13. Lecture 28 Flashcards
What is cortisol?
Primary glucocorticoid hormones in humans Glucocorticoid are a class of corticosteroids (steroid hormones)
Derived from its role in the regulation of glucose metabolism and ability to raise plasma glucose levels, synthesis in the adrenal cortex and its steroidal structure
Almost all body tissues are target sites and so cortisol is involved in a wide range of physiological processes (stress response, potent immunosuppressive and anti inflammatory activity, etc)
Slides 2-3
What is cushing syndrome?
Clinical symptoms from prolonged exposure to excess glucocorticoids
Seen in patients receiving glucocorticoid treatment or that overproduce cortisol
Signs:
Obesity in face (moon face), neck (buffalo pads), trunk and abdomen
Weakness
Muscle wasting
Slide 4
How is cortisol synthesized?
How is is moved?
The fasciculata and reticular is layers of the adrenal cortex contain the enzymes necessary to convert cholesterol to cortisol
The cortisol synthesized by the adrenal cortex diffuses our of the cells and into the blood plasma
90% of cortisol is transported bound to corticosteroid-binding globulin (transcortin), ~7% bound to albumin, ~3% is free
Slide 5
How does cortisol act on target cells?
Cortisol crosses plasma membrane of target cells and binds to intracellular receptors (virtually all tissues in body contain receptors for glucocorticoids)
Slide 6
What happens when cortisol binds to the cytoplasmic glucocorticoid receptor (GR)?
GR in its unbound Formica complexed to a chaperone protein
Binding of cortisol causes the chaperone to dissociate from the GR and allow the cortisol-GR complex to translocate to the nucleus
There the cortisol GR complex associates with glucocorticoid response elements (GREs) of multiple genes to either enhance or diminish gene expression
Slide 6
What is the hypothalamic-pituitary-adrenocortical axis?
Small bodied neurons in paraventricular nucleus of hypothalamus secrete corticotropin-releasing hormone (CRH) into interstitial fluid of median eminence
CRH enters hypophyseal portal venous plexus and travels to anterior pituitary
CRH binds G protein coupled receptor on cell membrane of corticotroph cells
This stimulates adenylyl cyclase and activates L type Ca channels which increases [Ca]i
Slides 7-8
What does cortisol control (feedback) in the anterior pituitary?
In the corticotrophs of the anterior pituitary, cortisol modulates gene expression to inhibit the synthesis of both CRH (corticotropin-releasing hormone) receptor and ACTH (adrenocorticotropic hormone)
elevated levels of cortisol in plasma inhibit the release of presynthesized ACTH stored in vesicles
Slide 7
What does cortisol control (feedback) in the hypothalamus?
Plasma cortisol decreases the mRNA and peptide levels of CRH in paraventricular hypothalamic neurons
Cortisol inhibits the release of presynthesized CRH
What are the 2 higher levels of corticotropin-releasing hormones (CRH) secreting neurons by the brain?
- The circadian and pulsatilla nature of ACTH and cortisol secretion
- Integration of signals form higher cortical centres that modulate the body’s responses to a variety of stressors
Slide 10
What bridges the endocrine and sympathetic nervous system?
The adrenal medulla bridges them
Adrenomedullary cromaffin cells synthesize and secrete epinephrine (adrenalin) and norepinephrine (small amount) into the circulation to act on distal tissues
Chromaffin cells are the structural and functional equivalents of the post ganglionic neurons in the sympathetic nervous system
Slide 11
What are the principal regulators of adrenomedullary hormone secretion?
The preganglionic sympathetic divers of the splanchnic nerves (which release acetylcholine) are principal regulators of adrenomedullary hormone secretion
Slide 11
What cell is the only one with enzyme for synthesizing epinephrine?
Chromaffin cells of the adrenal medulla are the only ones that have the enzyme for synthesizing epinephrine
Dopamine, norepinephrine, and epinephrine are synthesized from the amino acid tyrosine
Slide 12
What are the 7 steps of epinephrine synthesis and storage by the chromaffin cell?
- Cytosolic enzyme tyrosine hydroxylase converts tyrosine to L-dopa (rate limiting step)
- Cytosolic enzyme amino acid decarboxylase converts L-dopa to dopamine
- A catecholamine-H exchanger (VMAT1) moves dopamine into membrane enclosed dense core vesicles (chromaffin granules)
- Dopamine β-hydroxylase converts dopamine to norepinephrine
- Norepinephrine formed in the secretory grandukes moves out into cytosol
- Cytosolic enzyme phenylethanolamine-N-methyl-transferase (PNMT) converts NE to Epi
- Secretory granules in adrenal medulla take up the newly synthesized Epi (mediated by VMAT1)
Slides 13-14
How is epinephrine synthesis under control by CRH-ACTH-cortisol axis?
2 levels:
- ACTH stimulates the synthesis of L-dopa and norepinephrine
- Cortisol transported from the adrenal cortex by the portal circulation to the medulla unregulated PNMT in chromaffin cells
Stress that is sensed and propagated by CRH-ACTH-cortisol axis sustains the epinephrine response
Slide 15
What is pheochromocytoma?
Symptoms?
Diagnosis?
Treatment?
Tumor caused by hyperplasia of adrenal medullary tissue- catecholamines made and released in an unregulated fashion
Symptoms- typically wide ranging- hypertension, tachycardia, headache, episodes of sweating, anxiousness, tremor
Diagnosis- patient shows evidence of excessive adrenergic tone and increased amounts of urinary catecholamines
Treatment- surgical resection of the tumor
Slide 16
