From the Medulla to the Definitive Cortex is from the innermost to the outermost.
During fetal growth throughout the first year of life, the adrenals cortices develop into two zones, which contain the larger inner fetal zone and an outer definitive zone:
-The larger zone produces the steroid hormones - weak androgens DHEA (Dehydroepiandrosterone) and androstenedione (and ultimately the fetal Estrogen)
After birth, fetal zone goes away, and the definitive zone (called definitive because it will definitively differentiate after birth) proliferates into an outer glomerulosa and an inner fasciculata zone.
-Also, at around one year, the innermost reticularis zone has developed.
So, going from outer to inner, the order is:
- Glomerulosa zone
- Fasciculata zone GFR: (Acronym: Globular Filtration Rate)
- Reticularis zone
During pregnancy, the maternal adrenals hypertrophy and increase corticosteroid hormone production.
-The fetoplacental unit increases production of Estrogen, which allows the maternal liver to increase production of proteins, transcortin and SHBG (sex hormone binding globulin), which secrete into the blood plasma.
Anatomy:
-Adrenals are right above the kidneys.
-Blood goes down renal capillaries to reach medulla of adrenal cortex via renal artery.
-Not much blood reaches medulla (chromaffin cells), most of it bring deoxygenated.
-Blood then enters central vein in middle of medulla, then right adrenal vein and then the inferior vena cava.
Order of blood flow:
Renal artery --> renal capillaries --> arrives at medullary chromaffin cells --> central vein in middle of medulla --> right adrenal vein --> inferior vena cava
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| Three cortical zones and groups of corticosteroids they produce |
M = Mineralcorticoids (aldosterone etc.)
G = Glucocordicoids (cortisol etc.)
A = Androgens (testosterone etc.)
GFR = MGA, where G = M, F = G, and R = A
-All cortical steroids are lipophilic and can be secreted immediately since they act as transcription factors. Synthesized on demand.
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When dealing with the synthesis of corticosteroids, (Either M,G, or A), it is controlled by StAR (steroidogenic acute regulatory protein)
In females, 50% of circulating androgens are created by the adrenals, and the other 50% comes from the thecal cells in ovarian follicles, and during the menstrual cycle production by corpus luteum.
In males, most androgens, Testosterone and Dihydrotestosterone (T and DHT) come from the testicular source. In other words, the production of androgens in the adrenals is NOT very important.
*Androgen-Receptor pair take around 24 hours for transcription factor effect*
-Long half lives. Around 90 minutes for cortisol since it's under circadian rhythm and pulsatile control via ACTH secretion from the anterior pituitary. For aldosterone, about 15 minutes.
Carried via:
- High affinity Transcortin (CBG) which binds most of cortisol and corticosterone (another glucocorticoid used for stress response) and only about 20% aldosterone
- low affinity (non-specific) but high capacity albumin which binds 15% of cortisol and 40% aldosterone
- The rest is biologically active/free hormone that includes around 10% of the cortisol and another 40% of the aldosterone
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Receptors:
Both the mineralcorticoid receptor (MR) and the glucocorticoid receptor (GR) share homology
**Since cortisol is FAR more abundant than aldosterone, and since aldosterone is more discretely distributed (sent to kidneys, GI, and sweat glands), an enzyme 11β OH dehydrogenase is secreted to convert the active cortisol into the inactive cortisone, so that the MR can bind aldosterone preferentially.
-GR associated with heat shock protein (HSP) that renders it inactive, so the dissociation of the HSP allows cortisol to bind to GR.
-Non-genomic effects are fast
-Genomic effects are slow
-Cortisol exhibits both types of effects.
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Aldosterone's overall effect is to stimulate reabsorption of Na+ from tubular fluid into blood.
-In distal convoluted tubule and corticol collecting duct, aldosterone regulates synthesis and creation of Na+ channels in apical membrane (or the membrane away from the blood)
-Also regulates synthesis of subunits of the basal lateral membrane, or BLM (the membrane towards the blood) Na+/K+ ATPase pump - facilitating Na+ reabsorption from tubular fluid
-This is why when you have hypernatremia, you have hypokalemia, and when you have hyponatremia, you have hyperkalemia. It is all regulated by the Na+/K+ ATPase pump via homeostatic control.
-Aldosterone's effects maintains low Na+ intracellular concentration (the renal distal tubular cells that is) so that Na+ can enter cell down its concentration gradient through aldosterone-regulated apical membrane Na+ channels from tubular fluid --> blood. (as shown below)
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| Aldosterone effect on distal tubular cells |
Conn's syndrome = hyperaldosteronism
-Lots of Na+ reabsorption = hypertension + hypokalemia
-also associated with metabolic alkalosis (environmental pH too basic) because it increases H+ excretion (more H+ makes an environment more acidic) and increases retention of HCO3 (Bicarbonate, which is a weak base)
In the GI, aldosterone stimualtes Na+/H+ exchange in the colon which increases the absorption of Na+ (and Cl-) across cells into general circulation and increases H+ excretion.
Increase Na+ in the blood concomitantly acts with the stimulation of osmoregulators, which secretes ADH (aka vasopressin) from the posterior pituitary.
-This is limited to 15% by the "mineralcorticoid escape", which involves increase in Atrial natriuretic peptide (aka ANP, and the opposite effect of aldosterone) and the initiation of natriuresis (sodium excretion)
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11β-hydroxylase deficiency: primary cause of Congenital Adrenal Hyperplasia (CAH)
-11β-hydroxylase is the enzyme that is required to turn the very last precursor of cortisol and aldosterone into cortisol and aldosterone.
-No cortisol or aldosterone --> no negative feedback --> ACTH levels increase --> stimulation of precursor corticosteroids including: doeoxycorticosterone and 11β deoxy-cortisol
-deoxycorticosterone has some aldosterone activity. However, cortisol effects are defficient.
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Cortisol:
Carbohydrate metabolism and increase in blood glucose.
Direct effects:
Direct effects:
-Production of pyruvate, oxaloacetate and other amino acids needed for gluconeogenesis via protein catabolism.
-Production of glycerol from lipid catabolism produces glyceraldehydes, which is needed for gluconeogenesis.
Indirect effects:
-Cortisol increases circulating levels of FA's which decrease periphral tissue (muscle and fat) responsiveness to insulin. (a diabetic symptom)
-Decreasing uptake and cellular use of glucose; helping to increase blood glucose.
Decrease response to insulin --> decrease cellular use of glucose.
-With Cushing's syndrome, secondary diabetes type II in over 50% of patients is observed.
-In Cushing's syndrome, increased glucose increases insulin release (an indirect effect) which stimulates lipogenesis. (this changes fat distribution and explains why symptoms like the "buffalo hump" are seen in cushing's patients)
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Renal effects:
-Increase in GFR through vasodilation of afferent arterioles.
-Decrease in ADH from posterior pituitary (PP) --> increase in water excretion
-High levels of cortisol might stimulate mineralcorticoid receptor (MR) --> Na+ reabsorption and K+ with H+ secretion at the distal convoluted tubule (water-impermeable) and ADH sensitive collecting duct --> hypernatremia, hypokalemia, and hypertension
This means that if cortisol DOES stimulate the MR, then the high Na+ plasma concentration would stimulate osmotically-sensitive regions in the brain and increase ADH from PP. --> ECF would increase and BP would rise, a condition called apparent mineralcorticoid excess syndrome.
*This would probably only happen if the 11β-OH dehydrogenase enzyme that converts the active cortisol into the inactive cortisone were missing.
-Production of glycerol from lipid catabolism produces glyceraldehydes, which is needed for gluconeogenesis.
Indirect effects:
-Cortisol increases circulating levels of FA's which decrease periphral tissue (muscle and fat) responsiveness to insulin. (a diabetic symptom)
-Decreasing uptake and cellular use of glucose; helping to increase blood glucose.
Decrease response to insulin --> decrease cellular use of glucose.
-With Cushing's syndrome, secondary diabetes type II in over 50% of patients is observed.
-In Cushing's syndrome, increased glucose increases insulin release (an indirect effect) which stimulates lipogenesis. (this changes fat distribution and explains why symptoms like the "buffalo hump" are seen in cushing's patients)
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Renal effects:
-Increase in GFR through vasodilation of afferent arterioles.
-Decrease in ADH from posterior pituitary (PP) --> increase in water excretion
-High levels of cortisol might stimulate mineralcorticoid receptor (MR) --> Na+ reabsorption and K+ with H+ secretion at the distal convoluted tubule (water-impermeable) and ADH sensitive collecting duct --> hypernatremia, hypokalemia, and hypertension
This means that if cortisol DOES stimulate the MR, then the high Na+ plasma concentration would stimulate osmotically-sensitive regions in the brain and increase ADH from PP. --> ECF would increase and BP would rise, a condition called apparent mineralcorticoid excess syndrome.
*This would probably only happen if the 11β-OH dehydrogenase enzyme that converts the active cortisol into the inactive cortisone were missing.
However, for the hypertension as a cardiovascular effect, it seems more likely to happen if:
- There was a decreased synthesis of vasodilator prostaglandins (vasodilation = lowers BP)
- There was a stimulation of PNMT (phenylethanolamin N-methyl transferase) in the adrenal medullary chromaffin cells and methylation of noradrenaline to adrenaline (which increases BP)
- Increased sensitivity of vascular tissue to catecholamines and increased angiotensin II levels
- Angiotensin II is both a potent vasoconstrictor and also stimulates aldosterone production (which ultimately yields higher BP due to its Na+ reabsorption effects) in zone glomerulosa cells. (MGA = GFR, where M is mineralcorticoid and G is glomerulosa)
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Bone effects:
Glucocorticoids inhibit production of osteoblasts and increase osteoclastogenesis. Patients with chronically raised levels --> osteoporosis
Also, GFR is increased leading to inhibitory effects on renal Ca2+ reabsorption and an increased excretion of Ca2+ producing negative Ca2+ balance
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Gonads and reproductive effects:
Inhibit GnRH, decreasing LH and FSH release from AP (Anterior pituitary)
-Less stimulation of GnRH leads to less sexual function and physiological effects like amenorrhea.
-This also decreases libido, fertility, and stress-related effects in fetus
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Growth and development:
Stimulates the lung development in the late fetus
-Enhances surfactants produced by alveolar cells lining alveoli and small bronchioles in lungs.
-This increases organ expandability by reducing surface tension
-In the premature baby - needed for lung expansion since cortisol effects haven't yet occurred.
Cortisol --> Stimulates lung development
Excess causes depressed linear growth and bone development due to:
- Increased protein breakdown in muscle, connective tissue and bone matrix
- Inhibition of osteoprotegerin (inhibits osteoclast activity) and so osteoclasts resorb bone matrix, and stimulate RANKL, an osteoclast precursor differentiation factor.
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CNS Effects:
GR's and MR's are present in the brain
-Binding of hormones initiate endothelial cell production for the production of the Blood-brain barrier. (BBB)
-High concentrations however, are associated with neurological disorders such as depression and memory loss (loss of synaptic transmission)
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Stress response is immunosuppressive, anti-inflammatory, anti-allergic at high doses and therefore clinically relevant
Physiological effects of glucocorticoids is to keep the immune system in check by depressing it from time to time.
-By suppressing IL-2 production from CD4 Th and Th1 (T-helper) cells and preventing maturation and proliferation of the cells in response to Ag (Antigen) presentation
-By suppressing IL-2 production from CD4 Th and Th1 (T-helper) cells and preventing maturation and proliferation of the cells in response to Ag (Antigen) presentation
- Antigen - Substance that causes your immune system to produce antibodies against it.
Anti-inflammatory effects:
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| Normal Acute Immune Response |
-Inflammatory molecules to the area such as bradykinin
-Together with NO (Nitrous Oxide) initiate vasodilation and reddening of skin in area.
-Capillaries in area become leaky etc. leading to diapedesis. (movement of leukocytes toward cite of infection)
-Glucocorticoids inhibit release of inflammatory molecules like histamine etc. from leukocytes
-Stabilize the activation of cortisol and immune systems
-Used to treat disorders like rheumatoid arthritis and other autoimmune disorders. (ones that harbor symptoms of heavy inflammation)
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Anti allergic:
Example of an allergic reaction would have to be when histamine is released from mast cells leading to serious respiratory distress.
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Aldosterone:
Principal control system for the production and regulation of aldosterone in response to BP changes is the renin-angiotensin-aldosterone system (or RAA system)
Decreased BP --> Increased sympathetic activity + Stimulation of RAA --> Angiotensin II --> AT1R --> Aldosterone --> MR --> Increased Na+ reabsorption --> Increased plasma osmolarity --> Osmoreceptors stimulated --> V2R --> Increased water reabsorption --> ECFV expansion --> Increased BP response
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The RAA system
The juxtaglomerular cell responds to decreases in renal arterial blood pressure.
-Cells sit close to glomerulus of renal nephron, forming part of the walls of afferent arterioles through which blood reaches glomerular capillaries in Bowman's capsule.
-And adjacent to macula densa cells that detect the Na+ ion change
Renin can also be produced as a result of a decrease in Na+ ion concentration in the glomerular filtrate which is detected by the macula densa cells and communicated to the JG cells. Vasopressin and catecholamines on the other hand decrease renin release and provide both direct and indirect effect on the JG cells.
***Angiotensin II increases renal proximal rubular Na+ reabsorption, and in the CNS stimulates the thirst centers in the hypothalamus which stimulates ADH production. It also stimulates aldosterone production via a G-protein coupled AII receptor) as shown above.
Hypertension is caused by elevation of arterial blood pressure (aldosterone effects) and can be prevented using ACE inhibitors (angiotensin-converting-enzyme inhibitors)
-Together with NO (Nitrous Oxide) initiate vasodilation and reddening of skin in area.
-Capillaries in area become leaky etc. leading to diapedesis. (movement of leukocytes toward cite of infection)
- Diapedesis - The passage of blood cells through the intact walls of the capillaries, typically accompanying inflammation.
-Glucocorticoids inhibit release of inflammatory molecules like histamine etc. from leukocytes
-Stabilize the activation of cortisol and immune systems
-Used to treat disorders like rheumatoid arthritis and other autoimmune disorders. (ones that harbor symptoms of heavy inflammation)
-
Anti allergic:
Example of an allergic reaction would have to be when histamine is released from mast cells leading to serious respiratory distress.
-
Aldosterone:
Principal control system for the production and regulation of aldosterone in response to BP changes is the renin-angiotensin-aldosterone system (or RAA system)
Decreased BP --> Increased sympathetic activity + Stimulation of RAA --> Angiotensin II --> AT1R --> Aldosterone --> MR --> Increased Na+ reabsorption --> Increased plasma osmolarity --> Osmoreceptors stimulated --> V2R --> Increased water reabsorption --> ECFV expansion --> Increased BP response
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The RAA system
The juxtaglomerular cell responds to decreases in renal arterial blood pressure.
-Cells sit close to glomerulus of renal nephron, forming part of the walls of afferent arterioles through which blood reaches glomerular capillaries in Bowman's capsule.
-And adjacent to macula densa cells that detect the Na+ ion change
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| RAA System |
***Angiotensin II increases renal proximal rubular Na+ reabsorption, and in the CNS stimulates the thirst centers in the hypothalamus which stimulates ADH production. It also stimulates aldosterone production via a G-protein coupled AII receptor) as shown above.
Hypertension is caused by elevation of arterial blood pressure (aldosterone effects) and can be prevented using ACE inhibitors (angiotensin-converting-enzyme inhibitors)
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