Transcript Adrenal gland

Adrenal gland
Anatomy
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
Hormone secretion
• Adrenal cortex
– Steroid hormones
• Glucocorticoids
• Mineralocorticoid
• Androgens
• Adrenal medulla
– Neurotransmitter
• Epinephrine
• Norespinephrine
Functional zonation
• Zona glomerulosa
– Mienralocorticoid
secretion only
• No 17a-hydroxylase
• Tissue-specific
expression of 11betahydroxylase (CYP11B2)
• Zona fasciculata
– Glucocorticoids
production
• Difference in promoter
that activates 11betahydroxylase (CYP11B1)
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
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)
• 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
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
• Psychological stress
– Acute stress
• Increased cortisol secretion
– Chronic stress
• No alteration
– Depression
• Increased cortisol production
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
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
• 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
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)
• 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)
• 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