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    James F. Head

    The Adrenal Gland

    The goal of these lectures is to provide you with an understanding of how theadrenal gland functions in producing a range of hormones to regulate a number of

    homeostatic mechanisms. In the lectures, the major focus is on the nature of thevarious hormones, how and where they are produced, how their production is

    regulated, how they are transported in the blood, what they do and where, and how are

    they degraded. Some aspects of disease states associated with hypo or hyper-secretionand their consequences will be touched on in lecture and considered more in the

    discussion session. These considerations of pathological conditions, as previously in

    the course, are not intended to provide a detailed view into disease and treatment, but

    are primarily intended to emphasize the significance of the underlying control

    processes and the functional roles of the hormones.

    N.B. You are not asked to memorize the details of the molecular structures of

    any of the adrenal hormones or intermediates, only their general structural

    characteristics.

    Objectives.

    Describe location, structure and organization of adrenal gland Indicate how the general structure of cortical hormones dictates their physical

    characteristics, and how these dictate many functional characteristics.

    Describe the synthesis, transportation and mode of action of the corticalhormones

    Compare the regulation, transportation and effects of glucocorticoids,mineralocorticoids and adrenal androgens.

    Relate the functions of mineralocorticoids and glucocorticoids to the symptomsand signs of excesses and deficits in these hormones.

    Describe the synthesis and metabolism of adrenal catecholamines. Describe regulation of secretion, transportation and modes of action ofcatecholamines.Background

    The adrenals are a pair of glands weighing a total of about 10g, which are

    located one near each kidney.

    Fig 1. Diagram of sectionthrough adrenal gland showing

    layers and products.

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    Each adrenal is in fact two glands in one, the outer adrenal cortex that produces

    steroid hormones and the inner adrenal medulla that produces epinephrine and

    norepinephrine. The cortex (usually about 90% of mass of adrenal) and medulla are

    morphologically and embryologically distinct, and have distinct products and

    regulation.

    The adrenal is richly vascularized with arterial blood flow to both the cortex

    and medulla. Blood flowing through the cortex drains into medullary capillarysinusoids, hence part of the blood supply to the medulla is rich in cortical hormones.

    The cortex is itself stratified into three identifiable layers: the zona

    glomerulosa, which principally produces aldosterone, the zona fasciculata which

    produces mainly cortisol and the zona reticularis which produces cortisol and the

    androgens dehydroepiandosterone and androstenedione.

    Loss of the adrenal cortex by disease or surgery results in death within 1-2

    weeks, unless replacement treatment is instituted. Almost every organ system isaffected under these circumstances, although the most likely cause of death is

    circulatory collapse resulting from sodium depletion. If caloric intake is limited, death

    may result from hypoglycemia. Based on their ability to protect against these causes ofdeath, the adrenocortical hormones have generally been divided into

    mineralocorticoids and glucocorticoids. The prime mineralocorticoid is aldosterone,

    which is required for normal maintenance of sodium and potassium balance. The

    principal glucocorticoid is cortisol, which is involved in maintaining carbohydrate

    reserves as well as various other functions. The adrenal androgens have effects similar

    to (but weaker than) those of the male testicular hormones (T, DHT), and appear to be

    of importance in both sexes in mediating some of the changes occurring in puberty.

    The fetal adrenal is relatively bigger, for body size, than that of the adult, with alarge steroidogenic fetal zone. The role of the fetal adrenal will be discussed briefly

    below and more fully during the reproductive endocrinology section.

    The adrenal medulla arises embryologically from neuroectoderm and is

    innervated by neurons whose cell bodies reside in the spinal cord. Axons from thesecells pass through the paravertebral sympathetic ganglia to form the splanchnic nerves.

    The medulla stores about 5-6 mgs of the catecholamines epinephrine andnorepinephrine in secretory granules within the so-called chromaffin cells. Although

    the products of the adrenal medulla affect most tissues of the body, humans can survivewithout it so long as the rest of the sympathetic system is functional.

    Adrenocorticoids

    Overview.

    All adrenal cortical hormones derive from cholesterol. The specific product of a

    given cell depends on the enzymic complement of the cell and the responsiveness to

    different stimuli. The rate-limiting step in synthesis is the first, from cholesterol to

    pregnenolone, which is common to all members of this class of hormone (See Fig. 2). It

    is this step that is regulated by stimulating factors. The stimulatory factors (discussed

    below) promote the production of steroid acute regulatory protein (StAR) which

    stimulates the transport of cholesterol from the cytosol into the mitochondria where it

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    can be acted on by the first enzyme in the initial common pathway to yield

    pregnenolone.

    Although mineralocorticoid activity is predominantly associated with

    aldosterone and glucocorticoid activity with cortisol, high levels of each will produce

    the alternate effect. While cortisol has ten times the glucocorticoid effect of

    aldosterone, it normally has less than 0.25% of the mineralocorticoid effect. (Cortisol

    can readily bind to and activate the mineralocorticoid receptor protein, see below, but

    mineralocorticoid sensitive tissues contain an enzyme, type II 11-hydroxysteroid

    dehydrogenase, that converts cortisol to cortisone, greatly reducing its

    mineralocorticoid effects).

    Figure 2. Steroid hormone production in the adrenal cortex.

    The major steroid products of the adrenal cortex are shown in capitals.The steps inthe pathways, indicated by numbers, are catalyzed by the following enzymes: 1=20,22-desmolase, 2&7=17-

    hydroxylase, 3&8=17,20-desmolase, 4,5&6=3-hydroxysteroid dehydrogenase, 9&10=21-hydroxylase,

    11=17-hydroxysteroid dehydrogenase, 12&13=11-hydroxylase, 14=18-hydroxylase, 15=18-hydroxysteroiddehydrogenase. For this course you do not need to memorize these structures nor the enzyme names.

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    The secretion of steroids represents de novo synthesis, since the steroid

    hormones, unlike the catecholamines of the medulla, cannot be adequately stored. Being

    lipid soluble, they can simply diffuse across the membranes of the producing cells down

    their concentration gradient, to enter the circulation. Normally humans secrete about

    20mg of cortisol, 0.25mg of aldosterone and (in a young adult) 10-20mg DHEA per day,

    although this number can be increased many fold under prolonged stimulation.

    Once in the circulation, most of the steroids are bound to plasma bindingproteins, transcortin or corticosteroid binding globulin (CBG) and plasma albumin. Much

    of the adrenal androgens are modified by sulfation and travel mostly in that form boundto plasma albumin. Because binding of glucocorticoids is favored over aldosterone, about

    95% of the glucocorticoids are bound as opposed to about 60% of the aldosterone. Thistighter binding contributes to a longer half-life for corticosteroids in the plasma (about

    90 minutes for cortisol versus 30 minutes for aldosterone). The more stable DHEAS has a

    half life of 10-20hrs and its total plasma concentration therefore often exceeds that of theother adrenal steroids (in young adults). Clearance of the hormones is largely by renal

    and hepatic mechanisms.

    Free steroid hormones enter cells by passive diffusion and bind to cytoplasmicreceptor proteins (figure 3). They subsequently act on their targets mostly through

    effects at the nucleus. This is distinct from peptide and amine hormones which act via

    plasma membrane receptors. In the cytosol, mineralocorticoids bind preferentially to so-

    called type I receptors which are found in greatest amounts in the kidney, colon, sweat

    and salivary glands. Glucocorticoids bind preferentially to type II receptors found in

    various tissues of the body (as noted above, cortisol CAN bind to the type I receptor, but

    is usually intercepted in mineralocorticoid-sensitive tissues and enzymically inactivated).

    Figure 3. Generalized mechanism of action of steroid hormones.

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    Regulation of cortisol and adrenal androgen production by adrenocorticotropic

    hormone, ACTH.

    ACTH is derived in the pituitary from a prohormone, pro-opiomelanocortin

    POMC. It is required for normal function of the zona fasciculata and reticularis. In the

    absence of ACTH, these regions atrophy. ACTH can bind to specific receptors on the

    cells of all three layers of the adrenal cortex. In the zona glomerulosa it may have aminor role in influencing the production of aldosterone, although the prime regulator

    in this layer is angiotensin II (see below). For cortisol and androgen synthesis, thecirculating level of ACTH is the controlling factor, although the necessary enzymes for

    DHEA production are primarily located in the zona reticularis. On binding of ACTH tothe receptor there is a rise in intracellular c-AMP level that leads to the production of

    StAR protein, entry of cholesterol into the mitochondria and there the conversion of

    cholesterol to pregnenolone. Stimulation by ACTH leads to a rise in steroid hormone

    secretion within 1-2 minutes, peaking by about 15 minutes.

    The production of ACTH is under the control of corticotrophin releasing hormone

    (CRH) from the hypothalamus. The secretion of CRH by the hypothalamus, and henceACTH by the pituitary, follows a circadian rhythm, giving a peak rate of ACTH secretion in

    the early morning, before waking, followed by a steady decline through to the evening

    hours. Cortisol secretion parallels the changes in ACTH. Although both CRH and ACTHsecretion is subject to feedback inhibition by cortisol, the circadian rhythm appears to be

    the result of changes in the sensitivity of the CRH secreting cells to cortisol. Low

    sensitivity to cortisol in the morning hours results in less negative feedback, permitting

    higher rates of CRH secretion, resulting in a higher basal ACTH production and hence a

    rise in cortisol secretion. Increasing sensitivity during the course of the day leads to a

    decline in CRH, ACTH and hence cortisol levels. Stressful stimuli lead to increases in CRH

    secretion, by neural pathways, over-riding the diurnal rhythm. Chronic stress will lead tothe establishment of a new steady state production of ACTH and cortisol.

    Cortisol function

    Although many of the hormones of the adrenal gland are associated withstresses of one kind or another, cortisol has become popularly known as the "stress"

    hormone. In general terms, it is necessary to maintain vital functions during periods ofprolonged stress (usually physiological stress, but psychological stress can also be

    included) and to contain the inflammatory response. The functions of cortisol arediverse including many that are permissive. i.e. the hormone does not itself initiate

    changes but is required for the changes to be expressed fully. In particular, cortisol isrequired for catecholamines to be effective and it is the increased responsiveness to

    catecholamines which is responsible for a number of the effects of cortisol. With

    cortisol deficit, a decrease in cardiovascular responsiveness to catecholamines and

    reduced mobilization of fuel stores may account for observed increased vulnerability to

    "stress" and, conversely, an increase in cortisol, normally stimulated by "stress", is

    protective.

    Table 1 summarizes some of the effects of INCREASING levels of cortisol. This is

    followed by more detailed considerations of some of these effects.

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    Elevation of cortisol levels leads to:

    Increased blood glucose.

    As implicit in the term "glucocorticoid", increased cortisol leads to elevations of

    plasma glucose, largely by mechanisms which oppose insulin. These are summarized

    below and in Figure 4.

    Promotes catabolism.

    Facilitates the breakdown of protein from muscle and connective tissue to

    liberate amino acids used in gluconeogenesis. Stimulates production of gluconeogenicenzymes in liver.

    Decreases glucose utilization.

    Inhibits glucose transport into cells (but not in the brain).

    Decreases protein synthesis.

    Reduces rates of protein synthesis everywhere except in liver. Reduced rates ofsynthesis are at least in part because cortisol reduces the uptake of amino acids into

    muscle cells. With increased protein breakdown and reduced amino acid uptake,plasma amino acid levels rise.

    Alters fat metabolism.

    Increases rate of breakdown of peripheral fat to liberate fatty acids and glycerol

    for gluconeogenesis.

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    HOWEVER, increases central fat deposition i.e. on trunk and face. Hence in

    cortisol excess the limbs lose fat and muscle mass while the trunk and face become

    fatter. The basis for these redistributions of fat appear to be related to different

    receptor responsivities to cortisol in different adipose tissues.

    Figure 4. Effects of increased cortisol leading to elevated plasma glucose.

    Other functions of cortisol include:

    CNS effects.

    Feedback inhibition of CRH and ACTH production.

    May also affect perception. In cortisol deficiency taste hearing and smell arefrequently accentuated.

    Cortisol excess is associated with an initial euphoria followed by depression.

    Cardiovascular effects: Maintenance of circulatory system.

    Cortisol is required to maintain sensitivity to epinephrine and norepinephrine

    in the vasculature. In the absence of cortisol there is widespread vasodilation and fall inblood pressure.

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    Developmental effects.

    Permissive role in maturation of many fetal organ systems, intestinal enzymes

    and pulmonary surfactant. (Administration of corticosteroids during late pregnancy, if

    there is an anticipated premature birth, can be protective against respiratory distress

    syndrome).

    Renal effects: Free water clearance.

    In the absence of cortisol a patient is unable to produce a hypotonic urine and is

    therefore unable to eliminate free water. This can result in water intoxication. Inaddition to a fall in glomerular filtration, subsequent to falling blood pressure, ADH

    secretion is not depressed by hypo-osmolarity when cortisol is very low. There appears

    to be a functional relationship between ADH and CRH, such that ADH also appears to be

    able to promote ACTH production. The interplay between ADH and cortisol levels may

    therefore be complex.

    Bone effects: Promotes bone breakdown.

    In cortisol excess, osteoclastic activity is enhanced, hence promoting the

    development of osteoporosis.

    Immune function: Containing inflammatory response.

    In high doses, cortisol suppresses many of the bodys inflammatory responses

    and this function is harnessed pharmacologically with the use of synthetic

    glucocorticoids. The effects may be beneficial, such as in the reduction of swelling or

    tissue damage caused by inflammation (such as in rheumatoid arthritis), but may beharmful, such as allowing resurgence of a latent tubercular infection.

    Cortisol achieves its anti-inflammatory effects through many mechanisms,including: stabilizing lysosomal membranes (preventing release of degradative

    enzymes), decrease in capillary permeability (reducing entry of fluid and white cells

    into the inflamed area), depressing activity of phagocytes, suppression of synthesis ofinterleukin-1, inhibition of production of eicosanoids. By depressing antigen/antibody

    induced release of histamine from mast cells in the lung, it can also act to reduceallergic responses.

    Other issues:

    Consequences of pharmacological administration of glucocorticoids.

    Prolonged administration of pharmacological glucocorticoids leads to feedback

    inhibition of ACTH production, atrophying of dependent adrenal cells (zona fasciculata and

    reticularis) and hence reduced ability to generate cortisol. Withdrawal from long termglucocorticoid treatment must therefore be gradual to permit recovery of the patient's own

    cortisol generating system.

    Elimination of cortisol from the body

    Free cortisol in the plasma can be filtered in the glomerulus and appears in the

    urine. Cortisol is also enzymically reduced, mostly in the liver, to tetrahydrocortisol

    and conjugated with glucuronic acid which is also filtered at the kidney and excreted in

    the urine as glucuronide metabolites.

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    Adrenal androgens

    Adrenal androgens are produced in large quantities in the fetus and are very

    important during fetal development. This will be discussed more during considerations

    of reproductive endocrinology. Postnatally, adrenal androgen production is low but

    rises during the prepubertal period (adrenarche) and appears to contribute to eventsnormally preceding puberty, including the onset of axillary and pubic hair growth and

    growth and secretion from axillary sebaceous glands. In adult females the adrenals area major source of androgens and, after conversion into testosterone in the periphery,

    contribute to the stimulation of axilliary and pubic hair growth. Some androstenedioneis also converted in the periphery to estrogen. This appears to be the major source of

    estrogen in post-menopausal women whose ovaries are no longer active. There is some

    evidence that DHEA levels may have an influence on libido in women. In adult males,

    the androgenic contribution of the DHEA is insignificant in comparison to the powerful

    androgen testosterone, produced in the testes, and dihydrotestosterone produced fromtestosterone in the testes and peripherally. The levels of DHEA production are close to

    those of cortisol in a young adult, but decline with age. The functional role of DHEA inadults remains poorly understood, although various studies have attributed a range of

    functions. The decline with age has been used as the basis for an "industry" of dietary

    DHEA supplementation aimed at reversing the effects of aging. Consistent scientificevidence on the benefits of such supplementation remains lacking.

    Adrenal androgen production is mainly under the control of ACTH, although

    age-dependent changes in androgen production in the face of similar levels of ACTH,

    suggest other factors also have an influence.

    Free DHEA-S in plasma is filtered in the kidney and excreted in the urine mostlyas the sulfated form.

    Aldosterone function.

    As discussed in Renal Physiology, the primary function of aldosterone is to increasesodium reabsorption in the distal nephron, with important consequences for potassium

    levels. Its production is principally under the control of angiotensin II and of plasmapotassium, and ACTH to a lesser extent. In its absence, the body's fluid and electrolyte

    status is altered, although if sufficient cortisol is present, the mineralocorticiod effectsof this hormone may become sufficient to prevent progressive fluid loss.

    As the prime regulator, angiotensin II is itself produced in response to rising levels

    of renin. Renin is a protease produced by the granular cells of the juxtaglomerular apparatus.

    It cleaves circulating angiotensinogen to produce angiotensin I, which is rapidly converted

    into angiotensin II by converting enzyme in the lung and elsewhere (including intrarenally).

    Renin release is increased by a fall in the perfusion pressure at the afferent arterioles or by

    sympathetic stimulation via the renal nerve.

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    Fig 5. Regulation of aldosterone production

    Other factors influencing renin release include the sodium and chloride

    concentration of the tubular fluid passing through the macula densa, plasma electrolyte

    levels and, through a feedback loop, angiotensin II. Angiotensin II stimulates production

    of aldosterone by the cells of the zona glomerulosa via a receptor mediated rise in inositol

    1,4,5 trisphosphate, which leads to an increased StaR protein, entry of cholesterol into themitochondria, conversion of cholesterol to pregnenolone and hence entry into the

    synthetic pathway.

    It is notable that aldosterone levels are also increased by elevated estrogen, as

    during pregnancy. This follows an estrogen-stimulated increase in hepatic synthesis of

    angiotensinogen. Any renin in the circulation then leads to an enhanced production of

    AGII and thus aldosterone. The consequence of this is an expanded extracellular fluid

    volume.

    As discussed in Physiology, aldosterone acts to increase the activity of the

    Na/K ATPase in the basolateral membrane of target cells, in part by increasing the

    rate of entry of sodium on the luminal surface through added sodium channels.

    These effects are the result of modifications of expression of proteins at the DNA

    level. The changes may include increased synthesis of the basolateral ATPase and ofthe luminal membrane sodium channel, although increase in pump activity is also

    believed to be associated with increased ATP levels, possibly resulting fromincreased rates of production of some mitochondrial enzymes. (Other effects of

    aldosterone in the kidney and elsewhere, including possible non-genomic effects,

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    have been reported but remain under study. Since the mechanisms of action leading

    to some of these effects remain tentative, we will not discuss them at this time).

    In addition to the distal nephron, mineralocorticoid receptors are also found

    in other tissues where sodium is excreted, e.g. in the sweat and salivary glands and

    colon. Hyperaldosteronism results in sweat and saliva which are essentially sodium

    free.

    Adrenal medulla Catecholamines

    The cells of the medulla are modified postganglionic neurons. Innervation is

    via the splanchnic nerves. The medulla cells contain numerous secretory granules

    and stain with chromium; hence they have been given the name chromaffin cells.

    The chromaffin granules contain stored catecholamines, normally in the

    ratio of about 5:1 epinephrine to norepinephrine. ATP is also present in the granules

    in a ratio of about 1 ATP to 4 catecholamine molecules. Some peptide hormones,including enkephalin, -endorphin and precursors are also present in small

    amounts, although their functional significance is unclear.Biosynthesis of catecholamines in the medulla is from tyrosine leading to the

    formation of norepinephrine which is mostly converted to epinephrine (Figure 6).

    The enzyme which catalyzes the conversion of norepinephrine to epinephrine(phenylethanolamine-N-methyltransferase, PNMT) is inducible by cortisol. The

    arrangement of the medulla within the cortical layer, receiving blood rich in

    corticosteroids, may therefore have functional significance. In this case, it could be

    modulating or fine-tuning the ratio of epinephrine:norepinephrine released fromthe medulla such that elevated cortisol will increase the proportion of epinephrine.

    The contents of the granules are secreted in response to sympathetic

    cholinergic stimulation. Binding of acetylcholine to the chromaffin cells leads to a

    rise in intracellular calcium levels which promote exocytosis.

    Once released into the circulation, about half of the catecholamines are free in

    solution and about half are loosely associated with albumin. The hormones arerapidly cleared from the circulation, having a half-life in the circulation of only about

    10-15 seconds. About 90% is cleared on a single pass through the microvasculature.

    The rapid response time of the medulla and the fast turn-over of catecholamines is

    in sharp contrast to the more slowly responding cortex and longer lasting effects ofthe corticosteroids. However, since the overall role of the adrenal is maintaining

    homeostasis in the face of internal and external stresses, the two sets of hormonesprovide for a full and complementary range of responses.

    Adrenal catecholamines may be taken up by both neuronal and non-neuronal

    tissue. Catecholamines taken up by neurons may be repackaged for reuse or may be

    degraded by the neuronal cytosolic enzyme monoamine oxidase (MAO). Elsewhere

    in the body the catecholamines are inactivated enzymically by both MAO andcatecholamine-O-methyl transferase. Products of degradation are normally coupledwith sulfate or glucuronic acid and excreted in the urine. As with corticosteroids, the

    measurement of urinary concentrations of degradation products is a non-invasiveway of monitoring circulating hormone levels.

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    Figure 6. Biosynthesis of epinephrine (E) and norepinephrine (N) in the adrenalmedulla cell. PNMT = phenylethanolamine-N-methyltransferase

    Most if not all of the epinephrine in the circulation is adrenal in origin,

    although much of the circulating norepinephrine arises by diffusion from

    sympathetic synapses elsewhere in the body.

    Function of adrenal medulla

    The effects of the catecholamines are widespread with most cells having

    receptors of some kind. The plasma membrane receptors were originallysubdivided into and classes, although these have now been further subdivided.

    The effects of epinephrine and norepinephrine differ mostly by their effects onand 2 receptors. They are equally effective in stimulating1 receptors.

    Norepinephrine is a potent agonist and has little effect on2 receptors.

    Epinephrine is an even more powerful agonist in many organs and is a powerful

    2 agonist. The roles of the catecholamines have been extensively dealt with inother courses. Some are summarized here in table 2. Further consideration of their

    effects, especially in energy metabolism will also be given in other lectures in this

    course.

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    Table 2