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Med 412 > Week 27 Adrenals > Flashcards

Week 27 Adrenals Flashcards

1
Q

xfxfWhat are glucocorticoids primarily used for?

A

Anti-inflammatory or immunosuppressive agents.

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2
Q

What types of diseases are glucocorticoids used for?

A

Asthma, RA, IBS, cerebral edema, SLE, organ transplant rejection.

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3
Q

What are the 4 layers of the adrenal gland

A

CORTEX:
Zona Glomerulosa - Mineralcorticoids; Aldosterone
Zona Fasiculata - Glucocorticoids > Androgens; Cortisol
Zona Reticularis - Androgens > Glucocorticoids; DHEA, Androstenedione

Medulla: Catecholamines; Nor Epi, Epi

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4
Q

What is the precursor for steroid hormones produced in the adrenal cortex?

A

Cholesterol

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5
Q

What is the precursor for catecholamines produced in the adrenal medulla?

A

Tyrosine

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6
Q

From what 2 sources does the cholesterol used in steroid hormones come from?

A
  1. Circulating cholesterol with LDL **MAJOR SOURCE
  2. De novo synthesis of cholesterol from acetate.
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7
Q

What is the protein needed to produce any of the products of the adrenal glands from cholesterol?

A

Steriodogenic acute regulatory protein StAR

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8
Q

What is needed to convert cortocosterone to aldosterone?

A

Aldosterone synthase, only in the glomerulosa cells.

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9
Q

What regulates the synthesis of cortisol?

A

Stress induces release of CRH in hypothalamus.
CRH induces release of ACTH in ant. pituitary.
ACTH induces production of cortisol in Adrenal cortex (Zona fasiculata > Zona reticularis).

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10
Q

What is the action of glucocorticoids on blood glucose?

A

Counter regulatory action, increases blood glucose.

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11
Q

What regulates the release/synthesis of Aldosterone?

A

RAAS: Low BP or decreased Na/Cl causes release of Renin from juxtaglomerular cells.
Renin causes conversion of Angiotensinogen to Ang. I
Ang I converted to Ang II via ACE in lungs.
Ang II stimulates release of aldosterone from adrenal gland.

K+: Increased K+ levels directly stimulate aldosterone release so that Na can be exchanged for K and K is excreted via kidneys.

ACTH: directly stimulates synthesis of aldosterone via Melanocort 2 receptors, also minorly modulates aldosterone secretion.

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12
Q

Why measure the HCO3 serum levels when investigating a potential adrenal dysfunction?

A

Aldosterone (in the kidney) increases H+ in the urine and CO3- into the blood, increasing blood pH via alpha intercalated cells.
Increased CO3- (increased blood pH) could mean that there is increased aldosterone.
Could help differentiate between primary and secondary hyperaldosteronism when compared to ACTH levels.

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13
Q

What receptors does steroid hormones act on?

A

Nuclear receptors.
Lipid, can pass through membranes.

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14
Q

List the ligands (classic hormones and vitamins) that act on nuclear receptors and their receptor type.

A

Cortisol - glucocorticoid receptor
Testosterone - androgen receptor
Estrogen - Estrogen receptor
Progesterone - progesterone receptor
Aldosterone - mineralocorticoid receptor
T3 - thyroid hormone receptor
Vitamin D - Vitamin D receptor
All-trans retinoic acid - retinoic acid receptor

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15
Q

What are the requirements of nuclear receptors?

A
  1. Ligand binding domain.
  2. Dimerization domain.
  3. Nuclear localization signal.
  4. DNA binding domain.
  5. Activation domains.
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16
Q

What do nuclear receptor dimers bind to?

A

A specific sequence in the promoter of their target gene:
HORMONE RESPONSE ELEMENT.

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17
Q

What is the clinical significance of nuclear receptors?

A

Important targets for therapeutics.
Small molecule drugs.

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18
Q

How are steroid hormones metabolized?

A

Converted to an inactive compound in the liver.
Hydrophilic, eliminated as urinary metabolites.
Consists of reductions, oxidations, hydroxylations then a conjugation.

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19
Q

Composition of aldosterone in the blood.

A

30-50% free circulating, remainder bound to albumin.
Short half life (15-20 min).

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20
Q

How does aldosterone mediate its physiological effects?

A

Binds to mineralocorticoid receptor (nuclear receptor).
This both regulates gene expression and induces rapid effects.

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21
Q

To what receptors of the adrenal cortex does ACTH bind?

A

Menocortin-2 receptors (G-protein coupled receptors)

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22
Q

What are the actions of ACTH

A

Promotes free cholesterol formation.
Increases de novo synthesis of cholesterol.
Increases LDL uptake.
Increases StAR activity.

Maintains adrenocortical cells.

Regulates adrenal androgen secretion.

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23
Q

When are ACTH an cortisol levels. highest?

A

Highest in early morning, low at midnight.
Circadian regulation (dark/light).

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24
Q

How do glucocorticoids circulate in the blood?

A

90% are bound to corticosteroid-binding globulin (CBG or transcortin).
7% are bound to albumin.
3% free circulating cortisol.

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25
Where are glucocorticoid receptors found?
Almost all tissues. Regulates the expression of many genes.
26
Discuss glucocorticoid binding affinity
Bind GR and MR with equal affinity. Tissue specific regulation of cortisol metabolism prevents MR mediated cortisol effects.
27
Discuss the cortisone-cortisol shunt
11B-HSD1 in liver converts cortisone (inactive) to cortisol. 11B-HSD2 in kidney converts cortisol to cortisone (prevents cortisol binding to MR).
28
What is the clinical implication of the cortisone-cortisol shunt.
Skin expresses 11B-HSD1 so inactive cortisone applied topically becomes converted to active cortisol for localized treatment.
29
Physiological functions of glucocorticoids
METABOLISM Fed state: minimal effects Fasted state: Increases gluconeogenesis, glycogen deposition in liver. Decreases glucose uptake, increases catabolism of pr in muscle. Stimulates lipolysis in adipose. Reduces intestinal Ca absorption. Increases fluid and salt retention. IMMUNE Immunosuppressive and anti-inflammatory GROWTH AND DEVELOPMENT Promote differentiation and maturation of organ systems in fetal development. Suppress bone formation and inhibit fibroblast division and collagen synthesis. CV Increase CO, increase tone. REPRODUCTIVE Decrease LH/FSH release OTHER Cognition, behaviour, regulation of appetitie, libido, renal function
30
Sources of blood glucose
Exogenous: diet Endogenous: Glycogenolysis, Gluconeogenesis
31
Fates of blood glucose
Energy: glycolysis Storage: glycogenesis, lipid synthesis.
32
What is the effect of cortisol on blood glucose?
Raises blood glucose levels.
33
Pathological excess of glucocorticoids
Depression/psychosis Decreased LH, FSH, TSH, GH Glaucoma Peptic ulcerations HTN Overall diabetogenic effect Visceral obesity Decrease bone formation and linear growth Protein/collagen breakdown Immunosuppression/Anti inflammatory
34
Blood supply for adrenals
Aorta -> inferior phrenic artery -> renal arteries -> adrenal artiers -> plexus -> cortex -> medulla. Corticomedullary portal system. R adrenal vein -> IVC L adrenal vein -> inferior phrenic vein -> L renal vein -> IVC
35
What is the name of the cells of the adrenal medulla?
Chromaffiin cells or pheocromocytes.
36
Basic release of Epinephrine
Splanchnic nerve -> Ach -> Nicotinic receptor in medulla -> release epi
37
Basic release of Nor epi
Preganglionic nerve -> Ach -> nicotinic receptor on post ganglionic nerve -> Nor epi
38
Biosynthesis of catecholamines
Made from tyrosine from diet or phenylalanine in: Chromaffin cells of medulla, Postganglionic neurons of SNS, Noradrenergic & dopaminergic neurons of CNS, Paraganglia of periphery.
39
What is the rate limiting step of catecholamine synthesis
Conversion of tyrosine to Dopa via tryrosine hydroxylase
40
1/2 life of catecholamines
VERY short, 10-100 seconds. 50% bound loosely to albumin. Leads to wide fluctuations of levels in the plasma.
41
Discuss the spatial organization of catecholamine biosynthesis
Tryrosine taken into chromaffin cells via active transport. Conversion to dopamine occurs in cytoplasm. Dopamine transported to chromaffin granules for conversion to Nor Epi. (Final step in postganglionic neurons and some chromaffin cells). 80% of chromaffin cells Nor Epi is transported out of the granule nad converted to Epi in the cytoplasm. Epi transported to storage in chromaffin granule.
42
What enzyme converts Nor Epi to Epi?
PNMT. Is regulated by glucocorticoids via portal system.
43
Key enzymes in catecholamine metabolism
MAO (monoamine oxidase) COMT (catechol-O-methyltransferase)
44
Discuss the dynamic process of catecholamine metabolism
Granule leakage and sequestration Leakage metabolized by MAO and then loss via deamination. Release and reuptake to sequestration back into granule.
45
Discuss clinical applications of MAO inhibitors and ARIs
MAO inhibitors for severe depression ARIs (adrenergic reuptake inhibitors) for ADHD, narcolepsy, MDD
46
How does cocaine and amphetamines affect catecholamine levels?
Cocaine selectively blocks transport of MAOs, resulting in high levels of neurotransmitters in the synaptic cleft. Amphetamines competitively inhibit MAO transporters and vesicle transporters, resulting in increase [dopamine] and [Nor epi] in synaptic cleft. increased [catecholamine] at synapse results in sensations of euphoria, increased energy, improved focus, anxiety, paranoia, jitteriness.
47
Discuss the 3 catecholamine receptors
All are G coupled protein receptors Dopamine receptors; D1, D2 a Adrenergic receptors; a1, a2 B Adrenergic receptors; B1, B2, B3 alpha and beta interact with epi and nor epi.
48
D1 receptors
Found on cerebral, renal, mesenteric, and coronary vasculatures. Stimulation causes vasodilation.
49
D2 receptors
Found pre and post synapse of sympathetics, brain, lactotrophs. Stimulation causes inhibition of nor epi, ganglionic transmission, and prolactin.
50
a1 receptors
Found on heart, vessels, smooth mm. Stimulatory: vascular and sm mm ctx, Vasoctx, increased systemic resistance, increased BP
51
a2 receptors
Found on heart, vessels, smooth mm. Inhibitory: Inhibits nor epi release. Down regulates central sympathetic outflow. Decreases BP
52
B1, B2, B3 receptors
B1 - heart/kidney. More responsive to isoproterenol than to epi or NE. Stimulation = increased contractile force & HR, increased renin secretion, lipolysis Therapeutics: beta blockers for angina, HTN, arrhythmias. B2 - heart, lungs, vessels, kidneys, liver Stimulation = bronchodilation, vasodilatation in skm, glycogenolysis, release of nor epi. Therapeutics: inhaled formulations for asthma. B3 - heart, adipose tissue Regulates energy expenditure, lipolysis in white fat, thermogenesis in brown fat.
53
Stimuli for catecholamine production and secretion
Physiological stressor Psychogenic stressors Endocrine stimulation (Angiotensin II, Glucocorticoids)
54
How can primary and secondary adrenal insufficiency be differentiated?
ACTH levels
55
When suspecting low cortisol, when should your measure serum cortisol levels?
AM cortisol. Cortisol should be high in the morning, if not, this will confirm low cortisol.
56
Cushing's syndrome vs Cushing's disease
Syndrome = general high levels of cortisol. Disease = high levels of cortisol due to overproduction of ACTH in pituitary.
57
Clinical/conceptual approach to endocrine disorders
1. Hx + exam -> suspect diagnosis 2. Screen for high or low hormone 3. Confirm positive screen 4. Localize (if unable to localize, consult expert) 5. Treatment
58
Definition of primary adrenal insufficiency
Destructive process of adrenal gland leading to loss of glandular function.E
59
Epidemiology of primary adrenal insufficiency
35-140/ 1 million F:M = 2:1 Age 30-50
60
Clinical presentation of primary adrenal insufficiency
Hx: Weakness, fatigue, anorexia, GI upset, salt craving, postural symptoms. Exam: Orthostatic hypotension, wt loss, hyperpigmentation. Investigations: Hypo Na, Hypo K, normocytic anemia, neurtopenia, eosiniophilia, lymphocytosis, elevated creatine, Hyper Ca.
61
Biochemical results for primary adrenal insufficiency
Biochemical screen: AM cortisol low (should be high), ACTH high (should be low d/t proper cortisol feedback) Biochemical confirmation: ACTH stimulation test Administer large amounts of ACTH. Normal adrenal will respond by releasing large amounts of cortisol. Adrenal insufficiency; adrenal cortisol levels will be low, so serum cortisol will not increase in response to increased ACTH.
62
Localization to confirm primary adrenal insufficiency
High ACTH and low cortisol Imaging of adrenal gland Determine: AI - autoimmune adrenalitis Compression - bilateral adrenal mets Infection - TB, fungal, viral Hemorrhage - adrenal hemorrhage Infiltrative - Granular disease Surgery - bilateral adrenalectomy Genetic - Congenital adrenal hyperplasia
63
Treatment for primary adrenal insufficiency
Mineralocorticoid replacement - Fludrocortisone Glucocorticoid replacement - Hydrocortisone, Prednisone, Dexamethasone Sex steroid replacement is controversial
64
Definition of secondary adrenal insufficiency
Pathology of the pituitary, leading to reduced ACTH and adrenal hormone secretion.
65
Epidemiology of secondary adrenal insufficiency
150-280 / 1 million F>M Age >50
66
Clinical presentation of secondary adrenal insufficiency
Hx: weakness, fatigue, anorexia, GI upset, salt craving, postural symptoms. May have known pituitary pathology or hx of long-standing glucocorticoids. Exam: Orthostatic hypotension, wt loss, **NO HYPERPIGMENTATION d/t low ACTH Labs: Mineralocorticoid production is generally preserved so dehydration, hypotension, and hyper K are less prominent.
67
Biochemical results for secondary adrenal insufficiency
Screen: Low AM cortisol, Low ACTH Confirmation: Refer to endocrinology
68
Localization to confirm secondary adrenal insufficiency
Refer to endocrinology
69
Treatment for primary secondary insufficiency
May require glucocorticoid replacement
70
Clinical presentation of Cushing's Syndrome
Hx: Central obesity, hirsutism, diabetes, psych disturbance, osteoporosis, mm weakness. Exam: Obesity, HTN, facial rounding, facial plethora (increased blood flow), dorsocervical fat pad, supraclavicular fat pad, thin skin, easy bruising, striae, acnel. Labs: Hypo K in ectopic Cushing's
71
Biochemical results for Cushing's Syndrome
Screen: 1 of the following; 1 mg dexamethasone suppression test (normal cort will be <50) 24-hour urine free cortisol - repeat 2xs Midnight salivary cortisol - repeat 2xs Confirmation: Repeat any of the above tests.
72
Localization for Cushing's Syndrome
Adrenal adenoma (ACTH-independent) = High Cort, Low ACTH Pituitary (ACTH dependent)) = High cort, High ACTH, IPSS localizes Ectopic ACTH syndrome = High cort, High ACTH, IPSS does not localize MRI sella CT chest - ectopic CT abdo - adrenal Functional imaging - functional tumor
73
Treatment for Cushing's Syndrome
Tx of choice = surgical removal of the over-secreting tumour. Pituitary radiation if resection incomplete. Anti-adrenal meds: Ketoconazole, metyrapone, mitotane. Adrenalectomy if unilateral.
74
Definition of androgen producing tumour
Adrenal tumour overproducing androgens, often malignant.
75
Epidemiology of androgen producing tumour
0.3-4 / 1 million / year in children
76
Clinical presentation of androgen producing tumour
Rapid virilization: Total T >5 nmol/L Voice deepening Breast atrophy Increased mm bulk Clitoromegaly Increased libido
77
Biochemical results for androgen producing tumour
**RULE OUT EXOGENOUS GLUCOCORTICOIDS Screen: Elevated T, Elevated DHEAS Confirmation: Screening usually all that is required.
78
Localization for androgen producing tumour
CT abdo US pelvis Ovarian/adrenal vein sampling
79
Treatment for androgen producing tumour
Surgical removal of tumour May need chemo d/t malignancy
80
Virilization vs Hyperandrogenism
Virilization: Total T >5 nmol/L Voice deepening Breast atrophy Increased mm bulk Clitoromegaly Increased libido Hyperadrogenism: Total T 2-5 nmol/L Hirsutism Acne Androgenic alopecia Menstrual irregularities Infertility
81
What appetite stimulant has GC activity and can cause Cushing's Syndrome?
Megestrol acetate, Megace. Used for anorexia, cachexia, some cancers.
82
Discuss CYP450i interactions with GCs
Ritonavir or Cobicistat are strong CYP450 inhibitors and can delay clearance of some inhaled or injected steroids.
83
How are cortisol and ACTH levels impacted by exogenous steroids?
Both are low.
84
Recovery of HPA axis after surgical tx of Cushing's syndrome
Pituitary cells may require months to be functional after surgical tx. Adrenal insufficiency may develop after tumour removal. Treat with physiological dose of steroids and monitor for HPA axis recovery.
85

Med 412 (17 decks)

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