Notes on Adrenal Hormones
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Notes on Endocrinology
Notes on Adrenal Hormones
• Adrenal cortex is divided into 3 zones: zona glomerulosa (outer), zona fasciculata (middle), and zona reticularis.
• Zona glomerulosa, 15% of adrenal gland, secretes mainly mineralocorticoids.
• Zona fasciculata, 50% of adrenal gland, secretes glucocorticiods.
• Zona reticularis, 7% of adrenal gland, secretes androgens.
• Cells in all three layers have high lipid content, mainly cholesterol esters.
• Cholesterol is used for the synthesis of steroid hormones.
• This cholesterol is absorbed from: LDL uptake from blood, and synthesis from acetyl-CoA.
• All adrenocortical hormones represent chemical modifications of the steroid nucleus, a 21 carbon atom-4 ring structure derived from cholesterol.
• Secretion by zona fasciculata and zona reticularis is mainly controlled by the hypothalamic-pituitary system.
• Secretion by zona reticularis may be controlled by ACTH through a negative-feedback cycle.
• Low blood levels of glucocorticoids, mainly cortisol, stimulate neurosecretory cells in the hypothalamus to secrete corticotroin-releasing hormone, CRH, which promotes release of ACTH from anterior pituitary.
• ACTH flows in the blood to adrenal cortex, stimulating glucocorticoid secretion.
• ACTH binds to its receptors on the plasma membrane of zona fascitulata and reticularis cells, activating protein kinase A.
• Protein kinase A increases activity of cholesterol ester, hydrolase, increasing conversion of cholesterol esters to free cholesterol, which also leads to the formation of pregnenolone, a rate-limiting step in steroid synthesis.
• Thus, cortisol is produced from cholesterol esters.
FACTORS INFLUENCING FACTORS INFLUENCING ACTH ACTIVITY
STIMULATION
• CRH
• Cortisol decrease -adrenalectomy, metyrapone
• Sleep-wake transition
• Stress
• ADH
• alpha-adrenergic agonists
• beta-adrenergic antagonists
• Others: serotonin, Ach, interleukins, gastrointestinal peptides
INHIBITION
• Cortisol increase
• Encephalins
• GABA
• Opioids
• ACTH
Plasma Cortisol level increased by:
• Factors increasing ACTH production
• Stress
• Surgery
• Burns
• Infection
• Fever
• Psychosis
• Acute anxiety
• Prolonged and strenuous exercise
• Hypoglycaemia
Cortisol Metabolism
• Cortisol isn’t broken down in tissues where it exerts its functions, but is converted to a less active state called cortisone.
• Some is excreted in urine, unchanged.
• Some is degraded in liver to inactive dihydrocortisol and tetrahydrocortisol, which are conjugated with glucuronic acid.
• Thus, renal excretion of corticosteroids and their metabolites can measure steroid output and metabolism over a 24-hour period.
Mineralocorticoids
• Aldosterone is a major mineralocorticoid.
• It is Synthesised exclusively in the zona glomerulosa cells.
• It regulates homeostasis of two mineral ions, Na and K, that help regulate blood and volume.
• Aldosterone secretion is controlled by the rennin-angiotensin-aldosterone pathway.
• Dehydration > decrease in blood volume > decrease in BP > stimulation of juxtaglomerular cells in kidneys > increased rennin > liver produces angiotensin > increased angiotensin I > ACE converts angiotensin I to angiotensin II > adrenal cortex produces aldosterone > increased Na and water absorption in kidneys > increased blood volume > increased BP > vasoconstriction of arteries.
• ANP inhibits synthesis and release of aldosterone.
• Some converted in the liver to tetrahydroaldosterone glucuronide
• Some conjugated with glucuronic acid in liver and kidney at 18 oxo-position
• Very little free aldosterone in urine.
• Aldosterone stimulates K secretion in renal tubes.
Adrenocorticoretical Sex Hormones
• Sex hormones are produced mostly in zona reticularis.
FAQ
1. Define the following terms: Corticosteroid; Mineralocorticoid; Glucocorticoid; Androgen.
Corticosteroid: A 21-carbon steroid produced in response to ACTH (from pituitary gland), or produced due to release of angiotensin II. This class of steroids influences metabolism. They are used clinically for suppression of ACTH secretion by the anterior pituitary.
Mineralocorticiod: A type of corticosteroid chiefly influencing the regulation of electrolyte and water balance.
Glucocorticoid: A type of corticosteroid chiefly influencing carbohydrate, fat and protein metabolism.
Androgen: A hormone which produces male sexual characteristics
All the above hormones are produced by the adrenal cortex.
2. List the major functions of the glucocorticoids.
METABOLISM
Permissive activity to facilitate the mobilization of fuels.
gluconeogenesis (protein and fat to glycogen).
lipolysis.
ketogenesis.
Powerful antagonism of the actions of insulin on glucose metabolism, inhibiting insulin-stimulated glucose uptake in muscle and adipose tissue and reversing insulin suppression of hepatic glucose production.
MUSCLE
maintains contractility and work performance of skeletal and cardiac muscles.
increase Ach synthesis in myoneural junctions.
increase myocardial Na+,K+-ATPase and beta-adrenergic receptors.
Excess cortisol - decreases muscle protein synthesis, increases muscle catabolism and decrease muscle mass and strength.
BONE
inhibition of bone formation.
reductiion of synthesiis of type I collllagen.
decrease rate of diifferentiiatiion of osteoprogeniitor celllls to osteobllasts.
decreased absorptiion of callciium from GIT.
antagoniize actiions of callciitriioll, diimiiniish synthesiis of callciitriioll.
increase rate of bone resorption.
CONNECTIVE TISSUE
thinning of skin and capillaries by inhibiting collagen synthesis
increase capillary fragility.
VASCULAR SYSTEM
Required for maintenance of normal blood pressure.
Permits normal responsiveness of arterioles to the constrictive action of catecholamines and angiotensin.
decrease production of vasodilator prostaglandins.
decrease permeability of vascular endothelium.
KIDNEYS
Increase glomerular filtration rate.
iincrease gllomerullar pllasma fllow.
decrease pregllomerullar resiistance.
Increase ammonium ion generation from glutamate in response to acid load.
Increase phosphate excretion by decreasing reabsorption from.
PCT
Increase sodium retention and potassium excretion.
FETUS
Cortisol facilitates in utero maturation of the CNS, retina, skin, GIT and lungs.
CNS
Modulation of excitability, behavior, sleep and mood.
Salty taste and other sensory stimuli are dampened.
Improves ability to integrate sensations that are perceived and organize appropriate responses.
INFLAMMATORY and IMMUNE RESPONSES
Inhibition of reactions that are normally activated by inflammation.
Suppression of the immune system responses to foreign substances, hence its use in prevention of rejection of transplanted tissue of non-self origin.
*Cortisol is essential to the survival of the severely stressed, traumatized or infected individual.
3. What are the effects of cortisol on blood glucose? How is this effect mediated?
• Low blood levels of glucocorticoids, mainly cortisol, stimulate neurosecretory cells in the hypothalamus to secrete corticotroin-releasing hormone, CRH, which promotes release of ACTH from anterior pituitary.
• ACTH flows in the blood to adrenal cortex, stimulating glucocorticoid secretion, and raising blood glucose.
• The effect is mediated by receptors (neurosecretory cells in the hypothalamus), corticotrophs in the anterior pituitary, and effectors (cells of zona fasciculata)
4. What do we mean by the "permissive actions" of cortisol?
Cortisol works with other steroids to reinforce their actions.
5. Describe the functions of aldosterone.
• Stimulates active sodium reabsorption in the renal tubules.
• Stimulates active potassium secretion in renal tubules.
6. Why are aldosterone-blocking drugs administered to control hypertension?
Aldosterone works by retaining Na secretion through the kidneys, hence, increasing blood pressure. If the action of aldosterone is blocked, Na would be secreted by the kidneys, hence, lowering blood pressure.
7. A patient secretes an excess of cortisol but normal amounts of aldosterone. Will his blood pressure be affected? Explain.
Excess cortisol would cause higher than normal blood glucose, which further causes high BP. If the aldosterone levels are normal, the patient would become hypertense.
8. What are the functions of the sex hormones produced in the adrenal cortex?
Assist in development of secondary sexual characteristics; axillary and pubic hair, contribute to libido and are a source of estrogens after menopause.
9. How important is the adrenal cortex in the production of androgens in a normal man? A normal woman?
In both males and females, the adrenal cortex secretes androgens. The major androgen secreted is dehydroepiandrosterone (DHEA). Androgen secretion is stimulated by ACTH.
Introduction:
• ACTH controls secretion of cortisol and adrenal androgens.
• Low dose dexamethasone suppresses pituitary ACTH secretion (and therefore 17-hydroxycorticosteroid production and excretion) in people with a normal pituitary response to the negative feedback action of glucocorticoids.
• Angiotensin II controls secretion of aldosterone.
Regional adrenal functions:
Zona glomerulosa:
Produces: aldosterone.
Damage results in: Na loss, decreased ECF volume, low BP, circulatory shock, death.
Zona fasciculate and zona reticularis:
Produces: cortisol and androgens.
Damage results in: circulatory failure, inability of release glucose and fatty acids in plasma.
Medulla:
Produces: epinephrine.
Damage results in: inability of release glucose and fatty acids in plasma.
C21 steroids:
• Cortisol; excreted as H2O-soluble metabolites.
C19 steroids:
• Adrenal androgens: DHEA.
• Testosterone.
C18 steroids:
• Estrogens, eg., estradiol.
• Aromatase converts androgens into estrogens.
Steroid hormone synthesis:
Rate-limiting step: desmolase converts cholesterol to pregnenolone; this is also the starting point.
Zone glomerulosa: angiotensin II promotes synthesis.
• Pregnenolone to progesterone to 11-deoxycorticosterone to corticosterone to anderosterone.
Zona fasciculata and zona reticularis:
Enzyme deficiencies:
21-beta-hydroxylase deficiency:
• Causes decreased aldosterone in zona glomerulosa.
Effect in the zona fasciculata and zona reticularis:
• Decreased mineralocorticoids (decreased Na/ECF/low BP) and glucocorticoids (increased ACTH/androgen).
11 beta-hydroxylase deficiency:
Effect in the zona fasciculata and zona reticularis:
• Excessive androgen; increased BP.
• Causes decreased aldosterone in zona glomerulosa.
17 alpha-hydroxylase deficiency:
Effect in zona fasciculata and zona reticularis:
• Increased BP due to increased ACTH.
Effect in testes:
• Decreased testosterone.
Effect in ovaries:
• Decreased estrogens.
Actions of glucocorticoids:
• These include GH, glucagon, corisol, and epinephrine.
• Released under stress.
• Insulin decreases under stress.
Metabolic actions of cortisol:
• Protein degradation, lipolysis, mobilized plasma glucose.
Permissive actions of cortisol:
• Enhances activity of glucagon and catecholamines.
Control of ACTH and cortisol secretion:
• Stress releases CRH: increased in morning, and decreased during night. ACTH, endorphins released in end.
• ACTH causes release of cortisol; excessive secretion darkens skin - Addison's disease.
• Endorphin: pain modulators.
Cushing syndrome:
• Secondary hypercortisolism due to pituitary malfunction.
Physiologic actions of aldosterone:
Aldosterone tells collecting ducts in kidneys to absorb Na in exchange of K.
Tubule lumen becomes - charged; attracts H+ and K+.
Control of aldosterone secretion:
• ACTH stimulates aldosterone secretion.
• Rennin-angiotensin system promotes aldosterone secretion.
• RA system stimulated by sensory cells in juxtaglomerular apparatus; monitor afferent arteriole pressure.
Angiotensin II:
Secreted due to: low BP, low Na, increased simulation of juxtaglomerular cells.
Causes: vasoconstriction; increased TPR; release of aldosterone.
Aldosterone increased:
• Hemorrhage, sweating, hyperkalemia, etc.
Aldosterone decreased:
• Weightlessness (eg., outer space, water).
Addison's disease:
• Primary hypoaldosteronism.
• Primary adrenal insufficiency.
• High ACTH and hyperpigmentation.
• Hypotension: decreased glucocorticoids and mineralocorticoids.
• Increased renin and angiotensin.
• Loss of female body hair due to decreased androgens.
• Decreased glucocorticoids, decreased glucose.
• Increased ADH.
Secondary hyperaldosteronism:
• Blood collects in venous system.
• Decreased CO, BP.
• Caused due to CHF, hepatic cirrhosis, constriction of vena cava.
Additional Readings:
Basic Endocrinology
Introduction to Endocrinology
1. Hypothalamic-pituitary system
2. Adrenal Hormones
3. Antidiuretic Hormone (ADH) and ECF Regulation
4. Endocrine Pancreas
5. Growth Hormone
6. Adrenal Medulla
7. Hormonal Control of Calcium and Phosphate
8. Thyroid Hormones
9. Hormones of Male Reproduction
10. Hormones of Female Reproduction
11. Fluid Compartments of the Body
12. Notes on Hypothalamus Anterior Pituitary and Thyroid
13. Additional Notes on Female Reproduction
14. Hormonal Signaling Pathways
Related Topics
1. Histology of the Endocrine System
2. Histology of the Male Reproductive System
3. Histology of the Female Reproductive System
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