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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