Physiology - Endocrine - Adrenal gland

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  1. The major hormones secreted by the adrenal cortex are
    • CORTISOL which is a glucocorticoid
    • ALDOSTERONE which is a mineralocorticoid
    • Androgens are also secreted by the adrenal cortex
  2. These are ____ hormones involved in:
    • steroid
    • •reproduction and sexual differentiation
    • •development and growth
    • •regulation of metabolism and nutrient supply
  3. _______ is the obligate precursor for steroid hormones and is obtained from _______.
    • Cholesterol
    • dietary sources and de novo synthesis
  4. Cholesterol, a ___ carbon compound, is _______ in aqueous solution, and is transported by ________.
    • 27
    • insoluble
    • Low Density Lipoproteins (LDL)
  5. synthesis of steroid hormones starts in _______ and requires ____________.
    • mitochondria
    • trafficking between mitochondria and smooth ER
  6. The synthesis of steroid hormones is mostly handled by ______. The steroid nomenclature is mainly based on ______. Cortisol and aldosterone are ___ steroids.
    • cytochrome P450 enzymes
    • the number of carbons and position of hydroxyl
    • C21
  7. Cholesterol is intracellularly stored in _______ in _______ form when not used.
    The transfer of cholesterol to the inner mitochondrial membrane is chaperoned by a __________ protein where the first enzymatic process in steroid hormone synthesis occurs, __________. The enzyme, _______, converts cholesterol to ______.
    • lipid droplets
    • cholesterol esters
    • steroidogenic acute regulatory (StAR)
    • the cleavage of the side chain
    • side chain cleavage enzyme, P450scc
    • pregnenolone
  8. global biosynthetic pathways of steroid hormones
    • cholesterol -P450-> pregnenolone
    • pregnenolone -> progesterone or 17a-OH-pregnenolone
    • progesterone or 17a-OH-pregnenolone -> 17a-OH-progesterone
    • 17a-OH-progesterone -> cortisol

    • 17a-OH-pregnenolone -> androgens
    • androgens -> testosterone or estrogens
    • testosterone -> estrogens

    • progesterone -> corticosterone
    • corticosterone -> aldosterone
  9. enzymes only found in mitochondria
    • P450scc cholesterol side chain cleavage
    • 11b-hydroxylase, forming cortisol and corticosterone
    • aldosterone synthase, forming aldosterone
  10. producing sites
    • zona glomer.: aldosterone; no 17a-hydroxylase
    • zone fasti.: androgen and cortisol; no aldosterone synthase
    • zone reti.: androgen; no 21-hydroxylase
  11. Cortisol release and transport:
    • immediately after being made
    • 90% transported by corticosteroid-binding globulin (CBG), transcortin; <5% is free
    • half-life: 60-90 min
    • Plasma concentration: 5-20 ug/dL, much higher than aldosterone
  12. Aldosterone release and transport:
    • immediately after being made
    • ~50% bound to albumin (and CBG) w/ low affinity 
    • Half-life: 20 min
    • Plasma concentration: 5-10 ng/dL
  13. Molecular mechanism of cortisol
    • 1. transferred by binding to CBG
    • 2. comes off CBG and diffuse through plasma membrane
    • 3. binds to cytosolic glucorticoid receptor (GR)
    • 4. hsp released from GR, cortisol-GR complex moves through nuclear membrane
    • 5. dimerize and binds to the glucorticoid response elements (GRE) of DNA w/ the zinc fingers, together with other transcription factors
    • 6. RNA polymerase activated and RNA synthesized downstream to GRE
  14. Molecular mechanism of aldosterone
    • almost the same as cortisol, except
    • 1. binds to albumin or CBG
    • 2. acts on renal distal tubule cell
    • 3. receptor is called MR, mineralocorticoid receptor
    • 4. protein products regulate luminal Na chan and parts of Na/K ATPase, increasing the uptake of luminal Na+
  15. The MR receptor has a similar affinity for aldosterone and cortisol, and cortisol tends to have much higher plasma level, How do renal tubule cells respond to aldosterone exclusively?
    • 11β-hydroxysteroid dehydrogenase converts cortisol to inactive cortisone.
    • Liquorice inhibits 11b-OHSD and results in hypertension (excessive stim on MR by cortisol)
  16. Cortisol functions
    • Promote breakdown of muscle to AAs
    • Promote gluconeogenesis at liver
    • Block GLUT4 at muscle to take in glucose
    • Mildly promotes lipolysis, overpowered by insulin's lipid forming effect
    • Inhibits inflammation and immune responses
  17. Control of cortisol synthesis and secretion by the hypothalamic-anterior pituitary axis
    • cortisol is secreted in response to time of day and stress
    • hypothalamus produces corticotropin releasing hormone (CRH)
    • CRH stims anterior pituitary gland to release ACTH (adrenocorticotropin hormone)
    • ACTH enters circulation and eventually stims adrenal cortex to secret cortisol
    • Cortisol regulates its own production via negative feedback which acts on hypothalamus's release of CRH
  18. Control of cortisol synthesis by ACTH
    • GsPCR, cAMP, PKA
    • stimulates following steps
    • hydrolysis of cholesterol esters to cholesterol
    • transfer cholesterol to mitochondrial outer membrane
    • transfer cholesterol to mitochondrial inner membrane 
    • P450ssc produces pregnenolone
  19. Release of Aldosterone
    • in response to decrease blood volume, [Na+], increase [K+]
    • kidney secretes renin
    • renin converts angiotensinogen to angiotensin I
    • ACE converts angiotensin I to angiotensin II (vasoconstrictor)
    • A II stims adrenal cortex secretes aldosterone
    • aldosterone increases Na+ and water retention in kidney and BP
    • ACE blocker can decrease BP
  20. Blockade of aldosterone can lead to ____.
    Aldosterone secretion is inhibited by _____.
    • hyperkalemia
    • the atrial natriuretic peptide (ANP)-cGMP pathway (in outline, no explanation)
  21. Cushing's syndrome
    symptoms
    causes
    • high plasma cortisol
    • Weight gain, central obesity
    • Hypertension
    • Impaired glucose tolerance/diabetes mellitus
    • Purple striae (~60%)
    • Osteopenia/osteoporosis (~50%)
    • Proximal myopathy

    • 99% exogenous cortisol
    • rare cases:
    • anterior pituitary adenoma (ACTH-dependent)
    • adrenal adenoma
  22. Causes of hypoadrenalism
    • Common (~ >99%)
    • Abrupt cessation of exogenous sources of glucocorticoids
    • Rare (~ <1%)
    • Primary adrenal insufficiency: Adrenal cortex destruction; Addison's disease
    • Secondary: any pituitary disease causing hypopituitarism - CRH or ACTH deficiency
  23. Clinical features of Addison's disease
    • Weakness (~100%)
    • Weight loss (~100%)
    • Pigmentation (~95%) esp. gum and tongue
    • Postural hypotension (~25%)
    • Anorexia (~95%)
    • Nausea (~95%)
  24. Pigmentation in Addison's disease
    • low cortisol
    • high ACTH due to lack of negative feedback from cortisol
    • ACTH has a melanocyte stimulating hormone activity, resulting in pigmentation
  25. Adrenal medulla
    • Represents ___% of the adrenal gland
    • Is of _____ origin: develops in parallel with ________
    • Consists of _______ cells
    • Secretes _______: _______ hormones synthesized from ______.
    • Unlike steroid hormones, stored in _____
    • 10-20
    • neuronal (no axon though)
    • the sympathetic nervous system
    • chromaffin
    • EPINEPHRINE and NOREPINEPHRINE
    • CATECHOLAMINE
    • tyrosine
    • granules
  26. Synthesis of catecholamines
    • CHROMAFFIN cells
    • tyrosine -> DOPA, TH (tyrosine hydroxylase), cytosol
    • DOPA -> dopamine, AAD (amino acid decarboxylase), cytosol
    • dopamine is taken into granules
    • dopamine -> NE, DβH (dopamine β-hydroxylase), granual
    • NE diffuses back to cytosol
    • NE -> E, PNMT (phenyl... N-methyltransferase), cytosol
    • E is taken back to granules

    ATP consuming to take dopamine, E, NE to granule and store them there
  27. Molecular mechanisms of NE/E actions
    NE: increases free Calcium (α1, GqPCR, IP3+DAG), decreases cAMP (α2, GiPCR)

    Epinephrine: increases cAMP levels (β1/2, GsPCR)
  28. Functions of NE/E
    • NE and E (mainly via β-receptors):
    • stims kidney to produce renin ->-> inc. BP
    • inc. glucose production; gluconeogenesis; release lactate by glycogen breakdown in muscles

    • NE:
    • blood vessel constriction (inc. BP)

    • E:
    • dilate bronchiole (pulmonary vasodilation)
    • inc. heart contraction force and rate
    • stim adipose lipolysis
  29. secretion of NE/E
    half-life
    secretion mechanism
    • half-lives of NE and E: very short (1-3 min)
    • Stimuli as fear, anticipation of danger, hypoglycemia -> hypothalamus -> sympathetic system -> ACh released by stimulation of cholinergic preganglionic fibers (adrenal medulla can be compared to an enlarged specialized sympathetic ganglion) -> Ca -> exocytosis
  30. Pheochromocytoma
    • Tumors of the adrenal medulla
    • excess of NE/E
    • headaches, chest pain, extreme anxiety, cold perspiration, high BP, tachycardia (fast HR)
  31. β-blockers and amphetamines:
    • β-blockers are antagonists: used in treatment of hypertension. 
    • Amphetamines are agonists: used as general stimulants, nasal decongestants or appetite suppressants. If exposure to catecholamines is prolonged, the receptors get desensitized and the cells stop to respond to the hormones, which causes problem to treatment w/ β-agonists.
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Physiology - Endocrine - Adrenal gland
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Physiology - Endocrine - Adrenal gland
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