ADRENAL CORTEX AND CORTICOSTEROIDS

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ADRENAL CORTEX AND CORTICOSTEROIDS
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Zona glomerulosa

• Regulation
• Angiotensin II, K
• Impt enz P450 aldo
• Produces mineralocorticoids
• Functions
• Stims Na reabsn
• ? incrd ECF vol,
• Decrd plasma K,
• Incrd plasma pH

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Zona fasciculata

• Regulation
• ACTH
• Impt enzs
• P450c17, P450c11
• Produces
• Glucocorticoids
• Androgens (androstenedione, DHEA)
• Functions
• Stress response
• Metabolism
• Blood pressure
• Immune function impacts

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Zona reticularis

• Regulation, enzs, products same as zona
  fasciculata
• Functions
• Main androgen source in females

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Corticosteroids

• C21 pregnane derivs
• C19 androstane derivs C18 estrane derivs
• Progesterone, mineralocorticoids, glucocorticoids
• Lipophilic
• Assoc w/ blood proteins

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Pregnenolone produced directly from cholesterol,
the precusor molecule for all C-18, C-19 and C-21
steroids 
Cortisoldominant glucocorticoid in humans,
synthesized from progesterone in the zona
fasciculata of the adrenal cortex, involved in
stress adaptation, elevates blood pressure and
Na uptake, numerous effects on the immune system
 
Aldosterone the principal mineralocorticoid,
produced from progesterone in the zona
glomerulosa of adrenal cortex, raises blood
pressure and fluid volume, increases Na uptake 
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Progesterone a progestin, produced directly from
pregnenolone and secreted from the corpus luteum,
responsible for changes associated with luteral
phase of the menstral cycle, differentiation
factor for mammary glands
Testosterone an androgen, male sex hormone
synthesized in the testes, responsible for
secondary male sex characteristics, produced from
progesterone 
Estradiol an estrogen, principal female sex
hormone, produced in the ovary, responsible for
secondary female sex characteristics 
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Biosynthesis

• Cell specific
• Cholesterol precursor from cytoplasmic and membr
  pools
• Rate-limiting cholesterol ? mitoch matrix
• StAR incorporated into inner mitoch membr
• Varied mols stim synth de novo
• ACTH, LH, hCG
• ? cAMP ? ? ? StAR

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• PBR cholesterol channel
• Ubiquitous actd by StAR
• Assocd w/ mitoch porin
• Cyt P450 enzymes coded by CYP genes
• P450 scc catalyzes cholesterol ? pregnenolone
• Integral to inner mitoch membr
• Active site faces matrix

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Adrenal Cortex Steroidogenic Enzymes

• P450c17 catalyzes rxns
• Pregnenolone ? 17a hydroxypregnenolone or DHEA
• Not found in zona glomerulosa
• So no glucocorticoids prodd
• DHEA impt to androgen synth
• 3bHSD catalyzes rxns
• Pregnenolone ? progesterone and
• 17a hydroxypregnenolone ? 17a hydroxyprogesterone

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• P450c21
• Catalyzes rxns
• Pregnenolone ? 11-deoxycorticosterone (DOC) and
• 17a pregnenolone ? 11-deoxycortisol
• Specific to adrenal cortex
• DOC only in zona glomerulosa
• Only progesterone available
• 11-deoxycortisol in other zonae

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• P450 aldo (18 hydroxylase)
• Catalyzes 3 rxns
• DOC ? ? ? aldosterone
• In inner mitoch membrane
• Introduces C18 aldehyde grp
• Expression specific for zona glomerulosa
• Induced by
• Angiotensin II
• Elevated plasma K

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• P450c11
• Catalyzes rxn
• Deoxycortisol ? cortisol (hydrocortisone)
• In inner mitoch membr
• Expression specific for zonae fasciculata,
  reticularis
• Induced by ACTH

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Mineralocorticoids

• DOC secrd by zonae fasciculata, reticularis
• ACTH dependent
• Potent in vitro
• Zona glomerulosa secretes aldosterone
• Plasma levels influenced by postural changes
• CBG binds 20
• 40 bound to albumin

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• Free aldosterone cleared through kidneys
• Inactn in liver
• Reduction, conjugation
• ? incrd hydrophilicity, excrn
• Stims renal Na reabsn, K secrn
• ? regulation ECF volume, electrolyte composition

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Renal Na Reabsorption

• All Na filtered at glomerulus
• Approx 1 plasma Na excrd to urine
• Reabsn 65 by proximal tubule
• Reabsn 20-25 by distal tubule
• Reabsn 9 by cortical collecting duct
• BUT cortical collecting duct sensitive to
  hormones
• AVP
• Aldosterone

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Aldosterone at Cortical Collecting Duct

• Mineralocorticoid receptor
• Related to glucocort, progesterone, androgen
  receptors
• Ligand specific hormone-binding domain
• Sequence specific DNA-binding domain
• Several activities w/ ligand binding

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Apical Membr Na Channels

• Aldosterone receptor occupation ? stimn de novo
  synth, activity of Na channels
• Allows Na into cell w/ electrochem gradient
• Conserves Na in body
• ? Depoln luminal membr
• Dietary Na intake 6-8 g/day
• Aldosterone stimd reabsn max 30 g/day

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ADH-Regulated Ad Cyclase

• Aldosterone receptor occupation ? induction
  expression ad cyclase sensitive to ADH
• Impt to aquaporin synth, activation
• So concerted reabsn both water, Na
• Get isosomotic expansion ECF volume
• ? Incrd bp

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ATPase Activity

• Aldosterone receptor occupation ? stimn ATPase
• ATP needed to close electrolyte channels in
  luminal membr
• Usually closed, high ATP
• When open, K out of cells
• When aldosterone, ATPase active ? decrd ATP ?
  channel open ? K out of cell

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Renin-Angiotensin System

• Regulates zona glomerulosa
• Angiotensinogen
• Glycoprot
• Sim to CBG, TBG
• Secrd by liver
• Cleaved by proteinase (renin)

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• Renin catalyzes rxn angiotensinogen ? angiotensin
  I
• Rate limiting step of pathway
• In liver, kidney
• Secrd by cells of juxtaglomerular apparatus
• Incrd renin secrn w/
• Conditions ? decrd renal blood flow
• So w/ decrd pressure at glomerular afferent
  arteriole
• Angiotensin I cleaved by Angiotensin Converting
  Enzyme (ACE) ? angiotensin II
• ACE inhibitors lower bp
• Angiotensin II
• Biologically active

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• At zona glomerulosa
• Angio II receptor heptahelical, G protein-coupled
• Receptor occupation w/ angio II ? stimn PLC
• ? incrd intracell Ca
• ? aldosterone synth
• Also get actn PKC, MAP kinase, maybe tyr kinases
• ? prolifn zona glomerulosa, vasc sm muscle
• Also acts as potent vasoconstrictor by same
  pathway in vasc smooth muscle

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Regulation of Renin Secrn

• By feedback mechs at kidney JGA
• Incrd renin secrn w/
• Conditions ? decrd renal blood flow
• So w/ decrd pressure at glomerular afferent
  arteriole
• Macula densa Na sensor

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• Tubuloglomerular feedback
• Neg feedback between between macula densa NaCl
  concent and GFR
• If NaCl in lumen incrd, macula densa secrs
  adenosine
• ? afferent arteriole ? constriction ? decrd GFR
• Short-term adaptation to Na balance
• Also ? decrd renin secrn by JGA
• Long-term adaptation to Na balance
• If decrd ECF vol or decrd NaCl at JGA, get
  incrd renin secrn
• ? Incrd angiotensin II, so
• Vasc sm muscle constriction
• Aldosterone ? Na reabsn ? incrd ECF vol

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• Short-loop feedback
• Angiotensin II inhibits renin secrn from JGA
• Long-loop feedback
• Aldosterone secrn regulates Na concent ? renin
  regulation
• Plasma renin activity assocd w/ sleep rhythms
• Impt to bp during sleep cycles

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Atrial Natriuretic Peptide (Factor)

• Opposes action of aldosterone
• Decrs Na retention
• Decrs bp
• Prodd by cardiac muscle cells (esp RA)
• In response to stretch w/ incrd venous P
• ANP receptor is single-membrane span

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• In kidney, ANP
• Acts at afferent, efferent arterioles
• ? incrd bhp ? incrd GFR
• Acts at collecting duct
• Inhibits Na reabsn
• ? prodn autocrine prot
• Binds ANP receptor ? cGMP ? inhibn Na channel
• ? diuresis, natriuresis
• Inhibits renin secrn
• At adrenal, inhibits aldosterone secrn
• At brain, decrs salt appetite, ADH secrn
• At vasculature, incrs permeability of vessels ?
  fluid from IVF ? ISF/ICF
• Also dilates vessels

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Glucocorticoids

• Cortisol most widely studied
• Bound to CBG
• Free 4-10
• Liver metab
• Reduced, conjugated
• Cortisone ? cortisol

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Cortisol

• Aid in adaptation to adverse situations
• Widespread activities
• Receptor widely expressed
• Coordinated
• Lipophilic
• Passes through plasma membranes
• Penetrates BBB

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Glucocorticoid Receptor

• Classical action
• Homodimer
• Glucocort response elements at promoter regions
• Actn or suppression of transcription
• Also, transcriptional cross talk
• Prot-prot interactions of actd receptor other
  transcrn factor
• So other receptor/transduction pathways impacted
• Actn w/out ligand
• Stimn b2 adr receptor agonists

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Cortisol Activities

• Direct
• Ex Induces enzs involved in metab pathways
• Indirect
• Ex Maintains vasc reactivity to catecholamines
• Nongenomic
• Ex Induction PNMT in adrenal medulla

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Stress Response

• First adrenaline incrs liver glycogenolysis
• ? Free glucose
• BUT liver glycogen rapidly depleted
• Largest energy store triglycerides in adipose
  tissue
• Catecholamines, other hormones activate lipases ?
  free fatty acids glycerol

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• FFA ? cells
• ? b oxidation ? acetyl CoA
• ? Krebs cycle ? ATP
• Incrd ATP allosterically inhibits glycolysis
  enzs ? incrd plasma glucose
• Glucocorts facilitate lipolysis at adipose
• Permissive (Fig 15.17)
• Provides FFA for liver inductn lipolysis _at_
  adipose
• ? ATP, so incrd plasma glucose
• Induce liver gluconeogenic enzs
• ? Stimn liver gluconeogenesis
• Mobilizes aas from muscle
• Used for gluconeogenesis

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Cortisol Regulates Immune, Inflamm Responses

• Suppresses prodn cytokines
• Proinflammatory prots
• Suppresses transcrn COX2 (PG synthetase)
• Suppresses PG/leukotriene synth
• Also inhibits PLA2 so suppresses PGs
• Induces lipocortins
• Autocrine inhibitors of wbcs
• Suppresses/causes apoptosis of immune cells

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Cortisol Direct CNS Effects

• Overprodn or exogenous glucocorts ? memory
  impairment
• Hippocampal atrophy may be impt to posttraumatic
  stress disorder
• Limbic system impact ? impact on mood
• Normal cortisol reqd for normal mood
• Linkage to sleep cycles?
• Stimulates appetite

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Stress Signals

• Emotional (anxiety)
• Hypoxia, hypercapnia
• Hypoglycemia
• Decrd bp or ECF vol
• Infections
• Env tempt changes
• Ethanol consumption
• Long-term normocortisolemia reqd for acute
  responsiveness to other stress hormones

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Circadian Rhythm

• Environmental cues ? suprachiasmatic nucleus
• ? Paraventricular neurons ? CRH
• Lowest cortisol 6-8 a.m.
• Highest cortisol 6-10 p.m.

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Glucocorticoid Regulation

• Hypothal CRH
• ? ant pit corticotrophs ? ACTH release
• Neg feedback control by cortisol
• Pulsatile secrn
• In other brain areas
• Synth b endorphins
• Outside CNS
• Stim synth PGs (proinflammatory)

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• CRH-BP
• Secrd by liver, placenta
• CRH sink
• CRH receptors in ant pit
• CRH1R suppressed by cortisol
• Impt to neg feedback control
• Expressed in other brain areas where related to
  stress response
• Impt to parturition initiation
• CRH2R impt to vasodilation

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• ACTH
• POMC derivative
• Also b-LPH, a-MSH, b-endorphins
• Pulsatile secrn (CRH)
• Secrn stimd by AVP
• Secrn inhibd by glucocorticoids (cortisol)
• ACTH receptor
• G-prot coupled heptahelical
• Stims adrenocortical steroidogenesis

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