Physiology Block 3 Week 14 08 Adrenal Gland Flashcards
What steroid does each area of the adrenal gland produce?
Cortex:
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
Medulla
Zona glomerulosa
–aldosterone (mineralocorticoid)
Zona fasciculata and reticularis
–cortisol (glucocorticoid) and androgens (DHEA, androstenedione)
Medulla
–catecholamines
What steroid is produced by which zone is entirely determined by the zonal expression of specific steroidogenic enzymes
Loss of adrenocortical function =
Loss of adrenal medulla =
Bilateral Adrenalectomy =
Complete loss of adrenocortical function is fatal
Adrenal medulla is NOT necessary for life–does not have essential hormones (produces catecholamines)
Patients with bilateral adrenalectomy NEEDS treatment with glucocorticoid and mineralocorticoid, but not with catecholamine replacement
Major Steroid Hormones Produced by Adrenal Gland
Cortisol Aldosterone Corticosterone Dehydroepiandrosterone (DHEA) Androstenedione
Cortisol
MAJOR Glucocorticoid
Aldosterone
MAJOR Mineralocorticoid
Much more potent mineralocorticoid than cortisol
weaker glucocorticoid than cortisol
Corticosterone
Has both glucocorticoid and mineralocorticoid
weaker glucocorticoid than cortisol
more potent mineralocorticoid than cortisol
Rats and mice DO NOT make cortisol
–depend on corticosterone for glucocorticoid activity
Dehydroepiandrosterone (DHEA) and Androstenedione
Androgens (weaker than testosterone)
- -effects in early puberty
- -effects in menopause
What chemical differences between cortisol, corticosterone, and aldosterone could account for their different affinities for their cognate receptors?
Cortisol–2 hydroxyl groups
Corticosterone–1 hydroxyl group
Aldosterone–1 hydroxyl group + aldo carbonyl group
Steroidogenesis
- ACTH binds to its G-coupled membrane receptor
- Low density Lipoprotein (LDL) taken up and cholesterol esters stored in lipid droplets
- ACTH inc cAMP production
ACTH increases cAMP production has two effects
- Increases cholesterol ester hydrolase activity such that more cholesterol (released from lipid droplet) is available for transport to the mito
- Increases steroidogenic acute regulatory (StAR) protein activity
- -required for cholesterol transport across mito membrane
- -StAR transportation is rate-limiting step - Once cholesterol inside mito, steroidogenesis by specific enzymes to cortisol
- -first and last steps = mito enzymes
- -intermediate steps = smooth ER enzymes - Cortisol diffuses out of the cell
- -adrenal cortisol content is proportional to release
- -Cortisol (lipid) is not stored in granules like a peptide or amine
Steroidogenic Pathways
P450 side chain cleavage
P450c17 (17-hydroxylase)
3-beta-hydroxysteroid dehydrogenase
P450c21 (21-hydroxylase)
P450c11 (11-beta-hydroxylase)
P450scc
Mitochondrial
Catalyzes first step
Cholesterol to Pregnenolone
P450c17 (17-hydroxylase)
Smooth ER
Pregnenolone –> 17-OH-pregnenolone –> DHEA
Progesterone –> 17-OH-Progesterone –> Androstenedione
3-beta-hydroxysteroid dehydrogenase
Smooth ER
Only non P450 enzyme
3 reactions
Pregnenolone –> Progesterone
17-OH-pregnenolone –> 17-OH-progesterone
DHEA –> Androstenedione
P450c21 (21-hydroxylase)
Smooth ER
Progesterone –> 11-Deoxycorticosterone
17-OH-progesterone –> 11-deoxycortisol
P450c11 (11-beta-hydroxylase)
Mitochondrial
11-Deoxycortisol –> cortisol
What enzyme is most common decrease of function mutation in congenital adrenal hyperplasia?
P450c21 (21-hydroxylase)
Results in huge adrenal glands (size of the kidney!)
What will happen to cortisol production, adrenal 17-hydroxyprogesterone content, plasma DHEA, hypothalamic CRH release, plasma ACTH concentration, and adrenal size with a 90% reduction in fetal adrenal P450c21 expression?
What would happen to the fetus if the P450c21 mutation led to a 100% loss of enzyme function?
Cortisol is not being produced adequately
Need cortisol in developing fetus for lungs to develop
–results in ACTH increase!!!
ACTH results in the adrenal gland to work harder and get bigger (HYPERPLASIA)
The buildup of 17-hydroxyprogesterone spills into Androgen pathway–>Androstenedione
–lots of adrenal androgens produced
In boys, apparent after birth when androgen levels should come down
In girls, should have only very little testosterone
Exposure of a fetus to androgen results in turning a female phenotype into a male or ambiguous
Tx: If knew fetus had enzyme deficiency, what would you give the mother?
- -Dexamethasone–extremely potent glucocorticoid
- -crosses placenta and suppresses fetal ACTH
- -no hypertrophy = no androgen produced
Synthetic Glucocorticoids
Pharmaceutical
-minimal mineralocorticoid activity
Prednisone < Methylprednisone < Tiamcinolone «< Dexamethasone
Synthetic Mineralocorticoid
Fluorocortisol
Potent glucocorticoid but MUCH MORE POTENT mineralocorticoid activity
Mineralocoriticoid activity
Mineralocoriticoid activity is related to retaining salt, NaCl. Mineralocorticoids maintain electroylte balance by retaining Na+ and promoting K+ excretion.
Glucocorticoid Activity
Important for the biosynthesis and metabolism of carbohydrates, proteins and lipids
They are also involved in immune responses
Possess anti-inflammatory activity
Mechanism of Glucocorticoid Action via Glucocorticoid Receptor (GR)
Steroid hormones circulate plasma bound to binding proteins–long half-life
Cortisol bound to cortisol binding protein (CBG)
-dissociates and diffuses into the cytoplasm
Cortisol binds to GR
-dissociation from heat shock protein (HSP) complex
Conformational change allows cortisol-GR complex to enter the nucleus
–dimerizes and binds to glucocorticoid response elements (GRE) upstream from specific genes
Induces transcription of new mRNA and translation of new protein in the cytoplasm
–causes cellular function
Results in increased blood glucose over several hours (not instantaneous)
What if there was GRE mutation?
Every cell that responds to cortisol will be affected
Increased ACTH, leads to androgen synthesis, leads to hypertrophy
Glucocorticoid effect on CNS
Decrease in hypothalamic CRH
Decreases ADH (posterior pituitary) --induces water diuresis
Increase in appetite
–Cushing’s Syndrome
Glucocorticoid effect on cardiovascular
Absence of cortisol (adrenal insufficiency) results in hypotensive shock
Excess cortisol causes hypertension
Glucocorticoid effect on Liver
Increases gluconeogenesis = increased glucose
Glucocorticoid effect on Lungs
Required for normal surfactant production
Premature babies usually deficient in surfactant leading to respiratory distress syndrome
Glucocorticoid effect on Pituitary
Decreases ACTH (negative feedback)
Glucocorticoid effect on Kidney
Increases GFR
Glucocorticoid effect on Bone
Increase resorption = decreased bone formation
Osteoporosis
Glucocorticoid effect on Muscle
Catabolic
Decreases insulin sensitivity
Glucocorticoid effect on Immune System
Immune suppressive treatment to prevent graft vs. host in allogenic transplant recipients
Glucocorticoid effect on Connective Tissue
Decreases collagen synthesis
–easy bruising
Treatment for adrenal insufficiency
Steroids
-hydrocortisone = cortisol
Proopiomelanocortin (POMC) processing
POMC processed by prohormone convertase 1 (PC1) and PC2
–tissue specific expression of the enzymes results in different peptides produced
PC1 (anterior pituitary) = ACTH and beta-lipotropin production
PC2 (intermediate lobe of pituitary) cuts within ACTH and produces =
- gamma, alpha, and beta-melanocyte stimulating hormone (MSH) = hyperpigmentation in adrenal insufficiency
- corticotropin-like intermediate peptide (CLIP)
Stress effect on pituitary gland
Stress excites hypothalamus
Increases release of corticotrophin releasing hormone (CRH) from hypothalamic nerves into portal blood
At anterior pituitary, CRH stimulates increase of ACTH release into venous circulation
ACTH stimulates adrenal cortex to increase cortisol release
Cortisol effects:
- negative feedback on hypothalamus and anterior pituitary
- gluconeogenesis (inc glucose production)
- protein mobilization (AA needed for gluconeogenesis)
- fat mobilization (good source of energy)
- stabilization of lysosomes
–> results in relieving stress
In a patient with no adrenal function, what time would you prescribe for their cortisol replacement (assuming pills taken twice a day)?
Would you give the same dose each time?
Morning and lunch
Larger dose at 8am
Circadian rhythm peaks at 7-8AM, decreases throughout the day
Begins to increase again at 4am
ACTH and cortisol response to Insulin injection
Insulin injection increases glucose uptake in muscle
–sharp decrease in plasma glucose
Glucose sensors in hypothalamus cause CRH cell body depolarization
Increased CRH release into portal veins causes ACTH release
ACTH release causes and increase in plasma cortisol
Cortisol helps restore blood glucose to normal via gluconeogenesis, protein mobilization, and fat mobilization
Hypopituitarism–ACTH and cortisol response is lacking
What happens to adrenal gland size when has secondary adrenal insufficiency?
Low ACTH leads to loss of adrenal function and size
Even if give dose of ACTH, will not respond well because adrenal gland is not there in volume
Congenital Adrenal Hyperplasia (CAH)
21-hydroxylase insufficiency
Leads to decrease in cortisol
–no longer negative feedback inhibiting ACTH release
Drives steroidogenesis and increases adrenal growth (adrenal hyperplasia)
Substrates upstream block build up (17-hydroxyprogesterone and 17-hydroxypregnenolone)
- -this huge increase in substrate can lead to sufficient cortisol production to allow fetus to survive
- -will spill into androgen pathway
XX: causes virilization and ambiguous genitalia
XY: not apparent because have normally circulating testosterone
Dexamethasone (acts as an analog) fools brain into thinking there is excess cortisol, inhibiting ACTH release, inhibiting androgen production to prevent virilization
-will also have working surfactant
Which of the following will lead to a decrease ACTH secretion from the anterior pituitary?
Inhibitor of StAR action
Injection of ACTH
Glucocorticoid Receptor blocker
Adrenalectomy
Injection of ACTH has negative feedback effects on anterior pituitary and hypothalamus
“why would i make ACTH if you are going to provide it”
StAR–necessary for cortisol production and cholesterol transport
Inhibitor: cortisol would go down, and ACTH up
Activator: cortisol would go up and ACTH would go down thru negative feedback
GR Blocker–brain and pituitary think there is no cortisol; increases ACTH to inc cortisol
Adrenelectomy–there is no cortisol, so brain continually makes ACTH, but no adrenal glands to respond to it
Adrenal Insufficiency
Clinically significant decrease in cortisol release from adrenal cortex:
Primary and secondary insufficiency
Primary Adrenal Insufficiency
Addison’s Disease
Physical destruction of the adrenal gland
-loss of adrenal function
Hypothalamus and pituitary is relieved of cortisol negative feedback
-results in a large increase in plasma ACTH
ACTH cannot restore adrenal function because gland is destroyed
Secondary Adrenal Insufficiency
Hypopituitarism
Decrease in CRH decreases ACTH release
Low ACTH results in loss of adrenal function and size (atrophy)
Not enough ACTH to maintain adrenal function
- decreases amount of cortisol made
- even if gave injection of ACTH, adrenal gland is too small and weak to restore function and adequate production of cortisol
Causes of Primary Adrenocortical Insufficiency
Autoimmune (80%)
-recognizes own tissue as foreign and destroys it
Ex. Graves disease (hyperthyroidism), Hashimoto’s thyroiditis (hypothyroidism), type 1 diabetes mellitus (immune destruction of pancreas)
Tuberculosis (20%)
What is effect of removal of entire pituitary gland on zonae fasciculata and reticularis?
Controlled by ACTH. Due to lack of ACTH supplied by anterior pituitary, will dramatically shrink in size.
Appear as bilateral adrenal atrophy
What is effect of removal of entire pituitary gland on zona glomerulosa and medulla?
The zona glomerulosa and medulla do NOT shrink because not under control of ACTH
What is the effect of long term glucocorticoid treatment?
Can you just stop treatment?
There will be a suppression of ACTH by the glucocorticoid (cortisol) negative feedback–adrenal glands will shrink
Patient will display symptoms of glucocorticoid EXCESS DURING treatment
Patient will have secondary adrenal insufficiency if glucocorticoid therapy is abruptly stopped
Takes a long time for adrenal glands to regrow, so patients on long term glucocorticoid therapy have to be slowly and carefully weaned from therapy
As glucocorticoid dosage is weaned, plasma ACTH starts to increase.
-takes months for hypothalamus and pituitary to “wake up”
As ACTH increases, adrenal glands start to regrow and produce cortisol
An overshoot of ACTH is what causes the normalization of cortisol
Clinical features of adrenal insufficiency
Weakness
Fatigue
Anorexia
Weight Loss
What causes hyperpigmentation in primary adrenal insufficiency but not secondary?
In primary adrenal insufficiency the adrenal gland is not present. It signals that there is no cortisol.
ACTH is released to act on adrenal gland to produce it. Since no adrenal gland, ACTH builds up.
Overabundance of ACTH breaks down to melanocyte stimulating hormone (MSH) and CLIP, which cause hyperpigmentation
In Secondary Adrenal Insufficiency, there is an inadequate amount of ACTH produced–NO HYPERPIGMENTATION
Why does adrenal insufficiency cause hypotension?
Cortisol helps maintain sensitivity of vasoconstrictors
–permissive effect since cortisol itself it not a vasoconstrictor
Cushing’s Syndrome
Increased glucocorticoid activity in the blood
- exogenous: glucocorticoid therapy
- endogenous: excess cortisol from adrenal gland
Physical Features:
Fat pads, moon face, pendulous abdomen
-due to overeating and a specific effect of cortisol to redistribute fat
Red cheeks
-thin skin, polycythemia, increased blood flow
Bruisability
-thin skin, hypertension
Thin skin
-connective tissue effect
Striae
-stretch marks due to pendulous abdomen (purple)
Poor muscle development
-myopathy due to cortisol effect on muscle to provide AA as hepatic gluconeogenic precursors
Poor wound healing
-immune suppression
Cushing Syndrome: ACTH Independent
Cortisol = high ACTH = low
Benign Adrenal tumor making cortisol (unregulated) in the absence of ACTH
The tumor will grow
Ex. Glucocorticoid Therapy
- glucocorticoid activity high
- cortisol is high
- ACTH is low
Patients on Prednisone
- low ACTH and low cortisol because adrenal gland atrophy
- lots of glucocorticoid activity because of all the steroid they are taking
Cushing Syndrome: ACTH Dependent, Pituitary Tumor
Cushing’s Disease
Pituitary corticotroph tumor that has lost some sensitivity to cortisol negative feedback
–allows a higher ambient cortisol level (increased negative feedback set-point)
Pituitary Adenoma overproducing POMC and ACTH
ACTH increase causes cortisol increase
However, the tumor isn’t suppressed with normal amount of cortisol
The set point is continuously increased incrementally
ACTH is normal (reference range)
Adrenal glands are HUGE
Cushing Syndrome: ACTH Dependent, Ectopic Tumor
Cell that normally don’t make ACTH begin expressing POMC
Most common–neuroendocrine tumors
-have machinery to process POMC
Results in ACTH Dependent Cushing like pituitary tumor
What measurements could you do to differentiate Cushing’s Disease and Ectopic ACTH secretion?
Do MRI of the pituitary to visualize a tumor
How could you differentiate ACTH-dependent and ACTH-independent Cushing’s syndrome?
ACTH-dependent:
–ACTH is NOT low, is within the reference range
You suspect a patient is taking prednisone causing the Cushing’s phenotype. How could you distinguish that patient from one with endogenous ACTH-independent Cushing’s syndrome?
The cortisol levels will be lower if the patient is taking prednisone due to gland atrophy
In ACTH independent Cushing syndrome, a tumor is making a cortisol without the regulation of ACTH
How do you remove a pituitary tumor?
Transphenoidal route
–endonasally or sublabially
What will happen to cortisol secretion within a few hours after removing an ACTH-secreting pituitary tumor?
What should the surgeon prescribe these patients post-op?
Cortisol levels will drop
Needs to be on cortisol meds and weaned down
Which of the following will have a normal cortisol response to injection of ACTH?
Patient with primary adrenal insufficiency
Patient with secondary adrenal insufficiency
Patient on long-term glucocorticoid therapy
Patient 2 years after a unilateral adrenalectomy
Patient 2 years after a unilateral adrenalectomy
