Endocrine 1 Final: WE Adrenal

There are 4 primary functions that the adrenocorticotropic hormones serve in the body:

1. ___ and ___ balance

electrolyte, water

There are 4 primary functions that the adrenocorticotropic hormones serve in the body:

2. suppression of the ___ response

immune

There are 4 primary functions that the adrenocorticotropic hormones serve in the body:

3. regulation of ___ levels

glucose

There are 4 primary functions that the adrenocorticotropic hormones serve in the body:

4. alleviation of ___

stress

Positive Inducers of Adrenal Axis:

1. ___ (strongest inducer)

2. ___ ___ (~8am)

stress, early morning

Note that serum cortisol levels peak in the ___ and trough at night. Exercise, coffee, staying up late, etc can increase levels

morning

Therefore, dose glucocorticoids ___ in the morning and ___ at night

high, lower

Positive Inducers of Adrenal Axis:

3. Hypoglycemia (low sugar <__mg/dL)

80

Positive Inducers of Adrenal Axis:

4. Hyponatremia (low Na+ → induces axis to release ____ → leading to increased Na+ ____ to try and keep it in the body)

aldosterone, reabsorption

Positive Inducers of Adrenal Axis:

5. _____ and ____ (low blood volume caused by hyponatremia → induces the axis to release aldosterone → increases H2O retention/bp)

hypotension, dehydration

Positive Inducers of Adrenal Axis:

6. ___ (this is where dexamethasone suppression test is utilized)

obesity

Positive Inducers of Adrenal Axis:

7. ___ (high K+ → induces axis to release aldosterone → leading to increased K+ ___)

hyperkalemia, secretion

Positive Inducers of Adrenal Axis:

9. ___ blood pH (acidic pH (high H+) → induces axis to release aldosterone → leading to increased H+ ___)

low, secretion

cortisol, aldosterone, dexamethasone

Negative Regulators of Adrenal Axis (via feedback inhibition):

1. ____ (endogenous)

2. ____ (endogenous)

3. ____ (pure GC)

HPA Axis

1. A trigger (eg stress, dehydration) enters the hypothalamus and causes release of corticotropin releasing hormone (___) or corticotropin releasing factor (___)

CRH, CRF

HPA Axis

2. CRH or CRF interact with their receptors located on the ___ ___ ___

anterior pituitary gland

HPA Axis

3. Activation of CRHr or CRFr leads to release of adrenocorticotropic hormones (___) from the anterior pituitary gland

ACTH

HPA Axis

4. ATCH then activates the ACTH receptor located on the ___ __

adrenal cortex

HPA Axis

5. When the ATCHr is activated, this stumulates Gs protein → stimulates adenylyl cyclase → converts ATP to ___

cAMP

HPA Axis

6. Increase in cAMP leads to activation of protein kinase A (___)

PKA

HPA Axis

7. PKA triggers ____ mobilization, including cholesterol uptake via ___

cholesterol, endocytosis

HPA Axis

8. Cholesterol is converted to ___

pregnanolone

HPA Axis

9. Pregnanolone ultimately results in the production of ___, ___, and the weak ___

aldosterone, cortisol, androgens

High levels of aldosterone results in ___ ___ on the hypothalamus

negative feedback

Weak androgens = dehydroepiandrosterone (___) and androstenedione from the adrenal cortex

DHEA

Where is the adrenal gland located?

-on top of the __

kidney

3 layers of the adrenal gland

1. Zona ___ (outermost)

2. Zona ____

3. Zona ___ (innermost)

glomerulosa, fasciculata, reticularis

Zona glomerulosa (outermost)

-secretes ___

aldosterone

Zona glomerulosa (outermost)

-secretes aldosterone, resulting in ↑___+, __, and __

Na, H2O, bp

If there was a hypersecreting tumor in the Zona glomerulosa , this would result in hypersecretion of ___

aldosterone

hypersecreting tumor in the Zona glomerulosa → hypersecretion of aldosterone leads to the following:

-____

-____

-___ [H+] in blood

-____ K+ and H+ secretion

HTN, hypokalemia, low, high

Zona fasciculata (middle layer)

-secretes ___ and the weak androgen ___

cortisol, DHEA

Zona reticularis (inntermost layer)

-secretes ___ and the weak androgen ___

cortisol, DHEA

If there was a hypersecreting tumor in the Zona fasciculata/Zona reticularis, this would result in hypersecretion of ___ and weak ___

cortisol, androgens

hypersecreting tumor in the Zona fasciculata/Zona reticularis → hypersecretion of cortisol leads to the following:

-increased ___

glucose

hypersecreting tumor in the Zona fasciculata/Zona reticularis → hypersecretion of androgens leads to the following:

-___ (e.g., pubic axillary hair growth, coarse skin, deep voice)

virilization

The steroids produced from the adrenal cortex fall into 2 categories: ___ and ___

corticosteroids, androgens

Corticosteroids

1. ___ (carbohydrate-metabolizing)

2. ___ (Na+ retention)

glucocorticoids, mineralocorticoids

Androgens

1. _____

2. ____ (causes virilization-e.g., pubic axillary hair growth, coarse skin, deep voice)

androstenedione, DHEA

Drugs used diagnostically to determine the etiology of suppressed corticosteroid levels:

1. ____ (brand =Acthrel)

2. ____ (generic= Cosyntropin, brand =Cortrosyn)

CRH, ACTH

Primary Corticosteroid Suppression occurs at level of ___ ___

adrenal gland

Secondary Corticosteroid Suppression occurs at level of ___ ___

anterior pituitary

Tertiary Corticosteroid Suppression occurs at level of ___

hypothalamus

Although CRH and ACTH can be used clinically, their use is limited due to ___, short __-___ (as peptide hormones), and adverse effects such as ___ with ACTH

immunogenicity, half-lives, hyperpigmentation

All of the following peptides come from the same protein:

1. ACTH - stimulates cortisol release

2. γ-___ -melanocyte-stimulating hormone

3. γ-___ -fat metabolism

4. β-___ -stress relief

MSH, lipotropin, endorphin

ACTH can cause hyperpigmentation because it is proportional with melanocyte-stimulating hormone (__)

MSH

ACTH can cause hyperpigmentation. This may present as ___, ___, or __ on skin

bronzing, freckles, patchiness

Relative Potencies of Corticosteroids

-____ and ___ (GC = MC)

cortisol, cortisone

Relative Potencies of Corticosteroids

-____ (MC>GC)

fludrocortisone

Relative Potencies of Corticosteroids

-____, ___, and 6α-____ (GC>MC)

prednisone, prednisolone, methylprednisolone

Relative Potencies of Corticosteroids

-____, ___, and ____ (Pure GC)

triamcinolone, betamethasone, dexamethasone

Relative Potencies of Corticosteroids

-___ (Pure MC)

aldosterone

Corticosteroids exert their effects on thh body via mineralocorticoid receptors (type __) or glucocorticoid receptors (type ___)

I, II

____ is the endogenous agonist for the mineralocorticoid receptor

____ is the endogenous agonist for the glucocorticoid receptor

aldosterone, cortisol

Mineralocorticoid receptors (type I)

-these receptors are more __ in their distribution throughout the body

restricted

Mineralocorticoid receptors (type I)

-because these receptors are involved in electrolyte balance, then it should be no surprise they are located on ___, ___, __ glands, ___ glands, ___ gland, and ___

kidney, colon, salivary, sweat, pituitary, hypothalamus

Mineralocorticoid receptors (type I)

-are also ___ receptors that regulate the expression of specific proteins

cytoplasmic

Mineralocorticoid receptors (type I)

-are also cytoplasmic receptors that regulate the expression of specific proteins via their actions on aldosterone response elements (___) in genes

AREs

Mineralocorticoid receptors (type I)

-because the effects of corticosteroids depend upon protein synthesis, their effects are usually ___ (>3 hours)

delayed

Aldosterone–Mineralocorticoid Receptor (MR) Pathway

1. Signal for pathway = ___ (due to hypovolemia--characterized by low H2O and low ___)

hypotension, Na+

Aldosterone–Mineralocorticoid Receptor (MR) Pathway

2. ___ is released from the hypothalamus

3. ___ is released from the anterior pituitary

CRH, ACTH

Aldosterone–Mineralocorticoid Receptor (MR) Pathway

4. ___ is released from the zona glomerulosa of the adrenal cortex

aldosterone

Aldosterone–Mineralocorticoid Receptor (MR) Pathway

5. Aldosterone, due to its __ nature, is able to traverse the plasma membrane and bind to the mineralocorticoid receptor located in the ___

lipophilic, cytoplasm

Aldosterone–Mineralocorticoid Receptor (MR) Pathway

6. The aldosterone–MCR complex ___ and then binds to ___ on DNA, leading to activation of gene ____.

dimerizes, AREs, transctiption

Aldosterone–Mineralocorticoid Receptor (MR) Pathway

7. The production of mRNAs from gene transcription results in the translation of ____ (including Na+/K+/ATPase, Na+, or K+ channels)

proteins

Aldosterone–Mineralocorticoid Receptor (MR) Pathway

8. Translation of proteins including Na+/K+/ATPase, Na+, K+ channels ultimately increases sodium reabsorption back into the ___ (remember stimulus for pathway was low sodium in the blood)

blood

Note that the sodium channel that transports Na⁺ from the tubular lumen → into the nephron cells is called the amiloride-sensitive sodium channel because it can be inhibited by the ____ amiloride, which reduces sodium reabsorption.

diuretic

Glucocorticoid receptors (type II)

-these receptors are widely dispersed throughout the body including ___, ___ ___, ___, ___, and ___ tissue

hypothalamus, pituitary gland, liver, muscle, adipose

Cortisol stimulates ____, ___, and ___ by binding to the GCR

glycogenolysis, proteolysis, lipolysis

Cortisol stimulates glycogenolysis, proteolysis, and lipolysis, which ultimately increases blood ___

glucose

Glucocorticoid receptors are steroid receptors that ___ and regulate the expression of specific proteins via their actions on ___ ___ ___ (GREs)

dimerize, glucocorticoid response element

Glucocorticoid receptors regulates genes involved in ___-___ and ___ regulation

anti-inflammation, glucose

Glucocorticoid receptors (type II)

-because the effects of corticosteroids depend upon protein synthesis, their effects are usually ___ (>3 hours)

delayed

Glucocorticoid Receptor Pathway

1. Cortisol circulates in the blood mostly bound to blood proteins. When needed, cortisol dissociates from the blood protein and the free cortisol diffuses into the ___

cell

Glucocorticoid Receptor Pathway

2. The GCR in the cytoplasm of the cell is complexed (ie unavailable). When cortisol binds to the GCR, it causes the receptor to become ____ (free/active form).

uncomplexed

Glucocorticoid Receptor Pathway

3. The cortisol-GCR translocates into the ___ of the cell

nucleus

Glucocorticoid Receptor Pathway

4. The cortisol–GCR complex ___ and then binds to ___ on DNA, leading to activation of gene ____.

dimerize, GREs, transcription

Glucocorticoid Receptor Pathway

5. The production of mRNAs from gene transcription results in the translation of proteins (involved in ___ metabolism or ___ regulation)

glucose, immune

Remember, glucocorticoids are classified by their ability to metabolize ___ and thus increase ___ ___ levels

carbohydrates, blood glucose

effect of too little cortisol

-___ proteolysis

-___ lipolysis

-____ gluconeogenesis

-____ glycogenolysis

decreases, decreases, decreases, decreases

too little cortisol ultimately ___ blood glucose

decreases

effect of too much cortisol

-___ proteolysis

-___ lipolysis

-____ gluconeogenesis

-____ glycogenolysis

increases, increases, increases, increases

Effects of Glucocorticoids on the Immune System

1) prevents leukocyte ___ ("anti-inflammatory")

migration

Effects of Glucocorticoids on the Immune System

2) stabilizes ___ ___ (reducing histamine release + cytokines, decreasing allergies)

mast cells

Effects of Glucocorticoids on the Immune System

3) prevents vascular ___ (decreases swelling)

leakage

Remember, mineralocorticoids are classified by their ability to retain ___

sodium

Mineralocorticoids also promote the secretion of __+ and __+

K, H

Mineralocorticoids affect sodium, and because Na+ is osmotically active substance, ___ will follow the sodium and modulate blood pressure

water

What disease state is characterized by hyposecretion of corticosteroids?

Addisons

Addison's Disease

-patients may experience myopathy/weakness and ↓ blood pressure due to reduced ____ effects

mineralocorticoid

Addison's Disease

-patients may experience hypotension (from decreased Na+) due to reduced ____ effects

mineralocorticoid

Addison's Disease

-patients may experience normal/inflammatory immune response due to reduced ____ effects

glucocorticoid

Addison's Disease

-patients may experience altered electrical activity in the muscle, CNS, and cardiac system due to reduced ____ effects

mineralocorticoid

When the electrical activity is altered due to reduced mineralocorticoids, this is especially dangerous in the heart, as ___ K+ levels can lead to MI

high

Addison's Disease

-patients may experience hypoglycemia due to reduced ____ effects

glucocorticoid

Addison's Disease

-patients may have low lipid levels due to reduced ____ effects

glucocorticoid

Addison's Disease

-patients may have hyponatremia due to reduced ____ effects

mineralocorticoid

Addison's Disease

-patients may have hyperkalemia due to reduced ____ effects

mineralocorticoid

Addison's Disease

-patients may have have increased H+ levels and decreased pH due to reduced ____ effects

mineralocorticoid

Addison's Disease

-patients may have high H+ due to reduced ____ effects