH; or-adrenergic agonists and y—aminobutgric acid (GABA)
`probablg inhibit CRH release. The opioid peptides B-endorphin and enkephalin inhibit,
`and vasopressin and angiotensin ll augment,
`the secretion of CRH and ACTH. B-LPT,
`/3-lipotropin; POMC, pro-opiomelanocortin; LC,
`locus coeruleus; NE, norepinephrine.
`
`

`
`tem. Stress-related secretion of ACTH abolishes the circadian period-
`icity of ACTH levels but is, in turn, suppressed by prior high-dose
`glucocorticoid administration. The no_r1_nalVp_ul
`t,i¢le,_cl‘i;rc_a_di_an pattern
`of ACTH release is regulated by CRH; this my anisrn is the so-called
`
`'3
`_' "
`lmfl
`T CR(‘H”'§“eElrétil5n, in turn, is influenced by hypotha-
`laiviiicineurotransriiitters including the serotoninergic and cholinergic
`pathways. The immune system also influences the HPA axis (Fig. 321-
`4). For example:“‘i13”flaEfi?t15E6ry"‘“鑧‘f6Einé§ H "[tt1r}i6£' necrosis factor
`(TNF)-ct, interleukin (IL) la, IL-13, and IL-6] produced by monocytes
`increase ACTH release by st_ir_nplgting,_segretigngqfwglgljgggpfid/or A}/__P.
`Finally, ACTH release is regulated by the level of free cnorvtfsol in
`plasma. Cortisol decreases the responsiveness of pituitary corticotropic
`cells to CRH; the response of the POMC mRNA to CRH is also in-
`hibited by glucocorticoids. In addition, glucocorticoids inhibit the 10-
`cus coeruleus/sympathetic system and CRH release.
`seworneclianisnlpestablishes__thegp§ig;a
`in the control of
`ACTH secretion. The suppression o
`CTH secretion that results in
`zidrenalitropliy following prolonged glucocorticoid therapy is caused
`primarily by suppression of hypothalamic CRH release, as exogenous
`CRH administration in this circumstance produces a rise in plasma
`ACTH. Cortisol also exerts feedback effects on higher brain centers
`(hippocampus, reticiilar"systTerr1’,’a'iiEl septum) and perhaps on the ad-
`renal cortex (Fig. 321-4).
`'
`if Tlrepbiologic half—life of ACTH in the circulation is <10 min. The
`actioniof ACTH is also rapid; within minutes of its relé”:i”§€‘,”"tl’l‘e con-
`centration of steroids in the adrenal venous blood increases. ACTH
`stimulates steroidogenesis via activation of adenyl cyclase. Adenosine-
`3’,5’-monophosphate (cyclic AMP), in turn, stimulates the synthesis
`of protein kinase enzymes, thereby resulting in the phosphorylation of
`proteins that activate steroid biosynthesis.
`‘Nu
`RENIN-ANGIOTENSIN PHYSIOLOGY Renin is a proteolytic enzyme that is
`produced and stored in the granules of the juxtaglomerular cells sur-
`rounding the afferent arterioles of glomeruli in the kidney. Renin acts
`on the basic substrate angiotensinogen (a circulating a2-globulin made
`in the liver) to form the decapeptide angiotensin I (Fig. 321-5). An-
`gigtensin I is thegengymatiggllltggtgsfonned by angiotensin-convert-
`ingenzyme (ACE), why is present in many tissues (particularly the
`p r 'efidofl1‘5Ti'i1'r'i1'),Tt()t”li'e‘c>ctapeptige angiotensin II by
`the removal of the two C—terrninal amino acids. Angiotensin II is a
`potent pressor agentland exerts its action by a direct effect on arteriolar
`s uscle. Trfnaddition, angiotensin II stimulates
`roduction of
` £l.§§$_Z,E1{1_%} _g]§_J_,n1§.I;LLlosa of the adrenal’ cortex; the Hep-
`tapeptide angiotensin III may also stimulate aldosterone production.
`The two major classes of angiotensin receptors are termed AT] and
`AT2; AT1 may exist as two subtypes a and B. Most of the effects of
`angiotensins II and III are mediated by the AT1 receptor.vAngiortgn>-
`.,s,.i.q.ases.rapidlx..Q9_s;ggy angiotensin II (half—life, ~1 min), while the
`half—life of renin is more prolonged (10 to 20, min). In addition to
`circulating renin-angiotensin, many tissues have a local renin-angio-
`tensin system and the ability to produce angio-
`tensin 11. These tissues include the uterus.
`
`
`
`Part XIV Endocrinology and Metabolism
`2130
`
`
`Immune-adrenal axis
`
`’
`
`’
`
`‘
`
`I
`
`CRH-secreting
`neurons
`
`,
`
`: e
`G)
`
`p't -t
`
`8
`ACTH
`
`CRH
`
`Thermoregulatory
`centers
`
`Immune stimulus
`V
`
`Macrophages
`
`Inflammatory
`cytokines (IL-1oc,
`W, IL-6, ma
`
`
`
`
`
`
`Mediators of inflammation
`(elcosanoids, serotonin,
`PAF, bradykinin)
`
`The immune—adrenal axis. Cortisol has anti-inflammatory properties
`FIGURE 321-4
`hat include effects on the microvastulature, cellular actions, and the suppression of
`inflammatoru cutokines (the so—called immune—adrenal axis). A stress such as sepsis
`'ncreases adrenal secretion, and cortisol
`in turn suppresses the immune response via
`his sgstem. —, suppression; +, stimulation; CRH, corticotropin-releasing hormone;
`ACTH, adrenocorticotropic hormone;
`IL,
`interleukin; TNF,
`tumor necrosis factor; PAF,
`platelet activating factor.
`
`ulation is unclear. Some related peptides such as /3-lipotropin (,B—LPT)
`are released in equimolar concentrationsiiwith ACTH, suggesting that
`they are cleaved enzymatically from the parent POMC before or during
`the secretory process. However; [3-enclprphiri levels may or may not
`correlate with circulating levels of ACTH, depending on lthewnature of
`the stimulus.
`The major factors controlling ACTH release include CRH, the free
`c_c)r_tisol concentration in plasma, stress, and the sleep-wakeicgycle (Fig.
`321-3). Plasma,_A_C;l“_ljl_varies duriiigfhe day as a‘ result of its pulsatile
`secretion, and follows a circadian pattern with a peak just__.pri0r to
`waking and a nadirwl3éf6rfeh'sleeping. If a new sleep—wal<e cycle is
`adopted,'the pattern changes over several days to conform to it. ACTH
`and cortisol levels also increase in response to eating. Stress (e.g.,
`pyrogens, surgery, hypoglycemia, exercise, and severe emotional
`trauma) causes the release of CRH and arginine vasopressin (AVP)
`and activation of the sympathetic nervous system. These changes in
`turn enhance ACTH release, acting individually or in concert. For
`-.-- -..~.<.-«».-».-.
`example, release acts synergisticallyflwith CRH to amplify ACTH
`sEEc‘feti’on, ClH{Hi also sYtifiiiil'at'éS§“tli€i
`locus coeruleus/sympathetic sys-
`
`Circulating blood
`/ volume X
`RBna|_Na
`'e"e”"°“
`/l
`Aldosterone
`release
`
`Hen?‘
`pfggsslfig
`p
`\
`Juxtaglomerular
`cells
`
`Catecholamines
`
`-
`
`\
`
`.
`Angiotensin ll
`
`Angiotensinogen
`
`/ \
`
`.
`Renin release
`
`Maoula densa
`"feedback"
`
`Renai
`potassium
`eX°'e”°”
`
`'
`P
`Sgfirigm
`
`Converting enzyme /X Angiotensin I
`
`The interrelationship of the volume and potassium feedback loops on aldosterone secretion.
`FIGURE 321-5
`Integration of signals from each loop determines the level of aldosterone secretion.
`
`placenta, vascular tissue, heart, brain, and, par-
`ticularly,
`the adrenal cortex and kidney. Al-
`though the role of locally generated angiotensin
`II is not established, it may modulate the growth
`and function of the adrenal cortex and vascular
`smooth muscle.
`"The amount of renin released reflects the
`combined effects of four interdependent factors.
`The juxtaglomerular cells, which are special-
`ized myoepithelial cells that cuff the afferent
`arterioles, act as miniature pressure transducers.
`sensing renal perfusion pressure and corre-
`sponding changes in afferent arteriolar perfu-
`sion pressures. For example, a reduction in
`circulating blood volume leads to a Correspond-
`ing reduction in renal perfusion pressure and
`
`
`
`

`
`.‘)‘5‘~‘u5‘
`i
`.....-,t
`'i
`afferent arteriolar _pi:essure (Fig. 321-5). This change is perceived by
`th Juxtaglomerular celisfis a decreased stretch exerted on the afferent
`arteno ar H“E1e Juxtaglomerular cells release more renin into
`the renal circulation. This results in the formation of angiotensin I,
`which is converted in the kidney and peripherally to angiotensin II by
`ACE. Angiotensin II influences s9_<jj_g_ni_horiieos_tasis Vlglmfill/*0 major
`giggli renal blood flow so as to maintain a constant
`glomerular filtration rate, thereby changing the filtration fraction of
`sodium, and it stimulates the adrenal cortex to release aldosterone.
`Increasing plasma levels of aldosterone enhance renal sodium reten-
`tion and thus result in expansion of the extracellular fluid volume,
`which, in turn, dampens the stimulus for renin release. In this co text,
`¢n
`»«u...,,.9,«.-,»x- ..-.....r.w,
`.
`.-. _,. ,‘.,,__.,,—.
`the _renin-angiotensin-aldostergne_systemregulates , volume by ‘modi-
`f__3fi_n_gg,i',e_i;g,>1ierrio_d_3/_riamics,and tubular_so_dium transport.
`.2 A second ,g,g;i;;ol mechanism for renin release is ce'iitered in the
` cells,\§ group of distal convolutedtybiilarepithelial cells
`_.__
`.
`x(:lV"‘)-Lkléss.-h-‘V-‘V'f"'X‘
`,~,,,..v.<
`V"
`
` o> uggtaglornegv
`_
`lls. They 'may function as
`chemoreceptors, mom oring the sodium (or chloride) load presented
`
`-5..
`
`to the distal tubule. Under co/ri_dirtiVoris of.increased_delivei;y ofhfiltkered
`sodium to the macula dar§a’,‘ gsignallis conveyed,to"decrease‘juxta-
`()'rF€rT1T§ricellIfejfélfsejbffeiniifthereby modulating the glomerular
`
`“
`‘
`‘
`’h;é‘fi‘1terédioaiiiéfsddiuin.‘ ’
`‘ ~
`
`\R"‘I"lie '§’yin;5}:hezi,
`_
`t 1
`1 oils system regulates the release of renin in
`response t€;m3:s)sfli'ifiivption$'"t3f
`tlifégtiipmriwgilit posture. The mechanism is either
`a direct effect on the juxtaglomerular cell to increase adenyl cyclase
`activity or an indirect effect on either the juxtaglomerular or the macula
`densa cells via vasoconstriction of the afferent arteriole.
`
`of 3,21 Diisordjers’ of the Adrenal. Cortex
`
`
`
`ferent parts of the body. For example, pharmacologic doses of cortisol
`can deplete the protein matrix of the vertebral column (trabecular
`bone), whereas long bones (which are primarily compact bone) are
`affected only minimally; similarly, peripheral adipose tissue mass de-
`creases, whereas abdominal and interscapular fat expand.
`V. Glucocorticoids have anti-inflammatory properties, which are prob-
`ably related to effects on the microvasculature and to suppression of
`inflammatory cytokines. In this sense, glucocorticoids modulate the
`immune response via the so-called immune-adrenal axis (Fig. 321-4).
`This “loop” is one mechanism by which a stress, such as sepsis, in-
`creases adrenal hormone secretion, and the elevated cortisol level in
`turn suppresses the immune response. For example, cortisol maintains
`vascular responsiveness to circulating vasoconstrictors and opposes
`the increase in capillary permeability during acute inflammation. Glu-
`cocorticoids cause a leukocytosis that reflects release from the bone
`mmfi>"w”6 ibition of their egress through
`the capillary wall. a deipflletiinofi of circulating
`eosinophils and lymphoid tissue, specifically T cells, by causing a
`redi§tii'Biffi6n from the circulation into other compartments. Thus, cor-
`tisol impairicell-mediated immunity. Glucocorticoids also inhiflif the
`p$?fi§%?fi% tors of inflammation, such as the
`lymphokines and prostaglandins. Glucocorticoids inhibit the produc-
`tion and action of interferon by T lymphocytes and the production of
`IL-1 and IL-6 by macrophages. The £§jmm of glucocoiti-
`coids may be explained by an effect on IL-___,_iy,h;1gh_a_ppeda§§wtmonl3yeMap
`endog§p_Qfl$—PQ£I.Qgegi, (Chap. 1&6”).
`lucocoiticoids also inhibit the pro-
`duction of T cell growth factor (IL-2) by T lymphocytes. Glucocorti-
`coids reverse macrophage activation and antagonize the action of
`migration—inhibiting factor (MIF), leading to reduced adherence of
`macrophages to vascular endothelium. Glucocorticoids reduce pros-
`taglandin and leukotriene production by inhibiting the activity of phos-
`pholipase A2,
`thus blocking release of arachidonic acid from
`phospholipids. Finally, glucocorticoids inhibit the production and in-
`flammatory effects 0
`ra y inin, plate e -ac ivaing ac
`,
`‘d's'e‘r"6-
`t3ii‘iii'f‘Ifi:i’s"’p*r“o'l:aml3ly only at pharmacologic dosages that antibody
`pr
`oduction is reduced and lysosomal membranes are stabilized, the
`
`Finally, circulating factors influence renin release. Increased di-
`etary intake of potassium decreases renin release, whereas decreased
`potassium intake increases it. The significance of these effects is un-
`_
`_
`;.in&'z-.9256/r msaanu '
`.
`‘*--3....-..is.av
`‘clear. Angiqtensfifii exerts negative feedback control on renin release
`
`that is independent of alterations in renal blood flow, blood pressure,
`or aldosterone secretion. A)tl_‘l'(Zl..},2g[l‘
`c pepiLg_g.;‘.gl,s~o“ inhibit renin
`release. Thus, the control of renin re ease involves both mtrarenal
`(pressor receptorand rnacula densa) and extrarenal (sympathetic ner-
`vo__us system, potassium, angiotensin, etc.) mechanisms.‘
`ady—state
`renin levels reflect all these factors, with the intrar
`al mechani m
`
`.
`firé ominating.
`N mauv--Kn’
`Nader effect suppressing the release of acid hydrolases.
`Cortisol levels respond within minutes to stress, whether physical
`GLUCDCIJRTICDID PHYSIOLOGY The division of adrenal steroids into glu-
`(trauma, surgery, exercise), , depression), or
`cocoiticoids and mineralocorticoids is arbitrary in that most glucocor-
`physiologic (hypoglycemia, fever). The reasons why elevated gluco-
`ticoids have some mineralocorticoid-like properties. The descriptive
`corticoid levels protect the organism under stress are not understood,
`term glucocorticoid is used for adrenal steroids whose predominant
`but in conditions of glucocorticoid deficiency, such stresses may cause
`action is on intermediary metabolism. Their overall actions are di-
`hypotension, shock, and death. Consequently, in individuals with ad-
`rected at egllgancing the pggduction of the high-energy fuel, glucose,
`
`..».t ,_,.,.. ..,,,m, L»; -..,._,,.,,,,‘d
`renal insufficiency, glucocorticoid administration should be increased
`agtlgegucing all ggtliegnietabolic activ
`riot
`‘iféctly"‘ifii76l§75ii in that
`»l~V s. Sustained activationfhowef/er, results'ifi'a‘pathophysiologit>\ during stress.
`\\5 Cortisol has major effects on body water. It helps regulate the ex-
`state, e.g., Cushing’s syndrome. The principal glucocorticoid is cor-
`tracellular fluid volume by retarding the migration of water into cells
`Tisof(hydrocortisone). The effect of glucocorticoids on intermediary
`and by promoting renal water excretion, the latter effect mediatedflby
`metabolism is mediated by the GR. Physiologic effects of glucocor-
`ticoids include the regulation of protein, carbohydrate, lipid, and mu-
`suppression of vasopressin secrelion, by an increase in the rate of
`glomerular filtration, and by a direct action on the renal tubule. The
`cleic acid metabolism. Glucocorticoids raise the blood glucose level
`by antagonizing the secretion and actions of insulin, thereby inhibiting
`consequence is to prevent water intoxication by increasing solute-free
`water clearance. Glucocorticoids also have weak mineralocorticoid-
`peripheral glucose uptake, which promotes hepatic glucose synthesis
`(gluconeogenesis) and hepatic glycogen content. The actions on pro-
`tein metabolism are mainly §_g’J;t_2j.lI)Oll(3",_")I>'§_§_l.,l_l__[,l1_'lgV7 iri_an_in_crease in"p_,rg;_
`t down and hiltiriogen excfefion. In large part, these "actions
`reflect a mobilization of glycogenic~a_mair1o acid precursors from pe-
`ripheral suppoififigfstfuc ures, such as boriefskin, muscle, and con-
`nective tissue, due to protein breakdown and~irihibition__gf.prot§i_n
`
`syntlwagl amino acid uptake. Hyperaminoacidemia also facilitates
`gluconeogenesis by stimulating glucagon secretion. Glucocorticoids
`act directly on the liver to stimulate the synthesis of __certain egs,
`such asity§(1siHe”afii‘iE”f”fnsfer§§e7and/fiyptophan pyrrolase. Gluco-
`
`corticoidsiregigiclfiaifefaltty acid irr/iobilizatiori
`enhaficifigflfgactivation
`of ce § by lipid—mobilizing hormones (e.g., catecholamines
`and pituitary peptides).
`The actions of cortisol on protein and adipose tissue vary in dif-
`
`like properties, and high doses promote renal tubular sodium reab-
`sorption and increased urine potassium excretion. Glucocorticoids can
`also influence behavior; emotional disorders may occur with either an
`excess or a deficit of cortisol. Finally, cortisol su
`resses the secretion
`_*T_ W ‘me_
`.,......,..-o...
`TiV3tiX§,B§Plii?5,.(;°:.C_1:}_L_£3:.§l1L19.TE.i11..
`of Pituitary POMC am:
`
`an
`
`
`
`MINERALIICORTICOID PHYSIOLOGY Mineralocorfie
`two classes of cells—epithe1ial and nonepithelial.
`
`Effects on Epithelia Classically, mineralocorticoids are considered ma-
`jor regulators of extracellular fluid volume and are the major deter-
`minants of potassium metabolism. These effects are mediated by the
`binding of aldosterone to the MR in epithelial cells, primarily the prin-
`cipal cells in the renal cortical collecting duct. Because of its electro-
`
`

`
`
`
`TABLE 321-1
`Factor
`
`Factors Regulating Aldosterone Biosynthesis
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`renal-itself is capable of synthesizing angiotensin II. What role(s) the
`extrarenal production of angiotensin II plays in normal physiology is
`still largely unknown. However, the tissue renin-angiotensin system is
`activated in utero in response to growth and development and/or later
`in life in response to injury.
`Potassium ion directly stimulates aldosterone secretion, indepen-
`dent of the circulating renin-angiotensin system, which it suppresses
`(Fig. 321-5). In addition to a direct effect, potassium also modifies
`aldosterone secretion indirectly by activating the local renin-angioten-
`sin system in the zona glomerulosa. This effect can be blocked by the
`administration of ACE inhibitors that reduce the local production of
`angiotensin II and thereby reduce the acute aldosterone response to
`potassium. An increase in serum potassium of as little as 0.1 mmol/L
`increases plasma aldosterone levels under certain circumstances. Oral
`potassium loading therefore increases aldosterone secretion, plasma
`levels, and excretion.
`Physiologic amounts of ACTH stimulate aldosterone secretion
`acutely, but this action is not sustained unless ACTH is administered
`in a pulsatile fashion. Most studies relegate ACTH to a minor role in
`the control of aldosterone. For example, subjects receiving high-dose
`glucocorticoid therapy, and with presumed complete suppression of
`ACTH, have normal aldosterone secretion in response to sodium re-
`striction.
`Prior dietary intake of both potassium and sodium can alter the
`magnitude of the aldosterone response to acute stimulation. This effect
`results from a change in the expression and activity of aldosterone
`synthase. Increasing potassium intake or decreasing sodium intake
`sensitizes the response of the glomerulosa cells to acute stimulation
`by ACTH, angiotensin II, and/or potassium.
`Neurotransmitters (dopamine and serotonin) and some peptides,
`such as atrial natriuretic peptide, y—melanocyte-stimulating hormone
`(y-MSH), and B-endorphin, also participate in the regulation of al-
`dosterone secretion (Table 321-1). Thus, the control of aldosterone
`secretion involves both stimulatory and inhibitory factors.
`
`
`
`2132
`
`Part-XIV Endocrinology and Metabolism:
`
`chemical gradient, sodium passively enters these cells from the urine
`via epithelial sodium channels located on the luminal membrane and
`is actively extruded from the cell via the Na/K—activated ATPase (“so-
`dium pump”) located on the basolateral membrane. The sodium pump
`also provides the driving force of potassium loss into the urine through
`potassium-selective luminal channels, again assisted by the electro-
`chemical gradient for potassium in these cells. Aldosterone stimulates
`all three of these processes by increasing gene expression directly (for
`the sodium pump and the potassium channels) or via a complex pro-
`cess (for epithelial sodium channels) to increase both the number and
`activity of the sodium channels. Water passively follows the trans-
`ported sodium, thus expanding intra- and extravascular volume.
`Because the concentration of hydrogen ion is greater in the lumen
`than in the cell, hydrogen ion is also actively secreted. Mineralocor-
`ticoids also act on the epithelium of the salivary ducts, sweat glands,
`and gastrointestinal tract to cause reabsorption of sodium in exchange
`for potassium.
`When normal individuals are given aldosterone, an initial period
`of sodium retention is followed by natriuresis, and sodium balance is
`reestablished after 3 to 5 days. As a result, edema does not develop.
`This process is referred to as the escape phenomenon, signifying an
`“escape” by the renal tubules from the sodium-retaining action of al-
`dosterone. While renal hemodynamic factors may play a role in the
`escape, the level of atrial natriuretic peptide also increases. However,
`it is important to realize that there is no escape from the potassium-
`losing effects of mineralocorticoids.
`
`Effect on Nonepithelial Cells The MR has been identified in a number
`of nonepithelial cells, e.g., neurons in the brain, myocytes, endothelial
`cells, and vascular smooth-muscle cells. In these cells, the actions of
`aldosterone differ from those in epithelial cells in several ways:
`
`3.
`
`4.
`
`1. They do not modify sodium-potassium homeostasis.
`2. The groups of regulated genes differ, although only a few are
`known; for example, in nonepithelial cells, aldosterone modifies
`the expression of several collagen genes and/or genes controlling
`tissue growth factors, e.g., transforming growth factor (TGF) fl
`and plasminogen activator inhibitor, type 1 (PAI-1).
`In some of these tissues (e.g., myocardium and brain), the MR is
`not protected by the l1B—HSD II enzyme. Thus, cortisol rather
`than aldosterone may be activating the MR. In other tissues (e.g.,
`the vasculature), 11B-HSD H is expressed in a manner similar to
`that of the kidney. Therefore, aldosterone is activating the MR.
`Some effects on nonepithelial cells may be via nongenomic mech-
`anisms. These actions are too rapid—occurring within 1 to 2 min
`and peaking within 5 to 10 min—to be considered genomic, sug-
`gesting that they are secondary to activation of a cell-surface re-
`ceptor. However, no cell-surface MR has been identified, raising
`the possibility that the same MR is mediating both genomic and
`nongenomic effects. Rapid, nongenomic effects have also been
`described for other steroids including estradiol, progesterone, thy-
`roxine, and vitamin D.
`Some of these tissues—the myocardium and vasculature—may
`also produce aldosterone, although this theory is controversial.
`
`5.
`
`Regulation of Aldosterone Secretion Three primary mechanisms control
`adrenal aldostcrone secretion:
`the renin-angiotensin system, potas-
`sium, and ACTH (Table 321-1). Whether these are also the primary
`regulatory mechanisms modifying nonadrenal production is uncertain.
`The renin-angiotensin system controls extracellular fluid volume via
`regulation of aldosterone secretion (Fig. 321-5). In effect, the renin-
`angiotensin system maintains the circulating blood volume constant
`by causing aldosterone-induced sodium retention during volume de-
`ficiency and by decreasing aldosterone-dependent sodium retention
`when volume is ample. There is an increasing body of evidence in-
`dicating that some tissues, in addition to the kidney, produce angio-
`tensin H and may participate in the regulation of aldosterone secretion
`either from the adrenal or extraadrenal sources. Intriguingly, the ad-
`
`AN DROGEN PHYSIOLOGY Androgens regulate male secondary sexual
`characteristics and can cause virilizing symptoms in women (Chap.
`44). Adrenal androgens have a minimal effect in males whose sexual
`characteristics are predominately determined by gonadal steroids (tes-
`tosterone). In females, however, several androgen-like effects, e.g.,
`sexual hair, are largely mediated by adrenal androgens. The principal
`adrenal androgens are DHEA, androstenedione, and 11-hydroxyan-
`drostenedione. DHEA and androstenedione are weak androgens and
`exert their effects via conversion to the potent androgen testosterone
`in extraglandular tissues. DHEA also has poorly understood effects on
`the immune and cardiovascular systems. Adrenal androgen formation
`is regulated by ACTH, not by gonadotropins. Adrenal androgens are
`suppressed by exogenous glucocorticoid administration.
`
`

`
`LABORATORY EVALUATION OF ADRENOCORTICAL FUNCTION
`
`A basic assumption is that measurements of the plasma or urinary level
`of a given steroid reflect the rate of adrenal secretion of that steroid.
`However, urine excretion values may not truly reflect the secretion
`rate because of improper collection or altered metabolism. Plasma lev-
`els reflect the level of secretion only at the time of measurement. The
`plasma level (PL) depends on two factors: the secretion rate (SR) of
`the hormone and the rate at which it is metabolized, i.e., its metabolic
`clearance rate (MCR). These three factors can be related as follows:
`
`L= A:§R or SR=MCR><PL
`
`BLOOD LEVELS E Peptides The plasma levels of ACTH and angiotensin
`II can be measured by immunoassay techniques. Basal ACTH secre-
`tion shows a circadian rhythm, with lower levels in the early evening
`than in the morning. However, ACTH is secreted in a pulsatile manner,
`leading to rapid fluctuations superimposed on this circadian rhythm.
`Angiotensin II levels also vary diumally and are influenced by dietary
`sodium and potassium intakes and posture. Both upright posture and
`sodium restriction elevate angiotensin II levels.
`Most clinical determinations of the renin-angiotensin system, how-
`ever, involve mea