Adrenal cortex and mineralocorticoids

adrenal cortex

produces many steroid hormones, including cortisol, aldosterone, the adrenal androgens & small amount of estrogens

definitive zone adrenal gland

after birth, will form into the 3 zones of adult adrenal cortex; in fetus, produces fetal cortisol

fetal zone of adrenal glands

produces androgen precursors (DHEA & DHEA sulphate) that are further metabolized by fetal liver and placenta to produce high concentration of estrogens during pregnant, after birth this zone disappears

andrenal cortex sub layers

• zona glomerulosa

• zona fasciculata & zona reticularis

zona glomerulosa

lacks steroidogenic enzyme required for synthesis of cortisol and androgen precursors

zona fasciculata & zona reticularis

lack steroidogenic enzyme required for aldosterone synthesis

mineralocorticoids

steroid hormones that promote Na+ and fluid retention, and K+ excretion (electolyte balance)

what is the most important mineralocorticoid from physiological standpoint

aldosterone

for human what is the primary source of cholesterol

LDL cholesterol imported via LDL receptor from circulation

lipoprotein complexes

• produced by liver; protein studded spheres, hydrophilic exterior with hydrophobic core and transports lipids in circulation

low density lipoprotein (LDL)

• contain large amounts of cholesterol

• in adrenal cortex ACTH increases LDL receptors (and other mechanisms to increase free cholesterol and facilitate steroid synthesis = secretion)

receptor mediated endocytosis

• LDL bound LDL receptors cluster in clathrin-coated pits

• in endosome: dissociation of LDL and LDL receptor (receptor is typically recycled/returned to cell membrane)

• in lysosome, cholesterol esters in LDL hydrolyzed by hormone sensitive lipase (HSL): free cholesterol

some cholesterol derived from..

de novo cholesterol synthesis or mobilized cholesterol esters in lipid droplets

where is free cholesterol delivered

it is delivered to mitochondria

steroid hormone synthesis zona glomerulosa

• zona glomerulosa (outer layer, adrenal cortex)

• cytochrome P450 enzymes: large family of enzymes (compartment & tissue specific localization) that catalyze oxidation

• regulator Angiotensin II (primary regulator of alodsterone), increase steroidogenic acute regulatory protein & P450 levels

• expression of cytochrome P450 enzyme aldosterone synthase (P450aldo) leads to production of aldosterone

• cholesterol —> pregnenolone —> progesterone—> aldosterone

• no synthesis of glucocorticoids or sex steroid hormones because lack cytochrome P450 enzyme 17 a hydroxylase

aldosterone physiological effects

• promotes Na and fluid retention, and K excretion

• major target: distal tubule of kidney (stimulates exchange of Na and K)

• increased active resportion of sodium (Into exracellular fluid)

• as a result, increased passive resorption of water (follows sodium) with a consequent expansion of extracellular fluid volume

• due to ion exchanges, there is also increased renal excretion of potassium, to be excreted in urine

• these responses lead to increased blood pressure and blood volume; therefore elevated aldosterone signalling can be associated with hypertension

aldosterone signaling- mineralocorticoid receptor

• occurs in renal distal tubular epithelial cells

• mineralocorticoid receptor (MR)

• nuclear receptor that binds with equivalent affinity to both aldosterone and cortisol

• cortical concentration in circulation is much higher than aldosterone

• aldosterone sensitive cells express the degrading enzyme 11-B-hydroxysteroid dehydrogenase (11B-HSD), which converts cortisol into cortisone (biologically inactive- very weak affinity for MR)

• allows aldosterone to bind to MR without significant competition

non genomic effects aldosterone

• rapid non genomic actions that might participate in human hypertension and cardiovascular disease

• seem to be due to activation of unidentified cell surface receptor: unknown whether MR is invovled

what strongly stimulates secretion of aldosterone

elevated K+ in plasma

Vasopressin

• antidiuretic hormone

• important water retaining hormone in mammals (regulator of osmolality)

• increased plasma osmolality = secretion

• vasopressin binds to receptors, chiefly on cells of nephon collecting ducts (water rebasorbed to plasma instead of excreted)

• stimulates production of more intracellular water channels (aquaporin 2) and transfer of existing aquaporin 2 to cell membrane

• vasopressin also increases blood pressure by binding to receptors on vascular smooth muscle (causes blood vessels to contract)

stimuli for aldosterone secretion

• main stimulus: the hormone Angiotensin II

• elevated K+ in circulation

• to limited extent adrenocortiocotropic hormone/ACTH (GPCR: Gas mediated signaling) but most receptors for ACTH are localized in the zona fasciculata

intracellular Ca

• plays key role in early rate limiting step of aldosterone synthesis

• increased cytosolic ca promotes cholesterol transport to mitochondria in zona glomerulosa cells

renin

• enzyme released by kidney’s juxtaglomerular cells

• stored in granules and released in response to specific signals (Na levels, K levels, renal perfusion pressure, sympathetic nervous system)

• promoted when renal perfusion pressure is low, or there is low tubular Na+ (dehydration, hemorrhage_: suppressed with hypertension or high Na

angiotensinogen

glycoprotein prohormone synthesized in & secreted by liver, cleaved by renin while in blood

angiotensin I

not biologically active cleaved by ACE (angiotensin converting enzyme)

angiotensin-converting enzyme (ACE)

on cell membranes of certain tissues (vascular endothelial cells of lungs)

angiotensin II

main form of biologically active angiotensin; in addition to increase aldosterone has other key effects

aldosterone in circulation

• 50-70% bound to either albumin or (Weakly) to corticosteroid binding globulin

• 30-50% “free” in plasma

hypothalamus pituitary adrenal axis

• CRH secreting neurons

  • secrete corticotropin releasing hormone which is a peptide hormone that signals to corticotrophs to stimulate secretion of ACTH & other POMC derivatives

  • CRH secreted in response to stress (hypothalamus perceived threat to well being or homeostasis)

• corticotroph cells (in anterior pituitary)

  • secrete adrenocotricotropic hormone & other POMC derivatives (B-endorphin)

  • ACTH = peptide hormone that stimulates adrenal cortex to secrete glucocorticoids, mineralocorticoids, androgens

• adrenal cortex

  • cortisol is primary glucocorticoid hormone in humans helps body respond to stress (restore homeostasis)

which hormone has a notable circadian rhythm

adrenocorticotropic hormone (ACTH) has a notable circadian rhythm, characterized by high levels during early morning hours

cholesterol uptake acth

ACTH increases LDL receptors and regulates formation of microvillar channels in plasma membrane (trap HDL lipoprotein particles)

cholesterol mobilization

PKA phosphorylates and increases lipase activity of hormone sensitive lipase (HSL)

steroidogensis

ACTH increases StAR & P450scc levels & activities (& other levels of steroidogenic activities)

trophic effects of ACTH

chronic ACTH stimulation causes adrenocortical hyperplasia & hypertrophy

ACTH in adrenal cortex most receptors are where

most receptors in Zona fasciculata

when does adrenal secretion of androgens & estrogens begin

2-3 years before onset of puberty

what is adrenarche

correlates with appearance of a continuous zona reticularis in adrenal cortex

adrenal androgens are converted to

• converted in peripheral tissues to more potent testosterone and dihydrotesterone or via aromatase they can eventually be converted to estrone/estrogens

what acutely stimulates DHEA & adrostenedione

ACTH

premenopausal females

33-60% of testosterone & DHT from adrenal precursors

post menopause

almost all estrogens derived from aromatization of adrenal androgens

which blood binding proteins is cortisol bound to

• some to albumin

• most to corticosteroid-binding globulin

glucocorticoid receptors

• member of nuclear receptor superfamily of transcription factors (Type I/steroid receptor)

• have ligand binding domain, DNA binding domain that interacts with specific DNA sequences

• act as transctiption factors, have relatively delayed effects and aventually change protein levels in different targets

mineralcorticoid receptor

has equal affinity to both aldosterone and cortisol

can aldosterone bind to glucocorticoid receptor

yes, there is a considerable homology between glucocorticoid receptor and mineralocorticoid receptors

cortisol non genomic effects

• has non genomic effects by several mechanisms, including a membrane bound glucocorticoid receptor variant, and/or G protein dependent changes (and downstream kinases)

• early and rapid pro apoptotic, immune modulatory, & metabolic effects may compliment genomic effects

glucocrticoids general effects

• increase blood glucose levels via effects on carb, protein, and lipid metabolism

• stimulation of gluoconeogensis in liver (synthesis of glucose from amino acids and lipids) by increasing expression of gluconeogenic enzymes, also increase of glycogen deposition in liver

• inhibiting glucose uptake and utilization in skeletal muscle, adipose tissue (a form of insuln resistance)

• stimulating lipolysis in adipose tissue (glycerol = substrate for gluconeogensis, and increased release of free fatty acids into circulation for energy/sparing glucose)

• in skeletal muscle, cause atrophy and reduced protein synthesis (mobilization of amino acids = substrate for gluconeogensis)

• inhibit osteoblast function & induce negative calcium balance: increase calcium excretion by kidneys & inhibit calcium absorption in kidneys, in children excess glucocorticoid suppress growth via these actions and inhibiting IGF-1

• increase blood pressure

• in long term, promote increased central adiposity

• affect central nervous system, cognitive mood & function

glucocorticoids immune effects

• syppress immunologic responses at many levels

• decrease migration of inflammatory cells to site of injury

• decrease enzymes involved in synthesizing prostagalndins

• decrease lymphocyte counts (redistribution & apoptosis)

• decrease cytokine production from lymphocytes

• decrease antigen processing and antibody production

• synthetic gluocorticoids widely used as anti inflammatory/immune suppressing drugs to treat inflammatory conditions such as arthritis, asthma or dematitis

cushing syndrome

• excess cortisol (caused by excess ACTH from pituitary gland tumor or adrenal tumour or therapeutic administration of glucocrticoids)

• central obesity

• muscle weakness and wasting

• many other symptoms (Inhibition of bone formation)

addison disease

• insufficient cortisol, often accompanied by aldosterone deficiency; relatively rare; can be caused by infectious disease (tuberculosis, HIV) or most commonly by autoimmune destruction of the adrenal cortex

• decreased adiposity

• muscle weakness

• hypoglycemia

• also dehydration, hypotension, and Na & K imbalances

• 21 hydeoxylase deficiency

21 hydroxylase deficiency

• autosomal recessive disorder (genetic disorder)

• most common cause of congenital adrenal hyperplasia

• most severe form = deficiency of both cortisol and aldosterone

• reduced cortisol, reduced negative feedback, elevated ACTH that can cause hyperplasia of adrenal cortex, accumulation of cortisol precursors & diversion to more androgens