Lecture 11: The Adrenal Gland Flashcards
1
Q
What are the embryological orgins of the adrenal cortex and medulla?
A
Adrenal cortex = epidermal origin
Adrenal medulla = ectodermal origin
2
Q
Adrenal cortex releases what classes of hormones?
A
Corticoids and androgens
3
Q
Adrenal medulla releases what class of hormones?
A
Catecholamines
4
Q
What is released by the Zona glomerulosa, fasciculata, reticularis and adrenal medulla?
A
Zona Glomerulosa: Minearlocorticoid (aldosterone)
Zona Fasciculata: Glucocorticoids (cortisol)
Zona Reticularis: Androgens
Adrenal Medulla: Catecholamines (E and NE)
5
Q
What are the 3 kinds of hormones produced in the adrenal cortex?
A
- Glucocorticoids - Cortisol
- Mineralocorticoids - Aldosterone
- Sex steoids - DHEA and DHEAS
6
Q
Most common adrenal enzyme deficiency and what hormone levels are affected; how do we treat?
A
- 21 Hydroxylase deficiency
- Decreased cortisol
- Decreased mineralocorticoid
- Increased sex hormones
- Treatment involves replacing glucocorticoids and mineralocorticoids
7
Q
What are the signs and symptoms of 21-hydroxylase deficiency?
A
- Hypotension (decreased aldosterone)
- Sodium and volume loss
- Hyperkalemia
- Elevated renin
- Female: virilization of fetus and sexual ambiguity at birth
- Male: phenotypically normal, precocious pseudo-puberty, premature epiphyseal plate closure
8
Q
What is seen in 11β-Hydroxylase deficiency?
A
- Increased androgens
- Virilization of female fetuses
- Increased 11-deoxycorticosterone
9
Q
Signs and symptoms of 11 β-Hydroxylase deficiency?
A
- Hypertension
- Hypokalemia
- Suppressed renin secretion
10
Q
What is seen in 17 α-Hydroxylase deficiency; when are these patients diagnosed?
A
- Decreased androgens and cortisol
- Excess mineralocorticoids
- Patients diagnosed at time of puberty
11
Q
What are the signs and symptoms of 17-α-Hydroxylase deficiency?
A
- Hypertension
- Hypokalemia
- Hypogonadism
- Males: undescended tests
- Females: lack of secondary sexual development
12
Q
What are the target tissues of Cortisol; what 2 ways can it act?
A
- Tissues throughout the body
- Glucocorticoid Response Element (GRE)
- Non-genomic actions (endocannabinoids)
13
Q
What are some of the effects of cortisol on the liver, muscle, fat, cutaneous, immune system, endocrine, and GI?
A
Liver: increased gluconeogensis
Muscle: breakdown of muscle protein
Fat: promote lipolysis in extremities, central fat deposition
Cutaneous: skin thins, fragile blood vessels
Immune system = immune suppression
Endocrine = insulin resistance or glucose intolerance
GI = interferes w/ calcium absorption (risk of osteporosis)
14
Q
How is cortisol regulated?
A
- Begins w/ CRF (CRH) in hypothalamus released from PVN
- Binds CRF1 receptor (GPCR)
- Sitmulates release of ACTH from anterior pituitary
15
Q
What are some things that can stimulate the release of CRH from the hypothalamus?
A
- Low cortisol
- Stressors (hypoglycemia, hypotensions, fever, trauma, surgery)
16
Q
What is the principle hormone that stimulates the adrenal glucocorticoids; derived from and produced where?
A
- ACTH
- Derived from POMC
- Contains MSH (melanocyte stimulating hormone) activity
17
Q
What does excess ACTH commonly lead to?
A
Hyperpigmentation due to its MSH activity
18
Q
What is the long loop, short loop, and ultrashort loop as it pertains to CRH activity and feedback?
A
Long loop: cortisol from adrenal gland inhibiting release of CRH from hypothalamus
Short loop: ACTH from anterior pituitary inhibiting CRH release from hypothalamus
Ultrashort: CRH activity in hypothalamus inhibiting CRH release
19
Q
What is the rhythm of ACTH and cortisol release like; when do we see peaks?
A
- Cortisol levels are highest around 8am, and then gradually trail off for rest of day, peak again around 2pm and then 7pm, low in the late evening
- ACTH levels will peak just before this since it’s needed to stimulate production of cortisol
20
Q
Discuss the negative feedback by glucocorticoids onto CRH and ACTH?
A
- GC’s inhbit POMC transcription
- GC’s inhbit mRNA synthesis of CRH and ACTH
21
Q
What is the Dexamethasone suppression test (DST); discuss findings at low and high doses?
A
-
Low dose DST (cortisol analog)
- Determines if there is problem
- Usually overnight
- Pt is administered a supraphysiologic dose
- Normal response: suppression of ACTH and cortisol secretion
- Cushing: no suppression
2. High dose DST (cortisol analog)
- Helps determine the source of the problem (pituitary vs. adrenal Cushing)
22
Q
What is the Cosyntropin and how is it used; describe the test?
A
- Synthetic ACTH used in stimulation test (CST) for adrenal gland insufficiency
- *Step 1:** Administer Cosyntropin (ACTH)
- In healthy individuals, cortisol should increase from baseline
- If adrenals unresponsive and cortisol remains the same or rises only small amount, consider adrenal insufficiency
- If adrenals respond dramatically and cortisol increases substantially, consider secondary adrenal insufficiency
23
Q
What is Cushing Syndrome?
A
- Hypersecretion of Cortisol
- Usually an adrenal neoplasm
- Elevated cortisol but low ACTH
- An adrenal problem (primary endocrine disorder)
24
Q
What is Cushing Disease?
A
- Hypersecretion of ACTH
- Usually a pituitary gland tumor
- Overstimulates the adrenal cortex and excess cortisol secreted
- High serum ACTH and high cortisol
- A pituitary problem (secondary endocrine disorder)
25
If a patient with Cushing Syndrome was injected w/ exogenous glucocorticoids (dexamethasone), what do you predict would happen to their ACTH levels and cortisol suppression; WHY?
- ACTH levels would be **undetectable** and dexamethasone **fails** to suppress cortisol secretion
- Negative feedback loop itself is **functional** yet hypercortisolism continues (an adrenal problem)
26
If a patient with Cushing Disease was injected w/ exogenous glucocorticoids (dexamethasone), what do you predict would happen to their ACTH levels?
- ACTH would be **supressed**
- **Abnormal** negative feedback at level of pituitary
27
What are some of the signs and symptoms seen in patients with Hypercortisolism?
- "**Moon face**"
- Hirsutism
- Bruising
- Abdominal adiposity
- Stretch marks
- **"Buffalo hump"**
28
What is Addison disease?
- **Primary adrenal insufficiency**
- Chronic progressive destruction of adrenal gland
- High ACTH but low cortisol
- Adrenal response is blocked from the signal
- **Adrenal problem = not making cortisol**
- Cortisol levels will be low so the hypothalamus will be secreting a lot of CRH stimualting the pituitary to make ACTH, but the high levels of ACTH won't be able to have any effect.
29
What is Secondary adrenal insufficiency?
- Caused by exogneous glucocorticoid administration
- ACTH deficiency
- **Low** ACTH and **low** cortisol
- A **pituitary problem**
30
If a patient with Addison disease is injected w/ synthetic ACTH (cosyntropin), what do you predict would happen to their plasma cortisol levels?
No change since the adrenals can't respond to ACTH
31
If a patient with secondary adrenal insufficiency is injected w/ synthetic ACTH (cosyntropin), what do you predict would happen to their plasma cortisol levels?
They will **increase**, since the problem in these patients is a lack of ACTH being produced by the pituitary gland
32
Addison disease can be caused by?
1. Autoimmune disease of adrenal gland
2. Adrenal hemorrhage
* - Secondary to infection (i.e., N. meningitidis)*
* - Secondary to anticoagulant tx*
3. Infection
* - Tuberculosis*
* - N. meningitdis --\> **Waterhouse-Friedrichsen Syndrome***
4. Tumor
33
What is seen in Addison diease in regards to cortisol and adrenal steroid secretion?
- **Hypo**cortisolism
- **Hypo**secretion of **ALL** adrenal steroids
34
What are some of the signs and symptoms seen in Addison disease?
- **Hyperpigmentation**
- Weight loss
- Muscle weakness
- **Hypoglycemia**
- Hypotension
- Hyponatremia and hyperkalemia (due to **loss** of aldosterone!!!)
35
What are the actions of aldosterone; where does it act; what are the net results of its effect?
- Principle **mineralocorticoid** controlling **Na+ and K+** exchange in **distal nephron**
- Increases synthesis and acitivity of **Na+ channels** in **apical** membrane
- Increases the synthesis and activitiy of **Na+-K+ ATPase** in the **basolateral** membrane of the distal tubule
- Overall result = increase **Na+ reabsorption** and an increase in **K+ excretion and H+ excretion**
36
What is the affinity of the mineralocorticoid receptor for aldosterone and glucocorticoids; what system do we have in place to keep the system running smoothly and the key players involved?
- Equal affinities
- Cortisol-cortisone shunt
- **11**β-**HSD2** metabolizes cortisol to cortisone (inactive form)
- Protects the MR from cortisol binding and keeps it available for aldosterone
37
What can glycyrrhizic acid (licorice) cause; when else are these effect seen?
- Inhibits **11**β-**HSD2**
- Cortisol will have increased access to MR
- MR is overwhelmed by cortisol, especially in hypercortisolemic conditions (like **Cushings**)
38
What is Conn Syndrome?
- **Hypersecretion** of **Aldosterone**
- Usually an adrenal neoplasm
- **Adrenal problem (primary hyperaldosteronism)**
39
What is Secondary Hyperaldosteronism?
**- Hypersecretion** of **Renin**
- Excess renin from juxtaglomerular cells of the kidney
- A **k****idney problem**
40
What is Primary Hypoaldosteronism?
- **Hypo**secretion of aldosterone
- Destruction of adrenal cortex (Zona Glomerulosa)
- Defects in aldosterone synthesis
- An **adrenal** problem
41
What is Secondary Hypoaldosteronism?
- **Hypo**secretion of renin
- Deficient renin from juxtaglomerular cells of the kidney
- Inadequate stimulation of aldosterone
- A **kidney** problem
42
How does primary adrenal failure affects cortisol and aldosterone in comparison to an ACTH deficiency?
Primary adrenal failure ---\> **deficient** cortisol AND aldosterone
ACTH deficiency --\> **cortisol deficiency** but NO change in aldosterone
\*Effect of ACTH on aldosterone secretion is modest at best
43
What are the adrenal androgens; what do they rely on for activity?
- DHEA and DHEAS
- Precursors to human sex steroids
- Relies on 3β-HSD to extert androgenic or estrogenic activities
44
What is seen in female patients with adrenal carcinomas that secrete androgens?
- Females may feature: virilization, hirsutism, clitoromegaly, breast atrophy, deepening of voice, temporal recession, severe acne
45
Where are the catecholamines produced and from what pre-cursor?
- The adrenal medulla
- From L-Tyrosine
46
What is the enzyme involved in the rate limiting step of L-tyrosine to Epinephrine; what modulates this reaction; where does it occur?
- **Tyrosine hydroxylase**
- Controlled by sympathetic stimulation, upon ACh binding nAChRs
- The cytosol of Adrenal Medulla cells
47
Once dopamine is produced in the Adrenal medulla cells what occurs?
Stored in special secretory vesicles called "**chromaffin granules**" and converted to NE
48
What increases the synthesis of tyrosine hydroxylase and activity of dopamine β-hydroxylase?
Nicotinic receptor cell signaling upon binding of ACh from SNS
49
Upon stimulation by cortisol what occurs to the NE stored in chromaffin granules of the adrenal medulla?
- NE diffuses out of the granules via the **VMAT** and into the cytosol where it's converted by **Phenylethanolamine *N*-methyltransferase (PNMT)** to **epinephrine**
- Epinephrine then goes back into chromaffin granule via **VMAT** and is stored in a different storage vesicle until sympathetic stimulation causes exocytosis
50
What are Chromogranin's; where are they found and what are the contents?
- Chromogranins play a role in the biogenesis of secretory vesicles and the organization of components within the vesicles.
- Found within the Chromaffin granules with Epinephirne, some NE, Ca2+ and ATP
51
Cortisol induces the expression of which adrenomedullary cell enzyme?
- Phenylethanolamine-*N*-methyltransferase **(PNMT)**
- Enzyme that converts **NE to epinephrine**
52
What is monoamie oxidase (MAO); where is it found; why are they a clinically relevant drug targerts?
- Oxidizes catecholamines for metabolism
- Found in the CNS and peripheal tissues
- MAOI's are used to treat neuropsychiatric disorders
53
What is catechol-O-methyltransferase (COMT); where is it found; what is its function?
- Methylates catecholamines
- Found in the CNS and peripheral tissues
- Primary enzyme that **inactivates** catecholamines released from the adrenal gland
54
What can be measured to determine catecholamine production?
- Measuring of the breakdown products
- Catecholamines, metanephrines, and vanillylmandelic acid (VMA)
55
What is a Pheochromocytoma and what are the symptoms?
- Tumors of the chromaffin tissue, produce excess catecholamines
Symptoms wax and wane:
**- HTN**
- **Orthostatic HTN**
**- Sweating**
**- Palpitations**
**- Chest pain**
**- Flushing**
**- Anxiety**
56
What is the short-term stress response pathway?
- Stress causes nerve impulses to travel to spinal cord and then to adrenal medulla via pre-ganglionic sympathetic fibers, which stimulate the adrenal medulla to secrete catecholamines
- Increase HR, BP, bronchiole dialation, liver glycogenolysis, reduced GI activity, and increased metabolic rate
57
What is the prolonged stress pathway?
- Stress triggers hypothalamus to release CRH leading to increases ACTH from pituitary
- ACTH stimulates the production of mineralocorticoids and glucocorticoids from the adrenal cortex
- Mineralocorticoids contribute to retention of Na+ and H2O by kidneys, and increased BV and BP
- Glucocorticoids contribute to gluconeogenesis of proteins and fats, increased blood glucose, and immune system supression
58
What are exogenous glucocorticoids and what effect do they have?
- Cortisone, prednison, methylprednisone, dexamethasone
- May shut down ACTH production and adrenal cells that produce cortisol (**atrophy**)
- Exogenous glucocorticoids will mimic cortisols actions; symptoms of excess (**latrogenic = illness caused by medication**)
- CRH. ACTH, and cortisol will all be **decreased**
59
What are the aldosterone levels like in a patient with secondary/tertiary adrenal insufficiency?
- Even though ACTH does have a small role in the release of aldosterone, the levels will not be affected.
- Increased K+ levels and Angiotensin II levels play a larger role in the synthesis and secretion of aldosterone
- **RAAS has a MUCH greater effect!**
60
Where is epinephrine vs. norepinephrine synthesized?
- **NE** is synthesized inside the **chromaffin granules by DBH**
**- Epinephrine** is synthesized inside the **cytosol by PNMT**
61
Which receptor type responds equally to NE and E?
β1 receptor
62
What catecholamine do the α receptors and β3 respond better to?
Respond better to NE than E
63
Epinephrine is more potent than NE for which type of receptor; what response does this receptor mediate?
- β2 receptors
- Increase hepatic glucose output; decrease contraction of blood vessesl, bronchioles, and uterus
64
Where are β3 receptors found and what are some effects produced?
- Liver; adipose tissue
- Increase hepatic glucose output; increase lipolysis
65
Where are α2 receptors found and what are effects produced by them?
- Sympathetic presynaptic nerve terminals; beta cells of pancreatic islets
- Inhibit NE release; inhibit insulin release
66
What is the high dose dexamethasone test used to differentiate?
- Distinguish those w/ Cushing Disease vs. someone with an ectopic ACTH secreting tumor (i.e., lungs)
- High dose will suppress ACTH in Cushing disease (adrenals), but will have no effect on an ectopic source
67
What pathology is shown by this axis?
Addison Disease
68
What pathology is shown here?
Cushing Disease
69
Pt presents w/ HTN and Hypokalemia, the plasma aldosterone concentration is increased, while plasma renin concentraton is decresed, what should you suspect?
Primary aldosteronism (**Conn's syndrome**)
70
All congenital adrenal enzymes deficiencies are characterized by an enlargement of what? Due to?
- Enlargement of **Adrenal glands**
- Due to increased ACTH caused by low cortisol negatively feeding back to try and increase the levels
71
What stimulates the synthesis of DOPA?
- ACTH and Symptahtetic stimulation (ACh) stimulated **Tyrosine Hydroxlase** to convert Tyrosine ---\> DOPA
