Download - Adrenal gland
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Adrenal gland
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Anatomy
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Components
• Two compartments– Adrenal Cortex (outer layer)
• Three layers– Zona glomerulosa (15 %)– Zona fasciculata (75 %)– Zona reticularis (10 %)
– Adrenal medulla (inner layer)• Nerve tissue
• Highly developed vasculature
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Hormone secretion
• Adrenal cortex– Steroid hormones
• Glucocorticoids• Mineralocorticoid• Androgens
• Adrenal medulla– Neurotransmitter
• Epinephrine• Norespinephrine
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Functional zonation
• Zona glomerulosa– Mienralocorticoid
secretion only• No 17a-hydroxylase• Tissue-specific
expression of 11beta-hydroxylase (CYP11B2)
• Zona fasciculata– Glucocorticoids
production• Difference in promoter
that activates 11beta-hydroxylase (CYP11B1)
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Adrenal stroidogenesis
• Cholesterol– LDL from circulation
• Receptor-mediated endocytosis
– Uptake regulated by StAR• Regulated by cAMP
• Process– Mostly identical to gonadal steroidogenesis– Almost exclusively uses delta-4 pathway
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Regulation of glucocorticoid secretion
• Role of hypothalamus-pituitary axis– Hypothalamic CRF
• Stimulation of ACTH production by the anterior pituitary gland
– Increased secretion of POMC protein via increased transcription of mRNA
– ACTH• Interacts with receptors in Zona facsiculata• Increased cAMP production
– Increased steroidogenesis– Increased IGF-II production (tissue growth)
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• Glucocorticoids– Negatively feedback to hypothalamus and
anterior pituitary gland• Inhibition of CRF and ACTH secretion
• Pattern of ACTH secretion– Diurnal
• Circadian rhythm
– Pulsatile• More frequent in men
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Role of stress and immune system
• Proinflammatory cytokines– Secreted during inflammation by immune cells
• IL-1, IL-6, and tumor necrosis factor alpha• Increased ACTH secretion
– Direct stimulation of corticotroph– Argumentation of CRF secretion
• Physical stress– Increased CRF release
• CNS-mediated• Normal counter-regulatory response
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• Psychological stress– Acute stress
• Increased cortisol secretion
– Chronic stress• No alteration
– Depression• Increased cortisol production
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Glucocorticoids in circulation
• Over 90 % exist as bound-form– Alpha-globulin cortisol-binding globulin (CBG)
• Synthesized by the liver• Very high affinity to cortisol• Level affected by the estrogens (+) and
glucocorticoids (-)
• Metabolized by the liver and kidney– Converted to cortisone
• Reversible
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Mechanism of action
• Receptors– Intracellular/nuclear receptors
• Two variants (alpha and beta)
– GR-alpha• Bound to heat-shock proteins (HSP 90 and 70)
– Dissociation after interacting with the hormone
• Activation of genes
– GR-beta• Negative regulator of GR-alpha activity
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• Mediation of anti-inflammatory response– GR plus activator protein-1 (AP-1)
• Formation of Co-activator complex• Allows transcription of genes without GRE• Could be antagonistic
– Combination of GR with c-Jun or nuclear factor kappa –B
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Function of glucocorticoids
• Nutrient metabolism– Increased hepatic gluconeogenesis
• Increased enzyme synthesis
– Inhibition of glucose uptake by the peripheral tissues
• Catabolic action– Break-down of fats and muscles– Serve as substrates for gluconeogenesis or source of
energy
• Inhibits insulin action (diabetes)
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• Stress response– Maintenance of vasculature– Synthesis of catecholamines
• Sympathoadrenal activity– Stimulation of sympathetic nervous system– Further stimulation of lipolysis– Maintenance of body temperature (altered metabolism)
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• Immune system– Anti-inflammatory
• Prevention of lysozomal content leakage• Prevention of leukocyte infiltration• Atrophy of lymphatic system
– Decreased lymphocytes in circulation
• Regulation of IL-1beta production by activated monocytes
– Prevents over-stimulation of immune system