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Physiology > Physiology Block 3 Week 14 08 Adrenal Gland > Flashcards

Physiology Block 3 Week 14 08 Adrenal Gland Flashcards

1
Q

What steroid does each area of the adrenal gland produce?

Cortex:

  • Zona glomerulosa
  • Zona fasciculata
  • Zona reticularis

Medulla

A

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

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2
Q

Loss of adrenocortical function =

Loss of adrenal medulla =

Bilateral Adrenalectomy =

A

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

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3
Q

Major Steroid Hormones Produced by Adrenal Gland

A 
Cortisol
Aldosterone
Corticosterone
Dehydroepiandrosterone (DHEA)
Androstenedione
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4
Q

Cortisol

A

MAJOR Glucocorticoid

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5
Q

Aldosterone

A

MAJOR Mineralocorticoid

Much more potent mineralocorticoid than cortisol
weaker glucocorticoid than cortisol

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6
Q

Corticosterone

A

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

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7
Q

Dehydroepiandrosterone (DHEA) and Androstenedione

A

Androgens (weaker than testosterone)

  • -effects in early puberty
  • -effects in menopause
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8
Q

What chemical differences between cortisol, corticosterone, and aldosterone could account for their different affinities for their cognate receptors?

A

Cortisol–2 hydroxyl groups

Corticosterone–1 hydroxyl group

Aldosterone–1 hydroxyl group + aldo carbonyl group

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9
Q

Steroidogenesis

A
  1. ACTH binds to its G-coupled membrane receptor
  2. Low density Lipoprotein (LDL) taken up and cholesterol esters stored in lipid droplets
  3. ACTH inc cAMP production
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10
Q

ACTH increases cAMP production has two effects

A
  1. Increases cholesterol ester hydrolase activity such that more cholesterol (released from lipid droplet) is available for transport to the mito
  2. Increases steroidogenic acute regulatory (StAR) protein activity
    - -required for cholesterol transport across mito membrane
    - -StAR transportation is rate-limiting step
  3. Once cholesterol inside mito, steroidogenesis by specific enzymes to cortisol
    - -first and last steps = mito enzymes
    - -intermediate steps = smooth ER enzymes
  4. 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
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11
Q

Steroidogenic Pathways

A

P450 side chain cleavage

P450c17 (17-hydroxylase)

3-beta-hydroxysteroid dehydrogenase

P450c21 (21-hydroxylase)

P450c11 (11-beta-hydroxylase)

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12
Q

P450scc

A

Mitochondrial

Catalyzes first step

Cholesterol to Pregnenolone

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13
Q

P450c17 (17-hydroxylase)

A

Smooth ER

Pregnenolone –> 17-OH-pregnenolone –> DHEA

Progesterone –> 17-OH-Progesterone –> Androstenedione

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14
Q

3-beta-hydroxysteroid dehydrogenase

A

Smooth ER

Only non P450 enzyme

3 reactions

Pregnenolone –> Progesterone

17-OH-pregnenolone –> 17-OH-progesterone

DHEA –> Androstenedione

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15
Q

P450c21 (21-hydroxylase)

A

Smooth ER

Progesterone –> 11-Deoxycorticosterone

17-OH-progesterone –> 11-deoxycortisol

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16
Q

P450c11 (11-beta-hydroxylase)

A

Mitochondrial

11-Deoxycortisol –> cortisol

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17
Q

What enzyme is most common decrease of function mutation in congenital adrenal hyperplasia?

A

P450c21 (21-hydroxylase)

Results in huge adrenal glands (size of the kidney!)

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18
Q

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?

A

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
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19
Q

Synthetic Glucocorticoids

A

Pharmaceutical

-minimal mineralocorticoid activity

Prednisone < Methylprednisone < Tiamcinolone «< Dexamethasone

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20
Q

Synthetic Mineralocorticoid

A

Fluorocortisol

Potent glucocorticoid but MUCH MORE POTENT mineralocorticoid activity

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21
Q

Mineralocoriticoid activity

A

Mineralocoriticoid activity is related to retaining salt, NaCl. Mineralocorticoids maintain electroylte balance by retaining Na+ and promoting K+ excretion.

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22
Q

Glucocorticoid Activity

A

Important for the biosynthesis and metabolism of carbohydrates, proteins and lipids

They are also involved in immune responses

Possess anti-inflammatory activity

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23
Q

Mechanism of Glucocorticoid Action via Glucocorticoid Receptor (GR)

A

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)

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24
Q

What if there was GRE mutation?

A

Every cell that responds to cortisol will be affected

Increased ACTH, leads to androgen synthesis, leads to hypertrophy

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25
Q

Glucocorticoid effect on CNS

A

Decrease in hypothalamic CRH

Decreases ADH (posterior pituitary)
--induces water diuresis

Increase in appetite
–Cushing’s Syndrome

26
Q

Glucocorticoid effect on cardiovascular

A

Absence of cortisol (adrenal insufficiency) results in hypotensive shock

Excess cortisol causes hypertension

27
Q

Glucocorticoid effect on Liver

A

Increases gluconeogenesis = increased glucose

28
Q

Glucocorticoid effect on Lungs

A

Required for normal surfactant production

Premature babies usually deficient in surfactant leading to respiratory distress syndrome

29
Q

Glucocorticoid effect on Pituitary

A

Decreases ACTH (negative feedback)

30
Q

Glucocorticoid effect on Kidney

A

Increases GFR

31
Q

Glucocorticoid effect on Bone

A

Increase resorption = decreased bone formation

Osteoporosis

32
Q

Glucocorticoid effect on Muscle

A

Catabolic

Decreases insulin sensitivity

33
Q

Glucocorticoid effect on Immune System

A

Immune suppressive treatment to prevent graft vs. host in allogenic transplant recipients

34
Q

Glucocorticoid effect on Connective Tissue

A

Decreases collagen synthesis

–easy bruising

35
Q

Treatment for adrenal insufficiency

A

Steroids

-hydrocortisone = cortisol

36
Q

Proopiomelanocortin (POMC) processing

A

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)
37
Q

Stress effect on pituitary gland

A

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

38
Q

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?

A

Morning and lunch

Larger dose at 8am

Circadian rhythm peaks at 7-8AM, decreases throughout the day

Begins to increase again at 4am

39
Q

ACTH and cortisol response to Insulin injection

A

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

40
Q

What happens to adrenal gland size when has secondary adrenal insufficiency?

A

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

41
Q

Congenital Adrenal Hyperplasia (CAH)

A

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

42
Q

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

A

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

43
Q

Adrenal Insufficiency

A

Clinically significant decrease in cortisol release from adrenal cortex:

Primary and secondary insufficiency

44
Q

Primary Adrenal Insufficiency

A

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

45
Q

Secondary Adrenal Insufficiency

A

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
46
Q

Causes of Primary Adrenocortical Insufficiency

A

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%)

47
Q

What is effect of removal of entire pituitary gland on zonae fasciculata and reticularis?

A

Controlled by ACTH. Due to lack of ACTH supplied by anterior pituitary, will dramatically shrink in size.

Appear as bilateral adrenal atrophy

48
Q

What is effect of removal of entire pituitary gland on zona glomerulosa and medulla?

A

The zona glomerulosa and medulla do NOT shrink because not under control of ACTH

49
Q

What is the effect of long term glucocorticoid treatment?

Can you just stop treatment?

A

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

50
Q

Clinical features of adrenal insufficiency

A

Weakness
Fatigue
Anorexia
Weight Loss

51
Q

What causes hyperpigmentation in primary adrenal insufficiency but not secondary?

A

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

52
Q

Why does adrenal insufficiency cause hypotension?

A

Cortisol helps maintain sensitivity of vasoconstrictors

–permissive effect since cortisol itself it not a vasoconstrictor

53
Q

Cushing’s Syndrome

A

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

54
Q

Cushing Syndrome: ACTH Independent

A 
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
55
Q

Cushing Syndrome: ACTH Dependent, Pituitary Tumor

A

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

56
Q

Cushing Syndrome: ACTH Dependent, Ectopic Tumor

A

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

57
Q

What measurements could you do to differentiate Cushing’s Disease and Ectopic ACTH secretion?

A

Do MRI of the pituitary to visualize a tumor

58
Q

How could you differentiate ACTH-dependent and ACTH-independent Cushing’s syndrome?

A

ACTH-dependent:

–ACTH is NOT low, is within the reference range

59
Q

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?

A

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

60
Q

How do you remove a pituitary tumor?

A

Transphenoidal route

–endonasally or sublabially

61
Q

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?

A

Cortisol levels will drop

Needs to be on cortisol meds and weaned down

62
Q

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

A

Patient 2 years after a unilateral adrenalectomy

Physiology (20 decks)

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