tie to time
`
`
`
`s sections
`1 require-
`tolerance.
`
`ents gain
`increased
`tones that
`the pres-
`n patients
`
`in experi-
`cretion of
`s alloxan-
`=. Somato-
`c humans,
`tion, there
`nes. Thus,
`rglucagon—
`However,
`l levels are
`»etics. Fur-
`n secretion
`itimulating
`e of large
`id as being
`a relative
`iutes to the
`st in some
`.in- and the
`
`The Adrenal Medulla & Adrenal Cortex l 20
`
`There are 2 endocrine organs in the adrenal gland,
`one surrounding the other. The inner adrenal medulla
`(Fig 20-1) secretes the catecholamines epinephrine
`and norepinephrine; the outer adrenal cortex se-
`cretes steroid hormones.
`The adrenal medulla is in effect a sympathetic
`ganglion in which the postganglionic neurons have lost
`their axons and become secretory cells. The cells se-
`crete when stimulated by the preganglionic nerve fi-
`bers that reach the gland via the splanchnic nerves.
`Adrenal medullary hormones are not essential for life,
`but they help to prepare the individual to deal with
`emergencies.
`The adrenal cortex secretes glucocorticoids,
`steroids with widespread effects on the metabolism of
`carbohydrate and protein; a mineralocorticoid essen-
`tial to the maintenance of sodium balance and ECF
`volume; and sex hormones that exert minor effects on
`reproductive function. Unless mineralocorticoid and
`glucocorticoid replacement
`therapy is administered
`postoperatively, adrenalectomy is followed by col-
`lapse and death. Adrenocortical secretion is controlled
`primarily by ACTH from the anterior pituitary, but
`mineralocorticoid secretion is also subject to indepen-
`dent control by circulating factors, of which the most
`important is angiotensin II, a polypeptide formed in the
`bloodstream. The formation of angiotensin is in turn
`dependent on renin, which is secreted by the kidney.
`
`ADRENAL MORPHOLOGY
`
`The adrenal medulla is made up of interlacing
`cords of densely innervated granule—containing cells
`that abut on venous sinuses. Two cell types can be
`distinguished morphologically: an epinephrine-secret-
`ing type that has larger, less dense granules; and a
`norepinephrine-secreting type in which the smaller,
`very dense granules fail to fill the vesicles in which
`they are contained (Fig 20-2). Paraganglia, small
`groups of cells resembling those in the adrenal me-
`dulla, are found near the thoracic and abdominal sym-
`pathetic ganglia (Fig 20-1).
`
`In adult mammals, the adrenal cortex is divided
`into 3 zones of variable distinctness (Fig 20-3). The
`outer zona glomerulosa is made up of whorls of cells
`that are continuous with the columns of cells which
`form the zona fasciculata. These columns are sepa-
`rated by venous sinuses. The inner portion of the zona
`fasciculata merges into the zona reticularis, where the
`cell columns become interlaced in a network. The cells
`contain abundant lipid, especially in the outer portion
`of the zona fasciculata. All 3 cortical zones secrete
`corticosterone (see below), but the enzymatic mecha-
`nism for aldosterone biosynthesis is limited to the zona
`glomerulosa, while the enzymatic mechanism for
`forming cortisol and sex hormones is found in the 2
`inner zones.
`
`Figure 20-1. Human adrenal glands. Adrenocortical tissue is
`stippled; adrenal medullary tissue is black. Note location of
`adrenals at superior pole of each kidney. Also shown are extra-
`adrenal sites at which cortical and medullary tissue is sometimes
`found.
`(Reproduced. with permission, from Forsham PH:
`Textbook of Eml0crinalog_v, 4th ed. Williams RH [editor]. Saun-
`ders, 1968.)
`
`WCK1033
`Page 1
`
`277
`
`WCK1033
`Page 1
`
`

`
`ability tc
`tients wl.
`sterone c
`and stim
`
`produce
`reticulari
`
`glomerul
`The
`amounts
`seems to
`Other st
`mitochor
`
`is very si
`tures of 2
`
`Biosynth
`Nor:
`
`by the ad
`secrete n
`mans 80‘,
`vein is e
`circulatio
`The
`
`norepine}
`ter 13 an.
`
`epinephri
`ylation of
`of norep
`transferas
`fonnatior
`found in
`the adren.
`
`glucocort
`draining
`hypophys
`In re
`
`nephrinel
`is a 50—ll
`
`nephrine i
`but the ep
`pg/ml (0.
`epinephrit
`medulla a
`from the l
`
`The plasn
`nmol/L),
`dopamine
`half the ;
`medulla,
`comes fro
`nents of tl
`
`WCK1033
`Page 2
`
`2 78
`
`Section IV. Endocrinology & Metabolism
`
`under pituitary control, but the 3 zones of the perma-
`nent cortex represent only 20% of the gland. The
`remaining 80% is the large fetal adrenal cortex,
`which undergoes rapid degeneration at the time of
`birth. A major function of this fetal adrenal is secretion
`of sulfate conjugates of androgens that are converted in
`the placenta to androgens and estrogens which enter
`the maternal circulation. There is no structure compa-
`rable to the fetal adrenal in laboratory animals. In the
`mouse, cat, rabbit, and female hamster, there is a layer
`of cortical cells called the X zone between the zona
`reticularis and the medulla. This zone is maintained by
`pituitary gonadotropins, and it degenerates when an-
`drogen secretion increases during puberty in the male
`and during the first pregnancy in the female.
`An important function of the zona glomerulosa,
`in addition to aldosterone biosynthesis, is the fortna—
`tion of new cortical cells. Like other tissues of neural
`origin, the adrenal medulla does not regenerate; but
`when the inner 2 zones of the cortex are removed, a
`new zona fasciculata and zona reticularis regenerate
`from glomerular cells attached to the capsule. Small
`capsular remnants will regrow large pieces of adreno-
`cortical tissue. Immediately after hypophysectomy,
`the zona fasciculata and zona reticularis begin to at-
`rophy, whereas the zona glomerulosa is unchanged
`(Fig 20-3), because of the action of the renin-
`angiotensin system on this zone. However, in long-
`standing hypopituitarism, degenerative changes ap-
`pear in the zona glomerulosa. In hypopituitarism, the
`
`Lipochrome
`
`endoplasmic
`
`Agranular
`
`
`
`Golgi complex
`Granular
`reticulum
`
`Lysosome
`
`Figure 20—4. Diagrammatic representation of the cytologic fea-
`tures of steroid—secreting cells. Note the abundant agranular en-
`doplasmic reticulum,
`the pleomorphic mitochondria, and the
`lipid droplets. (Reproduced, with permission, from Fawcett DW,
`Long JA, Jones AL: The ultrastructure of endocrine glands.
`Recent Prog Horm Res 251315, 1969.)
`
`Cholinergic
`nerve ending
`
`Extracellular
`space
`
` gnse core
`
`vesicles
`
`Figure 20-2. Norepinephrine—secreting adrenal medullary cell.
`The granules are released by exocytosis and the granule contents
`enter the bloodstream (arrow). (Modified from Poitier J, Dumas
`JLR: Review of Medical Histology. Saunders, 1977.)
`
`Arterial blood reaches the adrenal from many
`small branches of the phrenic and renal arteries and the
`aorta. From a plexus in the capsule, blood flows to the
`sinusoids of the medulla. The medulla is also supplied
`by a few arterioles that pass directly to it from the
`capsule. In most species, including humans, there is a
`single large adrenal vein. The blood flow through the
`adrenal is large, as it is in most endocrine glands.
`During fetal life, the human adrenal is large and
`
`Capsule
`Zona glomerulosa
`
`Zona fasciculala .\
`
`i
`
`
`
`Zona reticularis ———— ‘T%
`Medulla\._, "
`
`
`
`6 leeks after
`hypophysectomy
`
`
`
`
`
`Figure 20-3. Effect of hypophysectomy on the morphology of
`the adrenal cortex of the dog. Note that the atrophy does not
`involve the zona glomerulosa. The morphology of the human
`adrenal is similar.
`
`
`
`
`
`WCK1033
`Page 2
`
`

`
`the perma-
`gland. The
`al cortex,
`me time of
`is secretion
`anverted in
`zhich enter
`ire compa-
`ials. In the
`
`:e is a layer
`11 the zona
`
`intained by
`; when an-
`.n the male
`116.
`nmerulosa,
`the forma-
`s of neural
`nerate; but
`emoved, a
`regenerate
`ule. Small
`of adreno-
`iysectomy,
`egin to at-
`unchanged
`the renin-
`
`r, in long-
`ianges ap-
`tarism, the
`
`nubr
`plasmic
`ulum
`
`
`
`-olgi complex
`Ilar
`Ium
`
`rytologic fea-
`agranular en-
`lria, and the
`FawcettDW,
`:rine glands.
`
`Chapter 20. The Adrenal Medulla & Adrenal Cortex
`
`279
`
`ability to conserve Na+ is usually normal; but in pa-
`tients who have had the disease for a long time, aldo-
`sterone deficiency may develop. Injections of ACTH
`and stimuli that cause endogenous ACTH secretion
`produce hypertrophy of the zona fasciculata and zona
`reticularis but do not increase the size of the zona
`glomerulosa.
`The cells of the adrenal cortex contain large
`amounts of smooth endoplasmic reticulum, which
`seems to be involved in the steroid—fonning process.
`Other steps in steroid biosynthesis occur in the
`mitochondria. The structure of steroid-secreting cells
`is very similar throughout the body. The typical fea-
`tures of such cells are shown in Fig 20-4.
`
`ADRENAL MEDULLA
`
`STRUCTURE & FUNCTION OF
`MEDULLARY HORMONES
`
`Biosynthesis, Metabolism, & Excretion
`Norepinephrine and epinephrine are both secreted
`by the adrenal medulla. Cats and some other species
`secrete mainly norepinephrine, but in dogs and hu-
`mans 80% of the catecholamine output in the adrenal
`vein is epinephrine. Norepinephrine also enters the
`circulation from adrenergic nerve endings.
`The details of the biosynthesis and catabolism of
`norepinephrine and epinephrine are described in Chap-
`ter 13 and summarized in Figs 13-3 and 13-5. Nor-
`epinephrine is formed by hydroxylation and decarbox—
`ylation of tyrosine, and epinephrine by the methylation
`of norepinephrine. Phenylethanolamine-N-methyl-
`transferase (PNMT),
`the enzyme that catalyzes the
`formation of epinephrine from norepinephrine,
`is
`found in appreciable quantities only in the brain and
`the adrenal medulla. In the medulla, it is induced by
`glucocorticoids in the large amounts found in the blood
`draining from the cortex to the medulla. After
`hypophysectomy, epinephrine synthesis is decreased.
`In recumbent humans, the normal plasma norepi—
`nephrine level is about 300 pg/ml (1.8 nmol/L). There
`is a 50—100% increase upon standing. Plasma norepi—
`nephrine is generally unchanged after adrenalectomy,
`but the epinephrine level, which is normally about 30
`pg/ml (0.16 nmol/L), falls to essentially zero. The
`epinephrine found in tissues other than the adrenal
`medulla and the brain is for the most part absorbed
`from the bloodstream rather than synthesized in situ.
`The plasma dopamine level is about 200 pg/ml (1.3
`nmol/L), and there are appreciable quantities of
`dopamine in the urine. There is evidence that about
`half the plasma dopamine comes from the adrenal
`medulla, whereas the remaining half presumably
`comes from the sympathetic ganglia or other compo-
`nents of the autonomic nervous system.
`
`In the medulla, the amines are stored in granules
`bound to ATP and protein. Their secretion is initiated
`by acetylcholine released from the preganglionic
`neurons that innervate the secretory cells. The acetyl-
`choline increases the permeability of the cells, and the
`Ca“ that enters the cells from the ECF triggers
`exocytosis (see Chapter I). In this fashion, the cate-
`Cholamines, ATP, and proteins in the granules are all
`extruded from the cell.
`The catecholamines have a very short half-life in
`the circulation. For the most part, they are methoxy—
`lated, then oxidized to 3—rnethoxy—4-hydroxymandelic
`acid (vanillylmandelic acid, VMA). About 50% of the
`secreted catecholamines appear in the urine as free or
`conjugated metanephrine and normetanephrine, and
`35% as VMA. Only small amounts of free norepineph-
`rine and epinephrine are excreted. In normal humans,
`about 30 ug of norepinephrine, 6 ug of epinephrine,
`and 700 pug of VMA are excreted per day.
`
`Effects of Epinephrine & Norepinephrine
`In addition to mimicking the effects of adrenergic
`nervous discharge (Table 13-1), norepinephrine and
`epinephrine stimulate the nervous system and exert
`metabolic effects that include glycogenolysis in liver
`and skeletal muscle, mobilization of free fatty acids,
`and stimulation of the metabolic rate (Table 20-1).
`Norepinephrine and epinephrine both increase the
`force and rate of contraction of the isolated heart. They
`also increase myocardial excitability, causing ex-
`trasystoles and, occasionally, more serious cardiac
`
`Table 20-1. Comparison of the effects of epinephrine
`and norepinephrine on some physiologic parameters.
`Where pertinent, the activity of the more active com-
`pound has been indicated as ++++ and the activity of
`the other is compared to it on a scale of + to ++++.
`
`on
`
`no
`
`cnon
`l
`CH,
`|
`NH,
`
`on
`
`no
`
`CHOH
`I
`CH,
`I
`NHCH,
`
`Norepinephrine
`
`Parameter
`
`Epinephrine
`
`Decreased (due
`to reflex
`bradycardia)
`
`Cardiac output
`
`Increased
`
`Increased
`
`Peripheral resistance
`
`Decreased
`
`++++
`++++
`++++
`+++
`+
`
`Blood pressure elevation
`Free fatty acid release
`Stimulation of CNS
`Increased heat production
`Glycogenolysis
`
`++
`+++
`++++
`++++
`++++
`
`WCK1033
`Page 3
`
`‘
`‘
`
`WCK1033
`Page 3
`
`

`
`SYDFIP
`aCt10l
`effeci
`
`systei
`
`mine:
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`cateci
`
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`when
`
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`
`the ra
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`norep
`tunate
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`
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`
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`structi
`side c
`contai
`that h:
`contai
`the C
`are the
`that hi
`
`
`
`280
`
`Section IV. Endocrinology & Metabolism
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`arrhythmias. Norepinephrine produces vasoconstric—
`tion in most if not all organs, but epinephrine dilates
`the blood vessels in skeletal muscle and the liver. This
`overbalances the vasoconstriction it produces else-
`where, and the total peripheral resistance drops. When
`norepinephrine is infused slowly in normal animals or
`humans, the systolic and diastolic blood pressures rise.
`The hypertension stimulates the carotid and aortic
`baroreceptors, producing reflex bradycardia that over-
`rides the direct cardioacceleratory effect of norepi-
`nephrine. Consequently, cardiac output per minute
`falls. Epinephrine causes a widening of the pulse pres-
`sure; but, because baroreceptor stimulation is insuffi-
`cient to obscure the direct effect of the hormone on the
`heart, cardiac rate and output increase. These changes
`are summarized in Fig 20-5.
`is produced by
`The increased alertness that
`catecholamines is described in Chapter 11. Epineph-
`rine and norepinephrine are equally potent in this re-
`gard, although in humans epinephrine usually evokes
`more anxiety and fear.
`The one effect of epinephrine that is shared to
`only a small extent by norepinephrine, at least in some
`species, is its glycogenolytic action. Epinephrine acti-
`vates phosphorylase in liver and skeletal muscle (see
`Chapter 17), and the blood glucose rises. The blood
`lactic acid also rises. The liver glycogen first falls and
`then rises as the lactic acid is oxidized (Fig 19-19).
`Plasma KJ" rises coincident with the glycogenolysis.
`
`Norepinephrine and epinephrine are almost
`equally potent in their free fatty acid—mobilizing activ-
`ity (see Chapter 17) and their calorigenic action. They
`produce a prompt rise in the metabolic rate which is
`independent of the liver and a smaller, delayed rise
`which is abolished by hepatectomy and coincides with
`the rise in blood lactic acid. The calorigenic action
`does not occur in the absence of the thyroid and the
`adrenal cortex. The cause of the initial rise in meta-
`bolic rate is not clearly understood. It may be due to
`cutaneous vasoconstriction, which decreases heat loss
`and leads to a rise in body temperature, or to increased
`muscular activity, or to both. The second rise is proba-
`bly due to oxidation of lactic acid in the liver.
`On the basis of their differential sensitivity to
`drugs, the effects of epinephrine and norepinephrine
`have been divided into 2 groups. Those in one group
`are brought about by catecholamines interacting with oz
`receptors in the effector organs, whereas those in the
`other group are brought about by catecholarnines in-
`teracting with B receptors (see Chapter 13 and Table
`13- 1). Drugs that are a blockers inhibit actions such as
`the pressor effects of the catecholamines. Drugs that
`are [3 blockers generally inhibit actions such as the
`chronotropic and inotropic effects of catecholamines
`on the heart and their glycogenolytic and free fatty .
`acid—mobilizing effects. B-Mediated effects are due to
`stimulation of adenylate cyclase, with resultant in-
`creased formation of cyclic AMP (see Chapter 17).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TotalperipheralArterialBPresistance
`
`(mmHg)
`
`rate
`
`Carfilf/Cm‘3i:Sp”tHeart
`
`Time (min)
`Epi = Epinephrine Nor = Norepinephrine
`
`
`
`
`
`
`
`Figure 20-5. Circulatory changes produced in humans by the
`slow intravenous infusion of epinephrine and norepinephrine.
`(Modified and reproduced, with permission, from Barcroft H,
`Swan HJC: Sytnpatlzeric Control of Human Blood Vessels. Ar-
`nold, 1953.)
`
`REGULATION OF ADRENAL
`MEDULLARY SECRETION
`
`Neural Control
`Certain drugs act directly on the adrenal medulla,
`but physiologic stimuli affect medullary secretion
`through the nervous system. Catecholamine secretion
`is low in basal states, but the secretion of epinephrine
`and, to a lesser extent, that of norepinephrine is re-
`duced even further during sleep.
`There is evidence that adrenal medullary secre-
`tion is increased when the “cholinergic sympathetic
`vasodilator” system discharges at the start of exercise,
`the increased epinephrine secretion reinforcing the
`vasodilatation produced by sympathetic vasodilator
`fibers to skeletal muscle (see Chapter 31).
`Increased adrenal medullary secretion is part of
`the diffuse adrenergic discharge provoked in emergen-
`cy situations, which Cannon called the “emergency
`function of the sympathoadrenal system. ” The ways in
`which this discharge prepares the individual for flight
`or fight are described in Chapter 13. It is worth men-
`tioning, however, that when adrenal medullary hor-
`mones are injected into control animals in the amounts
`secreted in response to splanchnic nerve stimulation,
`they exert effects on the musculature of the skin, kid-
`neys, and spleen that are only 10-20% as great as the
`effects produced by comparable stimulation of the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`WCK1033
`Page 4
`
`

`
`Chapter 20. The Adrenal Medulla & Adrenal Cortex
`
`281
`
`almost
`
`ig activ-
`un. They
`which is
`
`yed rise
`des with
`c action
`and the
`in meta-
`ve due to
`heat loss
`ncreased
`
`is proba-
`er.
`
`itivity to
`nephrine
`ne group
`ig with oz
`SC in the
`nines in-
`nd Table
`is such as
`
`rugs that
`:h as the
`olarnines
`free fatty
`are due to
`iltant in-
`>ter 17).
`
`l medulla,
`secretion
`secretion
`
`iinephrine
`line is re-
`
`ary secre-
`mpathetic
`f exercise ,
`ircing the
`asodilator
`
`is part of
`iemergen-
`zmergency
`he ways in
`l for flight
`/orth men-
`illary hor-
`ie amounts
`zimulation,
`: skin, kid-
`great as the
`ion of the
`
`sympathetic innervation of these structures. Thus, the
`action of secreted catecholamines in augmenting the
`effects of adrenergic nerve discharges on the vascular
`system is relatively slight.
`The metabolic effects of circulating catechola-
`mines are probably more important, especially in cer-
`tain
`situations. The
`calorigenic
`action of
`catecholamines in animals exposed to cold is an exam-
`ple. Animals with denervated adrenal glands shiver
`sooner and more vigorously than normal controls when
`exposed to cold. The glycogenolysis produced by epi-
`nephrine in hypoglycemic animals is another example.
`Hypoglycemia is a potent stimulus to catecholamine
`secretion, and insulin tolerance appears to be reduced
`when adrenal medullary secretion is blocked.
`
`Selective Secretion
`When adrenal medullary secretion is increased,
`the ratio of epinephrine to norepinephrine in the adre-
`nal effluent is generally unchanged or elevated. How-
`ever, asphyxia and hypoxia increase the ratio of nor-
`epinephrine to epinephrine. The fact that the output of
`norepinephrine can be increased selectively has unfor-
`tunately led to the teleologic speculation that the adre-
`nal medulla secretes epinephrine or norepinephrine
`depending upon which hormone best equips the animal
`to meet the emergency it faces.‘ The fallacy of such
`speculation is illustrated by the response to hemor-
`rhage,
`in which the predominant catecholamine se-
`creted is not norepinephrine but epinephrine, which
`lowers the peripheral resistance. Norepinephrine se-
`cretion is increased by emotional stresses with which
`the individual is familiar, whereas epinephrine secre-
`tion rises in situations in which the individual does not
`know what to expect.
`
`ADRENAL CORTEX
`
`STRUCTURE & BIOSYNTHESIS OF
`ADRENOCORTICAL HORMONES
`
`Classification & Structure
`The hormones of the adrenal cortex are deriva-
`tives of cholesterol. Like cholesterol, bile acids, vita-
`min D, and ovarian and testicular steroids, they con-
`tain the cyclopentanoperhydrophenanthrene nu-
`cleus (Fig 20-6). The adrenocortical steroids are of 2
`structural types (Fig 20—7): those that have a 2-carbon
`side chain attached at position 17 of the D ring and
`contain 21 carbon atoms (“C 21 steroids”), and those
`that have a keto or hydroxyl group at position 17 and
`contain 19 carbon atoms (“C 19 steroids”). Most of
`the C 19 steroids have a keto group at position 17 and
`are therefore called 17-ketosteroids. The C 21 steroids
`that have a hydroxyl group at the 17 position in addi-
`
`Figure 20-6. The cyclopentanoperhydrophenanthrene nu-
`cleus.
`
`tion to the side chain are often called 17-hydroxycorti—
`coids or 17-hydroxycorticosteroids.
`The C 19 steroids have androgenic activity. The C
`21 steroids are classified, using Selye’s terminology,
`as mineralocorticoids or glucocorticoids. All secreted
`C 21 steroids have both mineralocorticoid and
`glucocorticoid activity; mineralocorticoids are those
`in which effects on Na+ and K+ excretion predomi-
`nate, and glucocorticoids those in which effects on
`glucose and protein metabolism predominate.
`
`Steroid Nomenclature & Isomerism
`For the sake of simplicity, the steroid names used
`here and in Chapter 23 are the most commonly used
`trivial names. A few common synonyms are shown in
`Table 20-2. The details of steroid nomenclature and
`
`
`
`“C 21“ steroid (progcstcronv)
`O
`
`HO
`
`“C 19" steroid (clchydrocpizmdrostcronc1
`
`Figure 20-7. Structure of adrenocortical steroids. The letters in
`the formula for progesterone identify the A, B, C, and D rings; the
`numbers show the positions in the basic C 21 steroid structure.
`The angular methyl groups (positions 18 and 19) are usually
`indicated simply by straight lines. as in the lower formula. De-
`hydroepiandrosterone is a "17-ketosteroid" formed by cleavage
`of the side chain of the C 21 steroid 17-liydroxypregnenolone and
`its replacement by an O atom. Similar conversion of other C 21
`steroids to 17-ketosteroids occurs in the body.
`
`WCK1 033;
`Page
`
`
`
`WCK1033
`Page 5
`
`

`
`Chole
`
`Figure 20-
`ulosa. The 5
`the zona 1
`glomerulosz
`to aldostero
`OHDOC,
`l
`
`fects can
`creted in
`
`sterone, p
`rivatives 0
`The adren,
`gen, althol
`in the ovz
`adrenal ar
`secreted Ct
`all of the o
`
`jugated fo.
`The s
`determine<
`
`cally label
`which the
`
`diluted by '
`used to In
`mones.
`
`Species Di
`In all 5
`C 21 steroi
`sue appear
`terone, altl
`varies. Bir
`
`WCK1033
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`282
`
`Section IV. Endocrinology & Metabolism
`
`isomerism can be found in the texts listed in the refer-
`ences, but it is pertinent to mention that the Greek letter
`A indicates a double bond and that the groups which lie
`above the plane of each of the steroid rings are indi-
`cated by the Greek letter ,8 and a solid line (-OH),
`whereas those which lie below are indicated by a and a
`dotted line (---OH). Thus, the C 21 steroids secreted by
`the adrenal have a A4-3-keto configuration in the A
`ring. In most naturally occurring adrenal steroids, 17-
`hydroxy groups are in the CY configuration, while 3-,
`11-, and 21-hydroxy groups are in the ,8 configuration.
`The 18-aldehyde configuration on naturally occurring
`aldosterone is the D—fonn. L-Aldosterone is physiologi-
`cally inactive.
`
`Secreted Steroids
`Innumerable steroids have been isolated from ad-
`renal tissue, but the only steroids normally secreted in
`physiologically significant amounts are the mineralo-
`corticoid aldosterone,
`the glucocorticoids cortisol
`and corticosterone, and the androgen dehydr0epian-
`drosterone. The structures of these steroids are shown
`in Figs 20-8 and 20-9. Deoxycorticosterone is a
`mineralocorticoid that is normally secreted in about the
`same amount as aldosterone (Table 20-2) but has only
`3% of the mineralocorticoid activity of aldosterone. Its
`effect on mineral metabolism is usually negligible, but
`in diseases in which its secretion is increased, its ef-
`
`Table 20-2. Principal adrenocortical hormones
`in adult humans.
`___:.._._:_._____.___._:____._
`
`
`Average
`Average
`
`Amount
`Plasma Con-
`
`Secreted
`centration
`(mg/24 11)
`(Free and Bound)
`
`
`SynonymsName (pg/dl)
`20
` Compound F,
`
`hydrocor-
`tisone
`Compound B Corticosterone
`
`0.15
`Aldosterone
`Deoxycortico-
`0.20
`sterone
`
`
`
`
`
`Dehydroepian-
`drosterone
`
`15 (males)
`10 (females)
`
`*All plasma concentration values except DEA are morning
`values after overnight recumbency. (Data partly from Oddie
`CJ, Coghlan JP, Scoggins BA: Plasma desoxycorticosterone
`levels in man with simultaneous measurement of aldosterone,
`corticosterone, cortisol, and ll-deoxycortisol. J Clin Endo-
`crinol Metab 34: 1039, 1972.)
`
`Acetate
`/ (‘W3
`Cho|g5f3fo|
`0-O
`
`I7£- Hydroxylase
`
`NADpH_oa
`
`IIIHI
`
`llllllll
`
`Prognunokmu
`
`|7- Hydwxy prnqnenolono
`
`Dohydmoplundmntnrone
`
`
`
`
`H0/
`3 fi—Dehydrogenasa'//
`A5.A4lsomerase Q////////////////fl
`NAo*
`
`C
`,”3
`/////////////,<|5'° ’//////////////////////////
`I
`
`
`Ho/
`CH
`. 3
`//////////////. ‘l‘:'° ’//////////////////////////
`I
`"°”
`......._.._.:_..
`
`//////,
`‘I’.
`|
`
`A4-Androlienr
`3,17-dlonu
`
`I
`
`
`
`Testosterone
`
`Emmol
`
`Pmoutoronc
`
`:Hg0H
`so
`,
`
`I
`
`O4
`
`I7-Hydroxyproqutuano
`
`0/
`
`$H20H
`*0
`$___oH
`
`
`
`
`ll-Deoxycorllcosiaronu
`
`Q»?
`
`l|—Doa:ycortlsol
`
`lwzofi
`920”
`\\\\\\\\\\\\\\\\\\\<I3'0.\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\
`\\\\\\\\\\\\\\\\\\“l7:°
`"OH
`HO\
`I
`|
`
`
`_
`2! fl-Hydroxylase E
`_
`NADPH, 02
`E
`
`|
`
`‘
`
`0’
`
`of
`
`ll
`
`I
`H d
`3'
`y m” use
`NADPH'O2
`
`\
`\\\\\\\\\\\\\\\\\\\\\\\\\\\
`h
`
`
`
`
`
`
`
`
`
`
`
`
`
`Corllcoflernne
`
`
`
`Figure 20-8. Outline of hormone biosynthesis in the zona fasciculata and zona reticularis of the adrenal cortex. The major secretory
`products are underlined. The enzymes and cofactors for the reactions progressing down each column are shown on the left and from the
`first to the second column at the top of the chart. When a particular enzyme is deficient, hormone production is blocked at the points
`indicated by the shaded bars.
`
`
`
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`Page 6
`
`

`
` zhe refer-
`
`Chapter 20. The Adrenal Medulla & Adrenal Cortex
`
`283
`
`Acetate
`
`/
`Cholesterol
`
`\ Pregnenolone
`
`Progesterone
`
`Table 20-3. Relative potencies of corticosteroids compared to
`cortisol. Values are approximations based on liver glycogen de-
`position or anti-inflammatory assays for glucocorticoid activity,
`and effect on urinary Na"/K* or maintenance of adrenalecto-
`mized animals for mineralocorticoid activity. The last 3 steroids
`listed are synthetic compounds that do not occur naturally.
`(Data from various sources.)
`
` Glucocorticoid }Mine1-alocorticoid
`
`Cortisol
`Corticosterone
`Aldosterone
`De oxycorticosterone
`Cortisone
`Pre dnisolone
`90.-Fluorocortisol
`Dexamethasone
`
`Activity
`1.0
`0.3
`0.3
`0.2
`0.7
`4
`10
`25
`
`Activity
`1.0
`15
`3000
`100
`1.0
`0.8
`125
`~ 0.
`
`almost exclusively; dogs secrete approximately equal
`amounts of the 2 glucocorticoids; and cats, sheep,
`monkeys, and humans secrete predominantly cortisol.
`In humans, the ratio of secreted cortisol/corticosterone
`is approximately 7.
`
`Synthetic Steroids
`The glucocorticoids are among the increasing
`number of naturally occurring substances that chemists
`have been able to improve upon. A number of syn-
`thetic steroids are now available that have many times
`the activity of cortisol. The relative glucocorticoid and
`mineralocorticoid potencies of the natural steroids are
`compared to those of the synthetic steroids 9a-
`fluorocortisol, prednisolone, and dexamethasone in
`Table 20-3. The potency of dexamethasone is due to
`its high affinity for glucocorticoid receptors and its
`long half-life (see below). Prednisolone also has a long
`half-life.
`
`Steroid Biosynthesis
`The major paths by which the naturally occurring
`adrenocortical hormones are synthesized in the body
`are summarized in Figs 20-8 and 20-9. The major
`precursor of cortisol
`is 17oz-hydroxypregnenolone,
`and the major precursor of corticosterone and aldoste-
`rone is pregnenolone. The secreted steroids are synthe-
`sized by formation of the A“-3-keto configuration in
`the A ring and then hydroxylation in the 21 and,
`finally, the 11 position. Some of these reactions occur
`in the smooth endoplasmic reticulum and others in
`mitochondria (Fig 20—lO). Aldosterone is formed by
`replacement of the angular methyl group in position 18
`of corticosterone with an aldehyde group. Androgens
`are formed by side chain cleavage to form dehydroepi-
`androsterone and its derivatives, and estrogens are
`formed from androgens.
`
`Action of ACTH
`ACTH acts via adenylate cyclase and a protein
`kinase to increase the amount of free cholesterol that
`
`WCK1033
`Page 7 j
`
`
`
`Deo><\/corticosterone———l
`
`Corticosterone
`
`l8—OHDOC
`
`l8~Hydrox\/corticosterone<———i
`1
`(‘H,OH
`
`I
`
`=0
`
`HO
`
`CHO
`
`Aldosterone
`
`/
`o ’
`
`Figure 20-9. Outline of hormone synthesis in the zona glomer-
`ulosa. The steps from acetate to corticosterone are the same as in
`the zona fasciculata and reticularis. However,
`the zona
`glomerulosa contains the enzymes for converting corticosterone
`to aldosterone, whereas it lacks 17a-hydroxylase activity. 18-
`OHDOC, l8-hydroxydeoxycorticosterone.
`
`fects can be appreciable. Other steroids that are se-
`creted in small amounts include l8-hydroxycortico-
`sterone, pregnenolone, progesterone, some of the de-
`rivatives of dehydroepiandrosterone, and testosterone.
`The adrenals may also secrete small amounts of estro-
`gen, although most of the estrogens that are not formed
`in the ovaries are produced in the circulation from
`adrenal androstenedione. Dehydroepiandrosterone is
`secreted conjugated with sulfate, although most if not
`all of the other steroids are secreted in the free, uncon-
`jugated form.
`The secretion rate for individual steroids can be
`determined by injecting a very small dose of isotopi-
`cally labeled steroid and determining the degree to
`which the radioactive steroid excreted in the urine is
`diluted by unlabeled secreted hormone. This technic is
`used to measure the output of many different hor-
`mones.
`
`Species Differences
`In all species from amphibia to humans, the major
`C 21 steroid hormones secreted by adrenocortical tis-
`sue appear to be aldosterone, cortisol, and corticos-
`terone, although the ratio of cortisol to corticosterone
`varies. Birds, mice, and rats secrete corticosterone
`
`eek letter
`which lie
`are indi-
`
`9
`:
`y or and a
`creted by
`in the A
`oids, 17-
`while 3-,
`guration.
`)ccurring
`ysiologi-
`
`from ad-
`:CI‘Bt€d in
`nineralo-
`cortisol
`
`roepian-
`re shown
`one is a
`about the
`
`.has only
`srone. Its
`
`gible, but
`d, its ef-
`
`3 a
`
`plundrostorone
`
`1I
`
`mstane -
`I7-dlona
`
`)1‘ secretory
`nd from the
`t the points
`
`WCK1033
`Page 7
`
`

`
`284
`
`Section IV. Endocrinology & Metabolism
`
`ATP
`
`ACTH-->
`
`C‘
`
`Cyclic _.._. protein
`
`Active
`
`AT}: 4. protein
`
`Lipid
`droplet
`/*3
`
`Cholesterol
`
`8516-VS
`
`|—,-_Hydmxy_
`progesterone <———-——- Progesterone
`
`ll-Deoxycortisol
`
`g. Pregnenolone
`
`Protein
`
`Mitochondrion
`
`Figure 20-10. Mechanism of‘ action of ACTH on cortisol-secreting cells of the adrenal cortex. AC, adenylate cyclase; R, receptor.
`
`enters mitochondria and is converted to pregnenolone.
`The reactions involved are summarized in Fig 20-10.
`The cyclic AMP also acts in some way to increase the
`synthesis of, or possibly to phosphorylate, a protein
`that increases the conversion of cholesterol to preg-
`nenolone. ACTH acts in a similar fashion on the cells
`in the zona glomerulosa that secrete aldosterone, but
`angiotensin II and K+ stimulate aldosterone secretion
`without affecting cyclic AMP.
`
`Enzyme Deficiencies
`The consequences of inhibiting any of the enzyme
`systems involved in steroid biosynthesis can be pre-
`dicted from Figs 20-8 and 20—9. Single enzyme de-
`fects can occur as congenital “inbom errors of metabo-
`lism ” or can be produced by drugs. Congenital block-
`ade of the formation of pregnenolone causes the syn-
`drome of congenital adrenal hyperplasia. The hy-
`perplasia is due to increased ACTH secretion. The
`disease is severe, with diffuse adrenal insufficiency
`and death soon after birth. Androgen formation is
`blocked, and female genitalia develop regardless of
`genetic sex (see Chapter 23). Congenital 3/3—dehydro—
`genase, 21,8-hydroxylase, and 11,8-hydroxylase defi-
`ciency all cause congenital adrenal hyperplasia as-
`sociated with virilization. In this condition, glucocor-
`ticoid secretion is deficient, and ACTH secretion is
`consequently stimulated. The steroid intermediates
`that pile up behind the block are converted via the
`remaining unblocked pathways to androgens. In 3,8-
`dehydrogenase deficiency,
`the glucocorticoid and
`mineralocorticoid deficiency is usually fatal. 21B-
`Hydroxylase deficiency is usually incomplete, s