1. Adrenal gland

2. Anatomy

3. 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

5. Hormone secretion Adrenal cortex –Steroid hormones Glucocorticoids Mineralocorticoid Androgens Adrenal medulla –Neurotransmitter Epinephrine Norespinephrine

6. 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)

7. 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

9. 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)

10. 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

12. 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

13. Psychological stress –Acute stress Increased cortisol secretion –Chronic stress No alteration –Depression Increased cortisol production

15. 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

17. 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

18. 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

20. 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)

22. 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)

23. 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