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The Adrenal Glands


									The Adrenal Glands

     Chapter 14
• The overall function of the adrenal glands is
  to deal with chronic and acute stress
• It is involved in both the fight-or-flight
  response of the sympathetic NS and in the
  generalized stress response (alarm reaction)
• Specifically, hormones produced by the
  adrenal glands are involved in protection
  against immediate injury or stress and in
  protection against prolonged food and water
• Both adrenocortical hypo- and hyperfunction are
  life threatening
• Cortisol (or increased glucocorticoid sensitivity) is
  thought to be involved in all effects of chronic stress
   •   Visceral obesity
   •   Hypertension
   •   Diabetes mellitus
   •   Dyslipidemia
   •   Depression
• The hypofunction of the adrenal medulla on the
  other hand is not associated with any syndromes,
  but hyperfunction is life threatening
• The paired adrenal glands are located just above
  each kidney
• They receive the highest rate of blood flow per
  gram than any other part of the body, receiving
  blood from branches of the aorta, from the renal
  arteries, and from the phrenic arteries
• Blood flows into the adrenals in the outer cortex,
  then into fenestrated capillaries, then into venules
  located in the medulla) allowing cortical hormones
  to influence the medullary secretion and production
  of catecholamines
• The adrenal cortex and the adrenal medulla
  are from two different embryological origins
• The cortex, the largest part of the gland, is
  derived from mesoderm and is anatomically
  and functionally composed of three layers
  • Zona glomerulosa - outer layer that produces
    and secretes mineralocorticoids as regulated by
    the renin-angiotensin system
  • Zona fasciculata - middle layer that produces
    and secretes cortisol as regulated by ACTH
  • Zona reticularis - inner layer that produces and
    secretes hydroepiandrostene (DHEA & DHEA-S)
• The medulla is derived from
  neuroectodermal cells from the neural crest
• The medulla produces and secretes
  • ~ 80% of secreted hormone is epinephrine
              Adrenal Cortex
• The three main groups of hormones
  produced by the adrenal cortex are
  • Glucocorticoids
    • Cortisol
    • Corticosterone
  • Mineralocorticoids
    • Aldosterone
    • Deoxycorticosterone
  • Androgens
    • DHEA
    • DHEA-S
    • Androstenedione
• Cortisol is the main glucocorticoid in most
  mammals, including humans
• Corticosterone is the main glucocorticoid in
  some rodents, including rats
• ACTH regulates glucocorticoid synthesis and
  • ACTH binds to the melanocortin 2 receptor
    (MCR-2) located in the plasma membrane
  • ACTH binding increases cAMP and activates
    protein kinase A
• Activation of protein kinase A leads to an increased
  conversion of cholesterol esters to free cholesterol
  which can then enter the steroidogenic pathway
• ACTH also activates StAR which increases the
  transport of cholesterol into the mitochondria
  • The overall effect of this is to increase conversion of
    cholesterol to pregnenolone which then increases
    production of cortisol
• These effects are seen within minutes of increased
  ACTH and by 30 minutes, the amount of cortisol is
  increased 2-5x
  • In chronic stress, the zona fasciculata will undergo
    hypertrophy/hyperplasia so that cortisol output can be 10-
    20x higher than normal
• Secretion of ACTH, and therefore of cortisol,
  shows a major burst around 8 am, followed
  by brief bursts 7-15 times throughout the rest
  of the day
• [Cortisol] rises enough following each burst to
  inhibit ACTH secretion
• [Cortisol] decreases between bursts so that
  CRH and ACTH secretion is stimulated
  (feedback inhibition is removed)
• Exogenous glucocorticoids are administered for a variety of
   • To control serious (potentially life threatening) inflammatory and
     immune responses
   • Acute adrenocortical hypofunction
   • Usually the doses given are supraphysiological
• High-dose therapy or chronic therapy that exceeds the 10-15 mg
  of cortisol normally secreted inhibits the hypothalamic-pituitary
• In prolonged ACTH (functional) withdrawal, the adrenals atrophy
  and show reduced or complete loss of function
• When glucocorticoid therapy is discontinued, there will be a time
  that function remains suppressed
• Eventually, ACTH secretion will return to normal, but because the
  cortex is unresponsive, ACTH levels will be elevated
• Eventually the cortex will respond normally (may take up to 1
• 75-80% of cortisol circulates bound to
  corticosteroid-binding globulin (CBG)
• The amount of CBG normally present is 3-4 mg/dl
  and is saturated with cortisol when [cortisol] reaches
  28 µg/dl
  • Any increase in [cortisol] above that increases the amount
    of free cortisol and therefore the effects of cortisol are
  • Estrogens increase CBG production in the liver
• 15-20% of cortisol circulates bound to albumin
• 5% is free cortisol
• In the circulation cortisol has a half-life of ~
  70-90 minutes
• Cortisol can be converted to cortisone (which
  is biological inactive) in the circulation
• Both cortisol and cortisone are metabolized
  in the liver to a more soluble form that is
  conjugated with glucuronides so that they
  can be excreted in the kidney
• Because they are steroids, glucocorticoids enter
  cells by passive diffusion
• The glucocorticoid receptor (GR) is localized to the
  cytoplasm and when GR binds to cortisol, the
  hormone-receptor complex (H-GR) moves into the
• Once in the nucleus the H-GR binds to specific DNA
  sequences known as glucocorticoid-responsive
  elements (GREs)
• The H-GR, along with recruited transcription factors,
  bound to a GRE alters transcription of the gene(s)
  with which the GRE is associated
• We know that cortisol is necessary for life, but
  we don’t know why
• We know that most of cortisol’s actions are
  permissive (cortisol has to be present for
  initiation of processes, but doesn’t directly
  activate them)
• Intermediary metabolism
  • Cortisol reduces the synthesis of new protein and
    causes the degradation of existing protein
    (skeletal muscle and CT) so that there is an
    increase in delivery of amino acids to the liver
    which uses the aas in gluconeogenesis
• Carbohydrate metabolism
  • Cortisol decreases the use of carbohydrate as a fuel source by
    decreasing glucose transport
  • Cortisol deficiency is associated with increased susceptability
    to and diminished recovery from hypoglycemia
  • Cortisol excess leads to insulin insensitivity and hyperglycemia
• Protein metabolism
  • Protein synthesis is inhibited and protein catabolism is
    stimulated esp in muscle and CT
  • This increases the aa pool in the blood for use by the liver in
  • Cortisol excess leads to tissue wasting esp in muscle, bone
    and skin, and calcium is absorbed less and excreted more
• Fat metabolism
  • Cortisol increases the mobilization of fatty acids
    and glycerol from adipose tissue
  • Therefore fat catabolism is increased, however,
    fat anabolism is also decreased
  • Excess cortisol causes a redistribution of existing
    fat, causing adipocytes in the trunk and face to
    take up and deposit circulating fatty acids
    released from adipose tissue in the extremities
• Cardiovascular system
  • Cortisol is necessary to maintain normal vascular
    tone (cortisol withdrawal produces vasodilation)
    and vascular responsiveness
  • Cortisol is necessary to maintain normal body
    fluid volume
  • Cortisol is necessary to maintain renal function
    and glomerular filtration
  • Cortisol can act as a mineralocorticoid by
    stimulating Na+ reabsorption and K+ excretion
    (although this is normally done by aldosterone)
• Inflammatory and immune responses
  • Most of the anti-inflammatory effects of glucocorticoids
    require high (supraphysiological) doses
  • However, cortisol is thought to decrease expression of
    proinflammatory cytokines, increase the expression of
    anti-inflammatory cytokines, and increase the expression
    of specific cytokine receptors
  • If administered before a sepsis-producing agent,
    glucocorticoids prevent sepsis (or reduce its extent) by
    preventing inflammatory cytokine expression; if
    administered after, it can actually make things worse
    (because of increased cytokine receptors)
• Central nervous system
  • Glucocorticoids show feedback control of ACTH and CRH
  • In addition, cortisol has an effect on perception and emotion
  • Cortisol deficiency increases the senses of taste, hearing,
    and smell
  • Cortisol excess leads initially to euphoria, but ultimately leads
    to depression and a lowered threshold for seizures
• Development
  • Cortisol is important for normal fetal development of a
    number of organs (permissive)
  • Cortisol causes maturation of intestinal enzymes and is
    involved in the synthesis of surfactant
  • Administration of glucocorticoids in utero can lead to
    hypertension, obesity, and CAD postnatally, and post- natal
    administration can inhibit linear growth
• Aldosterone is the primary mineralocorticoid
  (although cortisol can do this if enough is
• Aldosterone production and secretion is
  regulated mainly by angiotensin II and
  plasma K+
• The main function of aldosterone is to
  increase Na+ reabsorption in the kidney,
  therefore the main stimulus for aldosterone
  secretion is controlled by the kidneys
• The nephrons of the kidneys (nephrons are
  functional units) contain a juxtaglomerular apparatus
  • The juxtaglomerular apparatus consists of modified
    myoepithelial cells (juxtaglomerular cells) surrounding
    renal afferent arterioles (blood is moving toward the
    glomerulus) and are continuous with the macula densa
    cells of the distal tubule which monitors [NaCl]
  • In response to reduced pressure or flow in the afferent
    arterioles, juxtaglomerular cells will secrete renin which is
    a hormone-enzyme that catalyzes the formation of
    angiotensin I from angiotensinogen in the circulation
  • Renin will also be secreted in response to reduced tubular
  • Angiotensin II is produced by the actions of angiotensin-
    converting enzyme which is located on vascular
    endothelial cell membranes
• Angiotensin II exhibits two effects
   • Causes arteriolar vasoconstriction to maintain blood pressure
     and GFR
   • Stimulates aldosterone secretion
• ANGII binds to the type 1 angiotensin receptor in the cell
  membrane which is coupled to G proteins that can
  activate phospholipase C and lipoxygenase
   • This leads to increased intracellular Ca2+ and lipid second
   • This leads to increased cholesterol transport into
     mitochondria (StAR-mediated) and expression of
     steroidogenic enzymes
   • Ultimately more aldosterone is produced and secreted
• The effects of renin on aldosterone secretion are solely
  due to an increase in ANGII
• Aldosterone can also be produced in response to
  increased plasma [K+] and ACTH (brief and limited
  response to ACTH)
  • As aldosterone increases K+ excretion, elevated [K+]
    depolarizes zona glomerulosa cells, increases
    intracellular Ca2+, and activates calmodulin-dependent
    kinases which facilitates aldosterone synthesis
• Aldosterone is only needed in small amounts so
  only 50-200 µg is produced daily
  • Normal [aldosterone] is 5-15 ng/dl
  • Upright posture stimulates more (effects on renin
    secretion) as does chronic sodium depletion (effects on
    total blood volume and then renin)
• As with glucocorticoids, mineralocorticoids
  are metabolized in the liver
  • They are usually conjugated with glucuronides to
    increase solubility and excretion in the kidney
• Most of the circulating aldosterone is free
  (unbound) so that its half-life is 15-20 minutes
• Mineralocorticoids bind to mineralocorticoid receptors
  (MRs) found in target tissues of the kidney, colon, and
  salivary glands (mainly)
• Although the affinity of MRs for aldosterone is equal to
  that for glucocorticoids, in target tissues cortisol is
  converted to cortisone
• Aldosterone binds to cytosolic MRs, and this hormone-
  receptor complex is translocated to the nucleus
   • The H-MR then initiates a cascade of events that leads to
     rapid serum- and glucocorticoid-regulated kinase activation
   • This activated kinase phosphorylates and activates apical
     Na+ channels, increasing Na+ influx and stimulating
     basolateral Na+ /K+ -ATPases
   • The H-MR complex also increases transcription of Na+
     channel and Na+ /K+ -ATPase genes
• Increased Na+ reabsorption causes depolarization
  of distal tubule cells
• This increase in membrane potential increases the
  driving force for K+ to leak out of the distal tubule
  cells, increasing K+ excretion
• Therefore, the more Na+ absorbed, the more K+
• Also, the distal tubule is permeable to water and
  Na+ reabsorption is accompanied by an increase in
  water reabsorption (prevents osmotic disturbances)
• [ANGII also stimulates ADH secretion from the
  posterior pituitary to increase water reabsorption]
• The overall effect of aldosterone (secreted in
  response to decreased blood pressure which
  may or may not have been caused by
  decreased blood volume) is to increase
  extracellular fluid volume (which can lead to
  an increase in blood volume)
• Increased volume will normally turn off the
  aldosterone secretion
• Excess aldosterone leads to an inappropriate
  increase in fluid volume, up to a few liters, but
  eventually it will stop
• This aldosterone escape is likely due to opposing
  mechanisms that react to increased blood
  volume/blood pressure
  • Aldosterone excess is offset by decreased proximal Na+
  • Increased glomerular filtration (increased urine output)
    due to ANP
  • Decreased renin-angiotensin because of increased blood
    pressure and renal blood flow, and increased [NaCl]
    (effects the macula densa)
• Aldosterone also increases reabsorption of Na+ in
  the salivary and sweat glands, and in the large
  intestines (potential sites of Na+ excretion)
             Adrenal Androgens
• DHEA and DHEA-S do not bind to androgen receptors
• Their main role is to act as precursors that can be
  converted to testosterone or estrogens
• The fetal adrenal produces lots of DHEA-S which is
  converted to estrogen in the placenta
• After birth the zona reticularis is fairly inactive until
  adrenarche (7-8 years of age) where levels of DHEA
  and DHEA-S initiated androgens increase to cause
  growth of pubic and axillary hair prior to onset of
• In humans the zona reticularis remains fairly active
  through the 20’s and then declines (like everything
  else) with age
      Disordered Adrenocortical
• Congenital enzymatic deficiency
  • These deficiencies lead to the progressive build
    up of precursors in the steroid biosynthetic
  • This is particularly important if they occur in the
    cortisol pathway as the precursors have no
    feedback control over ACTH, so ACTH levels
    increase stimulating biosynthesis upstream from
    the deficient enzyme
  • This causes adrenal hyperplasia and is known as
    congenital adrenal hyperplasia (CAH)
    Disordered Adrenocortical
• The most common form of CAH results from a mutation in
  steroid 21-hydroxylase (CYP21)
• CYP21 converts 17-hydroxyprogesterone to 11-
  deoxycortisol in the zona fasciculata
   • This leads to conversion of 17-hydroxyprogesterone to
     androgens leading to complete or partial virilization in girls and
     early puberty in boys
• CYP21 converts progesterone to 11-deoxycorticosterone
  in the zona glomerulosa
   • This leads to salt-wasting crises that causes severe volume
     depletion, hyponatremia and hyperkalemia
• Other forms are dependent on which enzyme is deficient
  and can lead to all sorts of different problems
      Disordered Adrenocortical
• Glucocorticoid-remediable aldosteronism
  • In this disorder, two genes encoding steroid synthesis
    enzymes, CYP11B1 and CYP11B2, are involved
  • Both are encoded by tandemly duplicated genes on
    chromosome 8
  • The 5’ end of CYP11B1 becomes fused with the 3” end of
    CYP11B2 during unequal crossover events
  • This results in the production of mineralocorticoids in the
    zona fasciculata in response to ACTH
  • The excess mineralocorticoid leads to hypertension and
  • Glucocorticoid administration will alleviate the symptoms
    (because it decreases ACTH secretion)
      Disordered Adrenocortical
• Glucocorticoid insufficiency
  • Primary hypofunction (Addison’s disease) can be
    caused by tuberculosis or anti-adrenal antibodies
  • Secondary hypofunction is caused by a deficiency
    in ACTH, usually as a result of supraphysiological
    doses of glucocorticoids or from pituitary
    insufficiency (either isolated to ACTH or more
    commonly as part of panhypopituitarism
     • Cortisol deficiency is not as great as with primary
       adrenal insufficiency
     • Aldosterone levels are normal
        Disordered Adrenocortical
• Cortisol excess (hyperadrenocorticism)
  • Primary is called Cushing’s syndrome
  • Secondary is called Cushing’s disease
  • The most common cause is iatrogenic because of the
    administration of exogenous high-dose glucocorticoids for
    treatment of various diseases
  • To reduce the effects of glucocorticoid treatment prednisone is
    often given
  • This allows the beneficial effects of glucocorticoid treatment to
    remain while reducing the suppressive effect on the
    hypothalamic-pituitary axis
  • Rarely, Cushing’s syndrome can also be caused by
    endogenous hypersecretion of adrenal glucocorticoids
  • Cushing’s disease results from overproduction of ACTH either
    by the pituitary or ectopic tumors
      Disordered Adrenocortical
• Primary aldosterone excess
  • Conn’s syndrome is caused by benign tumors that secrete
    aldosterone without any stimulation
  • One of the symptoms is secondary hypertension which is
    accompanied by hypokalemia and hypernatremia
  • The increase in BP occurs because of increased plasma
    volume and even though aldosterone escape occurs fluid
    volume has already increased so BP remains elevated
  • Some patients (5-10%) with essential hypertension
    (essential means no known cause; secondary is
    developed as a result of some other disease) show
    bilateral adrenal hyperplasia and elevated aldosterone
      Disordered Adrenocortical
• Secondary aldosterone excess
  • High levels of aldosterone are a result of
    continuous stimulation of the renin-angiotensin
    system due to low blood volume
  • Unlike the primary form of this disorder, [renin] is
    elevated along with [aldosterone] and blood
    volume will not be restored causing BP to be low-
       Disordered Adrenocortical
• Genetic disorders of mineralocorticoids (rare)
  • Pseudohypoaldosteronism
     • Levels of aldosterone are elevated in spite of symptoms consistent
       with aldosterone deficiency (volume depletion, hypotension,
       hyperkalemia, hyponatremia)
     • One type is caused by an autosomal recessive genetic mutation in
       the Na+ channel found in the apical membrane (causes it to be
     • The other type is caused by an autosomal dominant mutation in
       the mineralocorticoid receptor
  • Pseudoaldosteronism
     • Caused by an autosomal dominant mutation that activates the Na+
       channel found in the apical membrane
     • Levels of aldosterone and renin are low, but symptoms are
       consistent with aldosterone excess
              Adrenal Medulla
• The adrenal medulla is actually a modified
  sympathetic ganglion, except that the postganglionic
  cells have no axons
• The adrenal medulla is specialized to secrete
  catecholamines in response to action potentials from
  preganglionic neurons branching off of the
  splanchnic nerve
• Epinephrine is made from norepinephrine by the
  enzyme phenylethanolamine N-Methyltransferase
• Synthesis of PNMT is regulated by cortisol, which,
  because of the arrangement of blood vessels in the
  adrenals, is high, therefore PNMT levels are high
              Adrenal Medulla
• Catecholamine release occurs because of
  stimulus-secretion coupling
  • Preganglionic cells have an action potential
    releasing ACh into the synapse
  • ACh binds to receptors on the
    postsynaptic/postganglionic cell causing a
    depolarization and an influx of Ca2+
  • Ca2+ influx leads to exocytosis of the secretory
                Adrenal Medulla
• The half-life of catecholamines is less than 1 minute
  • Uptake by catecholamine-secreting cells for reuse
  • Uptake of receptor-catecholamine complexes by effector
  • Metabolic inactivation by the liver (excreted in the kidney
    as metanephrines or vanillymandelic acid)
• There are four types of epinephrine and
  norepinephrine receptors (all act through G proteins)
  • 1 and 2 receptors (higher affinity for norepinephrine)
  • 1 (respond equally to norepinephrine and epinephrine), 2
    (higher affinity for epinephrine), and 3, found only in
    adipose tissue (higher affinity for norepinephrine)
  • Epinephrine bound to  receptors on blood vessels
    causes vasoconstriction; binding to  receptors causes
               Adrenal Medulla
Receptor          Found In              Sensitivity     Second Messenger
           Most sympathetic target
   1               tissues              NE > E       Activates phospholipase C
           Gastrointestinal tract and
   2              pancreas              NE > E           Decreases cAMP

   1        Heart muscle, kidney        NE = E           Increases cAMP
           Certain blood vessels and
            smooth muscle of some
   2                organs              E > NE           Decreases cAMP

   3           Adipose tissue           NE > E           Increases cAMP
                 Adrenal Medulla
• Major actions of epinephrine
  • Arousal
     •   Pupillary dilation
     •   Piloerection
     •   Sweating
     •   Bronchial dilation
     •   Tachycardia
     •   Inhibition of GI tract smooth muscle
     •   Relaxation of uterine muscles
     •   Sphincter constriction
     •   General alertness
                 Adrenal Medulla
• Major actions of epinephrine
  • Metabolic
     • Provide more glucose (glycogenolysis and the Cori cycle) and
       free fatty acids (lipolysis)
  • Cardiovascular
     • Increases heart rate and vasoconstriction
     • Chronic epinephrine has been implicated in hypertension
• Clinical uses
  • -agonists are used to dilate bronchi for the treatment of
  • -antagonists are used to decrease CO for the treatment
    of hypertension
  • Epinephrine is given for severe allergic reactions
  • Norepinephrine is given to increase blood pressure
     Adrenal Medulla Disorders
• Catecholamine excess
  • Pheochromocytomas are (almost always) benign
    tumors of the adrenal medulla
  • Often present with sudden onset of, or increasing
    hypertension, tachycardia, sweating, tremor,
    palpitations, nervousness, weight loss and

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