JANSSEN EXHIBIT 2058
`
`Mylan v. Janssen IPR2016-01332
`
`JANSSEN EXHIBIT 2058
`Mylan v. Janssen IPR2016-01332
`
`

`

`The Adrenal
`
`Gland
`
`INTRODUCTION 540
`
`’
`
`SYSTEM FUNCTION: THE ADRENAL
`MEDULLA 549
`
`540
`
`The Synthesis, Storage, and Release of
`
`Catecholamines 549
`
`SYSTEM FUNCTION: THE ADRENAL
`
`Catecholamine Actions and
`
`CORTEX 540
`
`Regulation 550
`
`“R” 3"“ ACT" 5“
`Cortical Hormones: Their Actions and
`
`PATHOPHYSIOLOGY: MEDULLARY
`DYSFUNCTION 551
`
`Regulatm" 542
`Stermd B'°synthes'S 545
`PATHOPHYSIOLOGY: DISEASES OF
`CORTICAL OVER- AND
`UNDERPRODUCTION 545
`
`Diseases of Overproduction 545
`
`Diseases of Underproduction 548
`
`Catecholamine Overproduction 551
`Catecholamine Underproduction 551
`
`

`

`inferior phrenic artery
`
`Superior adrenal
`artery
`
`Middle adrenal
`artery
`
`
`
`Subcapsular plexus
`
`inferior adrenal
`artery
`
`Kidney
`
`Figure 34.1 Arterial supply to the adrenal glands. The adrenal
`arteries are not drawn to scale, nor drawn in their exact anatomic
`locations.
`
`testicular and ovarian veins. The left testicular/
`ovarian vein drains into the left renal vein, while the
`right testicular/ovarian drains right into the IVC.
`The medulla and cortex of the adrenal glands
`are separate in structure, function, and embryologic
`origin. The cortex arises from the mesoderm, while
`the medulla derives from the ectoderm. The meso-
`
`dermal gonadal ridge gives rise to the steroidogenic
`cells of the ovaries and testes as well as the adrenal
`
`cortex precursor cells, which migrate to the
`retroperitoneum. These mesodermal cortical cells
`are invaded by migrating ectodermal neural crest
`cells, which will become the medulla. Encapsulation
`of the adrenal gland around week 8 of fetal life
`creates a unified organ out of these two originally
`separate entities.
`
`SYSTEM FUNCTION: THE ADRENAL
`CORTEX
`
`The adrenal cortex makes up 80% to 90% of the
`adrenal gland by volume and comprises three histo-
`logically and functionally distinct zones, each of
`which makes a different steroid (FIGURE 34.3). Starting
`from the outermost,
`these layers are the zona
`glomerulosa, which produces aldosterone;
`the
`zona fasciculata, which produces cortisol; and the
`zona reticularis, which produces adrenal androgens,
`primarily DHEA (dehydroepiandrosterone) and
`androstenedione. (Some cortisol is produced in the
`zona reticularis.)
`1
`
`540
`
`l"E3i‘: will Endocrine Physiology
`
`INTRODUCTION
`
`The adrenal gland plays a pivotal role in human
`endocrine physiology. Although considered one
`gland anatomically, the adrenal gland functions as
`two distinct entities: the cortex and the medulla.
`
`These two portions of the adrenal originate from
`different embryonic tissues and have distinctly
`different physiologic roles.
`The outermost shell of the adrenal gland, the
`adrenal cortex, produces three kinds of steroid
`hormones: aldosterone, cortisol, and androgens.
`Aldosterone, a mineralocorticoid, modulates elec-
`
`trolyte and fluid balance by stimulating sodium re-
`tention in the kidney’s collecting ducts. Cortisol, a
`glucocorticoid, plays a crucial role in the body’s
`stress response, in the regulation of protein, glucose,
`and fat metabolism, in the maintenance of vascular
`tone, and in the modulation of inflammation. The
`
`adrenal androgens are most important during fetal
`life as a substrate for placental estrogen production,
`but they play a minor role during adult life. The
`adrenal medulla is the inner core of the adrenal
`
`gland; it produces the catecholamines epinephrine
`and norepinephrine, which are also important
`components of the stress response.
`Adrenal function is essential to human life.
`
`Adrenalectomy will lead to cardiovascular collapse
`and death within a few days from a lack of cortisol,
`which maintains blood vessel
`tone and blood
`pressure.
`
`SYSTEM STRUCTURE: ADRENAL
`ANATOMY AND EMBRYOLOGY
`
`The adrenals are triangular retroperitoneal or-
`gans located at the superior poles of the kidneys,
`lateral to the 11th thoracic and 1st lumbar verte-
`
`brae. These glands receive blood from the superior
`adrenal artery, a branch of the inferior phrenic; the
`middle adrenal artery, a branch of the aorta; and the
`inferior adrenal artery, a branch of the renal artery
`(FIGURE 34.1). This rich blood supply from three
`distinct locations explains why the adrenals are a
`frequent site of metastases from distant primary
`cancers. More importantly, the rich blood supply
`ensures the adrenals access to the bloodstream to
`facilitate hormonal secretion. The adrenal arteries
`
`anastomose (network) into a subcapsular plexus,
`which in turn branches into arteries that
`flow
`
`these arteries form capillary
`inward. Some of
`networks in the cortex and some form capillary
`networks in the medulla (FIGURE 34.2). The left
`adrenal vein drains into the left renal vein, while the
`right adrenal vein drains directly into the inferior
`vena cava (IVC). This drainage is analogous to the
`
`

`

`
`
`
`3
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`Medullary
`capillaries
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`W.
`
`34 The Adrenal Gland
`
`541
`
`capillaries
`
`Medullary
`artery
`
`......................
`
`Cortical
`
`vein
`Medullary
`vein
`~
`
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`J
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`’
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`
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`
`..
`
`Central vein
`
`Figure 34.2 Vasculature inside the adrenal glands. The subcapsular plexus gives rise
`to arteries that form medullary capillary beds and to arteries that form cortical capillary
`beds.
`
`CRH and ACTH
`
`Production of the steroids in the adrenal cortex
`
`is regulated by the hypothalamic-pituitary-adrenal
`(HPA) axis (FIGURE 34.4). At the top of the HPA axis,
`the hypothalamus releases corticotropin-releasing
`hormone (CRH), which stimulates the anterior pitu-
`
`itary to release pro—opz'omelanocortin, a precursor
`molecule that is cleaved into four main products:
`melanocyte-stimulating hormone, beta-lipotropins,
`beta—endorphins, and adrenocorticotropic hormone
`(ACTH). ACTH, also known as corticotropin,
`is
`released into the bloodstream and acts in the cortex,
`
`stimulating the synthesis and release of over 50
`
` airanVIaruiié
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`Figure 34.3 Adrenal zonation.
`
`> Capsule
`
`-——:> Mineralocorticoids
`Zona
`glomerulosa
`
`> Cortex
`
`Zona -e> Glucocorticoids
`> fasciculata
`
`Zona
`_ -—-----> Androgens
`_
`reticularis
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`

`

`542
`
`Part VIII Endocrine Physiology
`
`Circadian
`rhythm
`A
`Su rachiasmatic
`pnucleus
`
`Stress
`inputs
`
`.
`Hippocampus 0
`
`Hypothalamus\ Q‘
`
`fg
`
`, CFIH and/or AVP
`
`G
`
`
`
`Shortfeedback
`
`
`
`xoeqpeei5uo'1
`
`Free cortisol
`
`
`
`Figure 34.4 Hypothalamic—pituitary—adrenal axis. Stress, circa-
`dian rhythms, and negative feedback from cortisol all influence the
`paraventricular nucleus ofthe hypothalamus and modulate CRH out-
`put. Stressors may be organic in nature [such as hypoglycemia or in-
`fection] or psychological.
`
`steroid products, the most important of which are
`cortisol, the adrenal androgens, and aldosterone,
`although aldosterone is largely regulated in direct
`response to serum potassium levels and by an-
`giotensin II, a hormone that helps to regulate blood
`pressure. In a classic endocrine feedback loop, corti-
`sol directly inhibits both CRH production at the
`hypothalamic level and ACTH at the pituitary level,
`thereby acting as the main control mechanism for all
`adrenal cortical hormone production, with the
`exception of aldosterone.
`
`The cortex responds dramatically to stimulation
`from ACTH, which elevates steroid production within
`minutes. It does so by activating a receptor on the
`cortical cell membranes that is linked to a G protein
`(FIGURE 34.5). The G protein, in turn, activates adeny-
`lyl cyclase and raises the cAMP level, activating a
`protein kinase. The kinase phosphorylates and hence
`
`ACTH
`
` _
`
`.
`
`\ Mitochonrion
`
`A
`Protein
`kmase A
`
`\\
`
`If
`1 1—Deoxy\-\%',>_ Cortisol,‘
`cortisol
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`17-OH ‘<.?'—Preg <—4— Cholesterol T—’C“°‘e5‘°'Y'
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`Lipid droplet
`
`esters
`
`Figure 34.5 Action of ACTH on the adrenal cortex. AC, adenylyl
`cyclase; CEH, cholesteryl ester hydrolase; G, G protein (linking the
`receptor to the adenylyl cyclase]; LDL, low—density lipoprotein; Preg,
`pregnenolone [cortisol precursor); R, ACTH receptor; Smooth ER,
`smooth endoplasmic reticulum.
`
`activates the enzyme cholesteryl ester hydrolase
`(CEH), which promotes the conversion of cholesteryl
`esters into free cholesterol. The free cholesterol
`
`then supplies the steroid synthesis pathways, as
`described below. Chronic stimulation with excessive
`
`ACTH causes bilateral adrenal hypertrophy, while
`removal or destruction of the pituitary, which is
`responsible for producing ACTH, conversely leads to
`adrenal atrophy.
`
`Cortical Hormones: Their Actions and
`Regulation
`
`As steroids, the cortical hormones all share
`
`certain functional features. They are all secreted into
`the adrenal blood vessels and circulate from the
`
`adrenal veins to target tissues all over the body. At
`the target tissues, they dissolve into the lipid mem-
`branes of the tissues and pass into the intracellular
`cytosol. There, the steroids bind cytosolic receptor
`proteins, which in turn bind to particular DNA
`sequences, thereby initiating the transcription of
`mRNA, resulting in the synthesis of new proteins.
`As mentioned above and described in more
`detail below, the secretion of steroid hormones from
`
`the cortex is regulated by various kinds of negative-
`feedback loops. TABLE 34.1 summarizes the actions of
`the cortical steroids.
`
`

`

`34 The Adrenal Gland
`
`543
`
`
`
`Table 34.1 ACTIONS OF THE CORTICAL STEROIDS
`
`Main Actions
`Adrenal Hormone
`
`Aldosterone
`
`Cortisol
`
`- Increases salt and water reabsorption from kidney tubules
`- Increases K+ secretion in kidneys
`
`- Counterregulatory effects: increases blood sugar, increases
`catabolism of triglyceride and protein
`- Anti—inflammatory/immunosuppressant effects
`- Maintains blood vessel tone and hence blood pressure
`
`- Help determine male sex characteristics during fetal
`Androgens
`development and puberty
`
`Aldosterone Action Aldosterone plays a key role in
`the regulation of fluid balance by enhancing the abil-
`ity of kidney tubules to absorb salt and water in two
`ways. First, aldosterone directly stimulates the
`production and activity of Na+/K+—ATPase pumps
`located in the basolateral side of the cortical col-
`
`lecting ducts. These pumps exchange sodium for
`potassium, and aldosterone stimulation of these
`pumps leads to increased sodium reabsorption in
`exchange for potassium excretion. Remember that
`increased reabsorption of sodium leads to passive
`water reabsorption and increased extracellular fluid
`volume (see Chapter 22).
`Second, aldosterone increases salt and water
`reabsorption in the kidney by creating more apical
`Na+ channels, directly increasing sodium permeabil-
`ity on the luminal side of the cortical collecting ducts.
`Aldosterone also drives K+ secretion through its
`effects on the translocation of Na+. Increased Na+ re-
`absorption creates tubular electronegativity and
`drives paracellular K+ secretion (see Chapter 24).
`‘
`Finally, aldosterone acts on the HT-ATPase in the
`renal tubule and has other effects on acid-base bal-
`
`ance (see Chapter 25). Because it acts on the levels of
`these inorganic (mineral) electrolytes, it is termed a
`mineralocorticoid.
`
`Aldosterone Regulation Aldosterone regulation is
`unique in that it is the only adrenal cortical hormone
`that is secreted largely independently of ACTH. A
`small amount of ACTH from the pituitary is required
`for aldosterone release, but aldosterone is regulated
`mainly by two other control mechanisms: the serum
`potassium level and the renin—angiotensin-aldos-
`terone (RAA) system. Elevated potassium levels trig-
`ger aldosterone secretion, which in turn stimulates
`renal potassium excretion Via the Na+/K+ exchange
`pump to rectify the hyperkalemia. Low blood pres-
`sure stimulates the adrenal to secrete aldosterone
`
`through the RAA system. This increases salt reab-
`sorption and raises the extracellular fluid volume and
`blood pressure.
`
`Cortisol Action Cortisol has a multitude of actions,
`
`and derivatives of this hormone are used frequently
`in medical therapy. Cortisol is consequently one of
`the most challenging adrenal hormones to under-
`stand and at the same time one of the most clinically
`relevant. Cortisol is produced mostly by the fasci-
`culata, with some production in the reticularis.
`Although mainly exerting glucocorticoid activity (ex-
`plained below), cortisol also functions as a weak
`mineralocorticoid, with effects similar to those of al-
`dosterone. Cortisol’s precursor, corticosterone, also
`exhibits some glucocorticoid activity. About 20 to 30
`mg of cortisol is secreted per day by the adrenals,
`with 90% to 95% of circulating cortisol bound in the
`
`plasma to cortisol-binding globulin.
`Glucocorticoid action can be thought of mainly in
`two broad categories: metabolic and anti—inflamma—
`tory. Although the myriad metabolic actions of
`cortisol can be daunting, it is useful to remember that
`cortisol acts to prepare the body for stress. Teleologi-
`cally speaking, in times of stress the body does not
`have the energy surplus to build protein or add to
`triglyceride and glycogen stores; instead it requires
`rapidly usable energy for the brain in the form of glu-
`cose. Therefore, the body under stress will mobilize
`amino acids and fatty acids as substrates for gluco-
`neogenesis (see Chapter 31). Under glucocorticoid in-
`fluence, an increase in all gluconeogenic enzymes
`raises hepatic gluconeogenesis sixfold. Blood sugar
`levels climb, while peripheral uptake and utilization of
`glucose are decreased. To fuel this upregulated gluco-
`neogenic activity, cortisol increases the production of
`amino acids from muscle breakdown. Synthesis of
`protein and fat is halted, as the main focus is on
`survival and the mobilization of stores (catabolism)
`rather than on growth and repair (anabolism).
`This bolus of glucose is liberated from tissue
`energy stores instead of from the diet. Thus, gluco-
`corticoids are counrerregulatory hormones, alongside
`glucagon, epinephrine, and growth hormone. Gluco-
`corticoids reproduce glucagon action and oppose
`insulin action. However, glucocorticoids do not
`
`

`

`544
`
`Part VIII Endocrine Physiology
`
`
`
`The Insulin/Counterregulatory Balance
`
`
`
`The stress response induced by cortisol is intended to be only temporary. If
`exposure to cortisol is prolonged, as in long-term treatment with prednisone (a
`glucocorticoid administered as medicine), the body suffers deleterious effects. A
`constant elevation of cortisol levels disrupts the normal balance between insulin
`and cortisol, leaving the body in a prolonged state of catabolism, which can be very
`destructive.
`
`In Cushing’s disease, excess ACTH production leads to an abnormal elevation
`of cortisol and disruption of the metabolic balance. Skin striae, skin thinning, and
`muscle weakness ensue from excessive protein and collagen breakdown due to
`cortisol action. In diabetes mellitus, low insulin production disrupts the balance
`between cortisol and insulin. When diabetics experience physical stress such as
`illness or infection, cortisol levels increase and blood sugar levels increase, and
`therefore their insulin requirement goes up.
`
`
`
`
`promote glycogen breakdown as does glucagon. This
`phenomenon is known as glucocorticoid’s glycostatic
`effect. (See Integrated Physiology Box The Insulin/
`Counterregulatory Balance.)
`Cortisol also has powerful effects on the immune
`system, which accounts for the widespread use of
`glucocorticoids as anti-inflammatories and as im-
`munosuppressants. Cortisol reduces the inflamma-
`
`tory response by both blocking the early stages of
`inflammation and speeding up the resolution of
`inflammation. Inflammation is decreased in a number
`
`of specific ways:
`
`0 Stabilization of white cell granules, which
`release proteolytic enzymes during
`inflammation
`
`0 Decreased capillary permeability (which
`decreases edema)
`
`- Decreased production of prostaglandins and
`leukotrienes, both of which are powerful
`stimuli of inflammation
`
`0 Decreased leukocyte migration
`
`- Decreased interleukin-1 (IL-1) and IL-6 release
`
`0 Direct suppression of T cells
`
`0 Decreased production of lymphocytes and
`antibodies
`
`Because of the powerful immunosuppressant ef-
`fects of cortisol, patients taking glucocorticoids for
`prolonged periods should be considered immuno-
`compromised and at an increased risk for infections.
`Cortisol is also a powerful modulator of the
`allergic response, acting to decrease eosinophil
`production, increase eosinophil apoptosis, and limit
`the inflammation that can be deadly in anaphylaxis.
`Interestingly, cortisol increases red blood cell pro-
`duction in an unknown manner. Finally, cortisol acts
`
`to maintain blood pressure by potentiating cate-
`cholamines and by directly supporting blood vessel
`tone.
`
`Cortisol Regulation Cortisol is regulated by the HPA
`axis, as mentioned above. The median eminence of the
`
`hypothalamus is responsible for the production of
`CRH, which is produced in response to a host of stress-
`ful stimuli: trauma, infection, catecholamines, surgery,
`and so on. How the hypothalamus detects these stim-
`uli has not been completely worked out. CRH is also re-
`leased in a circadian manner, leading to a diurnal vari-
`ation with cortisol levels peaking in the early morning.
`CRH triggers ACTH release from the anterior pituitary.
`ACTH is also modulated by antidiuretic hormone
`(ADH), which acts synergistically with CRH to stimu-
`late ACTH release. Cortisol is almost exclusively regu-
`lated by ACTH, which activates cholesteryl ester hy-
`drolase (CEH) and ultimately increases the production
`of pregnenolone, a cortisol precursor. Cortisol inhibits
`CRH and ACTH in a classic negative-feedback loop.
`
`The Androgens The adrenal androgens, like the
`gonadal androgens, are male sex hormones—that is,
`they help determine and maintain male sex charac-
`teristics. The principal adrenal_androgens are an-
`drostenedione, dehydroepiandrosterone (DHEA),
`and DHEA-S. These hormones have a negligible effect
`on adult physiology compared to the gonadally
`produced hormones (such as testosterone), which
`account for the majority of sex hormone effects. They
`are about one fifth as potent as testosterone.
`Androstenedione can be converted to testosterone,
`which is in turn converted to dihydrotestosterone
`(DHT) and estradiol in extra-adrenal tissues. These
`androgens are most important during fetal develop-
`ment and puberty.
`
`

`

`In the fetus, the adrenal glands are much larger
`proportionally than in the adult, and a layer known as
`the provisional or fetal cortex exists, which is analo-
`gous to the adult reticularis. This layer produces
`DHEA-S, which is converted by the placenta into an-
`drogens and estrogens. Overproduction of DHEA—S,
`as in congenital adrenal hyperplasia (discussed
`below), can lead to fetal virilization in female infants.
`Adrenal androgens are also important during
`adolescence, when they stimulate the development
`of pubic and axillary hair in women, which is know as
`adrenarche. Adrenarche and puberty normally coin—
`cide, but they are actually two physiologically sepa-
`rate events. Androgen production continues into
`adulthood and declines with age. Androgens con-
`tinue to cause groin and axillary hair growth in adult
`. women. Many claims have been made about DHEA as
`a “youth hormone,” but at this point, there is little sci-
`entific evidence for the efficacy of DHEA replacement
`as a fountain of youth.
`
`Steroid Biosynthesis
`
`All the products of the adrenal cortex are steroid
`hormones, which have a standard four—ring structure
`and are produced by a similar biosynthetic pathway.
`Enzymes specific to each layer of the cortex influence
`the structural differences of the hormones produced.
`Cholesterol provides the basic four—ring steroid
`framework. Although the adrenals can synthesize
`cholesterol de novo from acetyl CoA, 80% of the
`cholesterol used in adrenal hormone synthesis comes
`from dietary cholesterol packaged as cholesteryl
`ester in circulating low-density lipoprotein (LDL) par-
`ticles. CEH converts the esters to free cholesterol in
`
`response to ACTH. The rate—limiting step in hormone
`biosynthesis is the transfer of cholesterol to the inner
`mitochondrial membrane of adrenal cells via the
`
`steroidogenic acute regulatory protein (SIAR), followed
`by the conversion of cholesterol to pregnenolone.
`This reaction is catalyzed by the enzyme desmolase.
`Once pregnenolone is made from cholesterol,
`the pregnenolone flows downhill through each zone
`of the cortex, undergoing successive modifications to
`the basic steroid ring. These modifications result in a
`distribution of various steroid products throughout
`the adrenal cortex (FIGURE 34.6). The steroids are re-
`leased immediately after synthesis; very little of the
`cortical hormones are stored. This is in direct con-
`
`trast to the medulla, which packages and stores its
`products for release under stimulus at a later time.
`Some enzymes in the steroid biosynthetic path-
`ways are common to all three zones, while others are
`unique to a specific adrenal zone. Pregnenolone
`flows across zones and also undergoes progressive
`transformation along each zone’s unique enzymatic
`
`34 The Adrenal Gland
`
`545
`
`pathway unless an enzyme deficiency in one pathway
`acts as a roadblock. Such a condition prevents fur-
`ther modification of the steroid product, leading to
`an excess of premodification substrate that will spill
`over into the remaining open routes. An example of
`this hormonal roadblock is found in the pathologic
`condition congenital adrenal hyperplasia (CAH).
`(See Clinical Application Box What Is Congenital
`Adrenal Hyperplasia?)
`
`PATHOPHYSIOLOGY: DISEASES
`OF CORTICAL OVER— AND
`UNDERPRODUCTION
`
`Levels of cortisol and aldosterone normally vary
`in response to changing conditions in the body. Dur~ '
`ing stress, cortisol levels rise. When blood pressure
`is low, aldosterone levels rise. Pathologic conditions,
`however, may interfere with the adrenal cortex’s
`normal response to stimuli. These conditions are
`classified as those that cause the overproduction of a
`hormone and those that cause underproduction. in
`cases of overproduction, the hormone is secreted at
`levels out of proportion to adrenal stimuli. In cases of
`underproduction, the adrenal cortex cannot mount
`the normal response to stimuli.
`
`Diseases of Overproduction
`
`Diseases of overproduction may be primary to
`the adrenal gland, or they may originate outside the
`adrenal (in which case hyperproduction is called
`secondary). For example, ACTH overproduction in
`the pituitary can stimulate a perfectly normal adrenal
`gland to overproduce cortisol. Chronic stimulation of
`the RAA system due to renal disease can cause a nor-
`mal adrenal to overproduce aldosterone. Isolated
`overproduction of androgens is much less common
`and usually arises from CAH and less commonly from
`adrenal carcinomas or adenomas.
`
`Hypercortisolism Excess glucocorticoid exposure,
`called hypercortisolism, can lead to a variety of
`disease manifestations and is one of the most serious
`
`adrenal derangements. Excess glucocorticoids may be
`the result of endogenous overproduction or exogenous
`administration of glucocorticoid drugs in higher—than—
`normal amounts. Endogenous cortisol overproduction
`can be classified into two categories: ACTH—dependent
`and ACTH—independent. ACTH—dependent causes ac-
`count for 85% of endogenous hypercortisolism and in-
`clude Cushing’s disease (also known as pituitary ade-
`noma), ectopic ACTH production (as occurs with some
`lung cancers), and ectopic CRH production, which is
`rare. ACTH—independent causes are primary to the
`adrenal gland. They include adrenal adenoma and
`adrenocortical carcinoma. Exogenous glucocorti-
`
`

`

`546
`
`Part VIII Endocrine Physiology
`
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`. M
`
`1 I [3-/zyc/2'()xy/rzse
`( C YPI IB I )
`
`----------- --
`
`.’)'o.-re(Iucl¢1.s‘e
`
`V s
`
`I I [3-/1ydro.x‘yl(1.s'e
`(CYPI 1132)
`
`I<8’-lzydr0.\ylase
`(CYP/1B2)
`
`................... __
`V
`
`Hydroxycorticosterone
`
`I 8—0xidase
`(CYPI 1 B2)
`
`
`
`V
`
`cH2oH
`I
`0
`H Hc = 0
`CH
`
`Ho
`
`CH3
`
`V
`
`cH2oH
`l
`o
`H HC = 0
`CH __OH
`
`Ho
`
`CH3
`
`0
`
`0
`
`Aldosterone
`
`Cortisol
`
`Zona glomerulosa
`
`Zona fasciculata
`
`OH
`
`CH3
`
`CH3
`
`0
`
`Dihydrotestosterone
`
`Zona reticularis
`
`Figure 34.6 Steroid biosynthesis. The line next to 2i—hydroxylase is highlighted to indicate the barrier to
`aldosterone and cortisol synthesis posed by 2i—hydroxylase deficiency. Such a barrier causes progesterone
`and i7—hydro><yprogesterone to build up, which decreases the rate of conversion of pregnenoione to
`progesterone and of i7—hydroxypregnenolone to i7—hydro><yprogesterone.
`in turn, pregnenolone and 17-
`hydroxypregnenolone build up and drive increased DHEA formation.
`
`coids—drug preparations like prednisone or large
`quantities of steroid inhalers—can also lead to hyper-
`cortisolism. Rarely, hypercortisolism is caused by ex-
`cess secretion of CRH from the hypothalamus.
`Hypercortisolism due to any cause yields a con-
`stellation of clinical findings known as Cushing syn-
`drome (as opposed to Cushing’s disease, which is
`one of many causes of Cushing syndrome). The signs
`and symptoms of cortisol excess, first described by
`
`Harvey Cushing in 1932, include truncal obesity, a
`round and full face (“moon facies”), a “buffalo hump”
`of fat on the posterior neck, pigmented skin striae,
`thinned skin and easy bruising, muscle weakness, os-
`teoporosis, hypertension, and hyperglycemia. The
`catabolic effects of cortisol cause muscle weakness,
`osteoporosis, striae, bruising, and hyperglycemia.
`The abnormal fat distribution is believed to be due to
`increased lipolysis, which affects the extremities
`
`

`

`34 The Adrenal Gland
`
`547
`
`more than the trunk, but a clear explanation for the
`moon facies and buffalo hump has yet to be found.
`Virilizing symptoms of hirsutism and acne can
`accompany ACTH-dependent hypercortisolism as a
`result of androgen overproduction from excessive
`ACTH. Hyperpigmentation is also seen with elevated
`ACTH levels and is believed to be caused by ACTH
`cross—reacting with melanocyte-stimulating hormone
`(MSH)
`receptors on melanin-producing cells.
`(See Clinical Application Box Diagnosing Cashing
`Syndrome with Lab Tests.)
`
`Hyperaldosteronism As with hypercortisolism,
`hyperaldosteronism can be classified into two
`categories: primary (arising from the adrenal) and
`secondary (extra-adrenal). Primary hyperaldostero-
`nism, known as Conn ’s syndrome, arises most often
`from an aldosterone—producing adrenal adenoma. Hy-
`pokalemia, hypernatremia, diastolic hypertension,
`polyuria, and muscle weakness (secondary to low
`potassium levels) are characteristics of hyperaldos-
`teronism. Plasma renin levels are low owing to the
`negative feedback from elevated aldosterone levels.
`
`
`
`'i.i::CL|N|CAL
`APPLICATION
`
`
`
`WHAT IS CONGENITAL ADRENAL HYPERPLASIA?
`
`A newborn girl in the hospital nursery is discovered to have abnormal findings on
`examination of her genitals. She has an enlarged clitoris and a single urogenital sinus
`instead of separate openings for the vagina and urethra. She also has low blood
`pressure and a high plasma K+ level. With a putative diagnosis of congenital adrenal
`hyperplasia, the infant receives hydrocortisone and fludrocortisone (a medicinal
`mineralocorticoid) and is placed on daily salt supplements. The family is referred to
`a surgeon and a psychiatrist for consultation.
`Patients with congenital adrenal hyperplasia (CAH) have a genetic deficiency of
`2]—hydroxylase, an enzyme that transforms progesterone to corticosterone in the
`glomerulosa and transforms 17-hydroxyprogesterone to cortisol in the fasciculata.
`When this enzyme is absent, the aldosterone and cortisol precursors encounter a
`“block” and accumulate. Encountering this backup, progesterone and 17-hydroxy
`progesterone can overflow into the androgen biosynthetic pathway, where they are
`converted by 17, 20—lyase into DHEA and androstenedione, creating a surplus of
`androgenizing hormones (and a deficiency of aldosterone and cortisol, which cannot
`be made without 21-hydroxylase). Because of the lack of cortisol, which normally
`provides negative feedback to the brain, the hypothalamus and pituitary continue to
`churn out CRH and ACTH to make up for the cortisol deficit, leading to adrenal
`hypertrophy and even more pregnenolone production.
`Excess pregnenolone in the context of 2l—hydroxylase deficiency results in more
`DHEA production. Normally, DHEA has only a minor effect on females, as a stimulus
`for pubic and axillary hair growth and as a substrate for testosterone production.
`However, in female fetuses undergoing sexual differentiation, large amounts of DHEA
`result in clinically significant levels of testosterone, which in turn can lead to virilized
`external genitalia. At birth, female infants with CAH may be mistaken for male or may
`have what is known as ambiguous genitalia. Male infants with CAH initially may go un-
`diagnosed as they do not have ambiguous genitalia. (They are exposed to virilizing
`testosterone in utero as part of normal genital development.)
`A lack of cortisol and aldosterone can be disastrous for both male and female
`
`infants. Aldosterone deficiency in many cases leads to a salt—wasting crisis with
`profound hyponatremia, hyperkalemia, hypotension, and acidosis. Lack of cortisol
`impairs carbohydrate metabolism and can lead to death from loss of blood vessel
`tone and blood pressure normally maintained by cortisol.
`Glucocorticoid administration makes up for cortisol deficiency and suppresses
`
`ACTH, thereby decreasing excess pregnenolone and hence androgen production.
`Mineralocorticoid and salt administration counteract the salt wasting due to
`aldosterone deficiency, which is present in the majority of cases. Now that the genetic
`basis of CAH has been clearly elucidated, prenatal diagnosis and even treatment are
`possible.
`
`
`

`

`548
`
`Part VIII Endocrine Physiology
`
`
`
`.--;C_L|N|CAL
`
`APPLICATION
`
`
`
`DIAGNOSING CUSHING SYNDROME WITH LAB TESTS
`
`Several tests are available to help diagnose Cushing syndrome, each with varying de-
`grees of sensitivity and specificity. The first and most direct test is measurement of
`the plasma cortisol level, which is done at night. Normally, circadian rhythms dictate
`a drop in cortisol secretion during the night. However, because night-time depression
`in cortisol levels does not occur to the same extent in patients with Cushing syn-
`drome, their late—night plasma cortisol levels may be elevated. A salivary cortisol test
`has also been recently introduced to assess night-time cortisol secretion. In addition,
`because increased plasma cortisol leads to increased renal cortisol filtration and ex-
`cretion, Cushing syndrome can be detected with a 24-hour collection of urine—free
`cortisol.
`
`The dexamethasone-suppression test is used to detect ACTH-dependent causes of
`Cushing syndrome. The test entails the administration of dexamethasone, followed
`by measurement of ACTH levels. Dexamethasone is a glucocorticoid and normally
`suppresses ACTH secretion just as cortisol does. However, ACTH-secreting pituitary
`adenomas or _ectopic sources of ACTH do not respond to negative feedback normally
`but continue to secrete ACTH even in the presence of increased cortisol levels. (This,
`indeed, is the pathologic reason for the hypercortisolism in the first place.) There-
`fore, a failure to suppress the ACTH level upon dexamethasone-suppression testing
`is indicative of an ACTH-dependent cause of hypercortisolism. Imaging studies can
`then help locate the tumor that might be secreting ACTH. The sensitivity and speci-
`ficity of this test, however, are not ideal.
`
`
`Diagnosis is made by demonstrating a failure to sup-
`press aldosterone production after intravenous
`saline loading.
`The hypertension seen in primary hyperaldos—
`teronism is
`typically mild, due in part
`to the
`phenomenon of aldosterone escape (also called miner-
`alocorticoid escape). Because primary hyperaldos—
`teronism affects only one of several renal modes of
`control over the extracellular fluid volume, the kidney
`can compensate through its other modes of volume
`control. The unregulated aldosterone secretion in-
`creases salt reabsorption in the distal tubule, leading
`to increased water reabsorption and increased fluid
`volume; however, other renal mechanisms respond