lecture 9/10: adrenal medulla and cortex I

mesoendodermal

embryologic origin of adrenal corotex

transcortin and albumin

90% of cortisol is bound to plasma proteins. What is the plasma protein?

albumin, transcortin

60% of aldosterone is bound to what plasma proteins?

-cortisol has a longer half life due to more of it being bound

-60 min to 20 min

compare half lives of cortisol and aldosterone

absolutely! most potent mineralcorticoid

is aldosterone necessary for life?

-cytosol receptor on the principal cells of renall collecting ducts

where does aldosterone bind?

sodium reabsorption, potassium and hydroen excretion

-water reabsorption

major effects of aldosterone:

-RAAS system has greatest control

-ACTH is permissive

-extracellular potassium concentration

controllers of aldosterone secretion:

aldosterone

hormone associated with salt sparing, hypokalemia, metabolic alkalosis

mostly.... it is necessary during stress

-the most potent glucocorticoid

is cortisol necessary for life?

-binds cytosol receptor on various cells in liver, muscle/bone, and adipose tissue

site of action of cortisol

-catabolic on MSK, diabetogenic, anti-inflammatory

what are the major effects of cortisol

-ACTH controlled, and induced by stress

controllers of cortisol secretion

cortisol

hormone associated with hyperglycemia

no, they are very weak androgens

-tho they do serve as precursors to more important sex hormones

is androstenedione/DHEA necessary for life?

in early age, contributes to normal development of pubic and axillary hair

-contributes to systemic testosterone/estrogen levels which are esp important for post-menopausal women

-virilizing effect pathologically in women

Major effects of DHEA

ACTH

DHEA secretion is controlled by

conversion of cholesterol to pregnenolone by cholesterol desmolase

-performs cholesterol side chain cleavage

the first step in synthesis of the steroid hormones:

cholesterol desmolase

what is the rate limiting enzyme in steroid hormone biosynthesis

there is none! all steroid hormones coome from de novo synthesis from cholesterol

storage of steroid hormones

steroidogenic acute regulatory protein (StAR)

a protein that mediates the transport of intracellular cholesterol across the inner mitochondrial membrane to cholesterol desmolase enzyme

progesterone, cortisol, 11-deoxycorticosterone, corticosterone, aldosterone

name the 21 carbon pregnanes

27

how many carbons is cholesterol

androgens: 19

estrogen: 18

how many carbons are androgens and estrogens

17-hydroxylase

__________ enzyme is not in the glomerulosa layer so only the fasciculata and reticularis can synthesize cortisol

ACTH and CRH

circulating cortisol exerts negative feedback control of

POMC

corticotrophs synthesize ACTH by post-translational processing of what large precursor protein?

-increase cholesterol binding to cholesterol desmolase

-increase pregnenolone production

-increase StAR protein

generates all substrates needed to make cortisol

what are the most immediate actions of ACTH when it binds to MC2R receptor on adrenal cortex?

free cortisol

negative feedback of both cortisol and DHEA

melanocortin-2 receptor (MC2R)

What receptor does ACTH bind to in adrenal cortex?

cortisol, despite multiple other secretory products

what is the main regulator of the transcription of POMC?

binds to cytosolic receptor, which then moves to the nucleus where it binds to GREs and modulates gene expression and thus inhibits the synthesis of both the CRH receptor and ACTH.

does coortisol bind cytosolic or nuclear receptors?

-plasma cortisol decreases the mRNA and peptide levels of CRH iin paraventricular hypothalamic neurons

cortisol's negative feedback on CRH in hypoothahlamus

-episodic and circadian; lowest during sleep, highest in morning

-

pattern of cortisol and ACTH secretoni

-decreases fibroblast proliferation, decreasing connective tissue

-blocks collagen formation resulting in poor wound healing

effect of cortisol on skin

-catabolic effect on amino acids results in muscle wasting

-increased resorption of bone

effect of cortison on bone and muscle

-increases glycogen via gluconeogenesis

-inhibits insulin uptake of glucose by muscle and fat

effect of cortisol on the liver

-down regulates AA transporters, decreasing protein synthesis and increasing protein degradation

-promotess FFA release form adipose cells, induces expression of hormone sensitive lipase

describe the catabolic effects of cortisol

Hormone Sensitive Lipase (HSL)

• Enzyme in the adipose cell that is responsible for the hydrolysis of triglyceride into FFAs and glycerol, which then leave the adipose cell and enter circulation

• Inhibited by the hormone insulin

-interferes with insulin receptor, increasing blood glucose

-increases expression of gluconeogenic enzymes

-promotes FFA oxidation and ketone body production

describe the diabetogenic effect of cortisol

osteoporosis

chronic glucocorticoid exposure always leads to

-induces osteoblast apoptosis, also decreases colllagen synthesis

-osteoblast death leads to increased levels of RANKL, stimulatinig osteoclasts to resorb bone

-decrease calcium uptake from GI

detail cortisol's effect on bone

-bone resorption; RANKL stiimiulates osteoclasts

increased RANKL indicates

-increase synthesis of proteins that maintain lysosomal membrane (damaged lysosomes release many inflammatory cells)

-down regulate inflammatory cytokinens

-increase expression of lipocortins

-inhibits lymphocyte replication

detail the antiinflammatory effects of cortisol

-enhances myocardial performance; increased response to catecholamines

-decrease production of prostaglandins

-decreases vascular permeability

cortisol's effect on vascular system

increase GFR by causing vasodilation of afferent arterioles

effects of cortisol on the kidney

decrease REM sleep, can cause insomnia

-lower threshold for seizures

effects of cortisol on the CNS

-facilitates development of disaccharidase necessary for milk digestion and lung surfactant

-much of fetal cortisol comes from mom during early gestation

effect of cortisol on fetal development

3B-hyroxysteroid dehydrogenase

oxidizes pregnenolone to form progesterone in aldosterone synthesis

21 B hydroxylase

converts progesterone to 11-deoxycorticosterone in production of aldosterone

11 B-hydroxylase

converts 11-deoxycorticosterone to corticosterone in production to aldosterone

aldosterone synthase

-UPREGULATED by angiotensin II

converts corticosterone to aldosterone

•No storage pool of pre-synthesized aldosterone is available in the glomerulosa cell for rapid secretion.

•Secretion of aldosterone by the adrenal is limited by the rate at which the glomerulosa cells can synthesize the hormone

is there a storage form of aldosterone?

increasing activity of desmolase (SCC enzyme) and aldosterone synthase

ACTH, extracellular K+, and ang II increase secretion of aldosterone by

depolarizes glomerulosa cell membrane to activate calcium channels

how does increased plasma K+ increase aldosterone secretion?

-low plasma K+

-atrial natriuretic peptide (secrete from heart with high blood pressure)

inhibitors of aldosterone secretion:

hyperkalemia and loss of sodium

what causes death within a few days from lack of aldosterone?

increase sodium reabsorption

increase K+ and H+ excretion

-lack of aldosterone---> salt wasting, hypovolemia, hyperkalemia, metabolic acidosis

main effects of aldosterone

11-B-hydroxysteroid converts cortisol to cortisone, which has a weaker mineralcorticoid activity

-allows the aldosterone to bind more tightly to its receptor!

the affinity of mineralcorticoid receptors for cortisol is nearly the same as their affinity for aldosterone. how does the kidney overcome this to to use aldosterone?

11-B-hydroxysteroid dehydrogenase

this enzyme converts high levels of cortisol to a weaker form, cortisone, allowing for increased action of aldosterone

11-B hydroxysteroid dehydrogenase

-prevents cortisol from being converted to cortisone, thus more cortisol can bind to mineralcorticoid--> aldosterone like effects without high aldosterone

natural black licorice contains glycrrhizin which has a binding affinity to what enzyme?

-high consumption of black licorice

-mutation in gene coding for 11-B-dehydroxysteroid dehydrogenase 2 enzyme

2 ways by which a pt may present with signs of hyperaldosteronism, but have normal serum aldosterone and high cortisol metabolites

9a Fludrocortisone

synthetic, more potent form of aldosterone given pharmacologically

dexamethason> methylprednisone>prednisone

synthetic glucocorticoid with highest level of cortisol activity

testosterone, DHT or estrogen

DHEA and androstenedione convert to what in peripheral tissues?

males: little importance in childhood, hair growth; testes produce DHEA

females: MAJOR source of androgens, esp after menopause

rule of adrenal cortex androgens in males and females

adrenal androgens

__________ are called 17-ketosteroids and their metabolites can be measured in urine

autosomal recessive

inheritance of congenital adrenal hyperplasias

congenital adrenal hyperplasia

in ALL of these conditions, cortisol will not be synthesized and thus ACTH will be high; this continuous stimulation will cause hyperplasia of adrenals

increase in progesterone (aldosterone production

-increase 17-hydroxyprogesterone (cortisol production)

-100 fold increased androgen production due to shunting of pathway

a 21-hydroxylase defect will result in increase in what substrates?

-no aldosterone: hypotension, hyperkalemia, metabolic acidosis

-no cortisol: hypoglycemia

-females: masculination of genitalia, enlarged clitoris

-males: precocious puberty, aggressiveness

signs and symptoms of 21-hydroxylase defect

21-hydroxylase deficient CAH

-complete block is incompatible with life

most common CAH

test urine for weak androgen metabolites: 17-ketosteroids

how can you test for 21-OHase deficent CAH?

- 11-deoxycorticosterone in aldosterone production

-11-deoxycortisol in cortisol production

-these substrates act as weak mineralcorticoids

defect in 11-B hydroxylase will increase what substrates?

-decreased cortisol--> hypoglycemia

-increased (weak) mineralcorticoids: hypertension, hypokalemic, metabolic alkalosis

-increased weak androgens: virilization of females, precocious puberty in males

signs and symptoms of 11B-hydroxylase defect

precursors for aldosterone synthesis: pregnenolone and progesterone

defect in 17a-hydroxylase result in an increase in what substrates?

-hypertension, hypokalemia, metabolic alkalosis, mild hypoglycemia, undeveloped genitalia in males, genetic females affected later on

-HIGH aldosterone

presentation of 17a-hydroxylase defect

-11-deoxycorticosterone and corticosterone

-allows some cortisol activity in 17-hydroxylase CAH

substrates in aldosterone synthesis pathhway that may act as weak glucocorticoids

17a-hydroxylase CAH

which CAH?

21 hydroxylase CAH

which CAH?

11B-hydroxylase CAH

which CAH?

11-deoxycorticosterone

aldosterone precursor that can act as a mineralcorticoid and has some cortisol like effects

3B-hydroxysteroid dehydrogenase deficiency

enzyme in pivotal in production of all cortex hormones; fatal if deficient

cholesterol desmolase deficiency

fatal in utero as it prevents placenta from making necessary progesterone, which is essential to maintaining pregnancy

17,20 lyase deficiency

presents as a 17-OHase defect

you're chill :) produce adequate 11-DOC

effect of aldosterone synthase defect

Primary cushing's syndrome

•Elevated cortisol due to cortisol producing tumor of Adrenal Gland

•Low ACTH

•Increased Mineralocorticoid activity (high Cortisol = high Cortisone)

secondary cushing's disease

•Elevated Cortisol AND Androgens

•Due to hyper-secretion of ACTH

•AP tumor or sometimes lung tumor

Cushing's syndrome

pt presents withh muscles loss/weakness in arms and legs, decreased bone density, immune suppression, diabetes mellitus, think

cushings on kidney and vasculature

-effects capacity of body to convert cortisol to cortisone

-excess cortisol mimics aldosterone-- HTN, hypokalemia---> arrhythmia

cushings on the liver

-cortisol increases gluconeogennesis and increases insulin resistance causing hyperglycemia

cushings on repro

-cortisol exerts negative feedback on hypothalamus, decreasing GnRH release

-infertiliity, decreased libido, irregular menses

cushings on adipose tissue

-cortisol increases fat breakdown, preferentially in tissues not in the central area/face/ neck

-results in central obesity, moon facies

cushingss on skin and connective tissue

-increased cortisol decreases fibroblast prolferation, decreasing collagen synthesis

-result in skin atrophy, easy bruissing, puruple striae

cushings on muscle

-increasesd cortisol increases proteolysis, decreases protein synthesis, thus decreasing muscle growth in cardiac and skeletal muscle

-cardiomyopathy, heart failure, proximal muscle weakness

cushing syndrome caused by adrenal tumor

what causes these findings from dexamethasone suppression test?

Low dose: no decrease in blood cortisol

ACTH level: Low

In most cases, the high dose test is not needed

ectopic cushing syndrome

what causes these findings from dexamethasone suppression test?

Low dose: no decrease in blood cortisol

ACTH: high

High-dose test: no decrease in blood cortisol

cushing syndrome cauused by pit tumor

what causes these findings from dexamethasone suppression test?

Low dose test: no decrease in blood cortisol

High dose test: expected decrease in blood cortisol

most common: cushing disease

most common cause of ACTH dependent cushing synddrome

exogenous intake

most common cause of ACTH independent cushing syndrome