Adrenal Physiology - Trachte Flashcards
What are the three zones of the Adrenal Gland?
- The outermost zone, the Zona glomerulosa, synthesizes the mineralocorticoid aldosterone
- The middle zone, the Zona fasciculata, and the innermost zone
- The Zona reticularis, synthesize the glucocorticoid cortisol and the androgens dehydroepiandrosterone (DHEA) and androstenedione
What embryological tissue is the Adrenal Gland derived from?
neural crest
What are the components of the Glucocorticoid Endocrine Axis?
Hypothalamus => CRH: corticotropin releasing hormone (via circadian rhythm/stress stimulation)
Anterior Pituitary => ACTH: adrenocorticotrophic hormone
Adrenal Gland => Cortisol: the principal actor of glucocorticoids
What are the four general actions of the Glucocorticoids?
- Immune System Fxn => suppressed
- Liver Fxn => Gluconeogenesis
- Muscle => Protein catabolism
- Adipose tissue => Lipolysis
Corticotropin Releasing Hormone (CRH) half life? Place of synthesis? Receptor? Effect?
Short t1/2 ~ 9 min
Synthesized in hypothalamus
Anterior pituitary corticotrophs have CRH R1 receptor
Gs-protein coupled receptor
Stimulates adenylyl cyclase to increase cAMP concentrations
Proinflammatory cytokines and chronic stress promote release of CRH
Corticotroph CRH R1 receptor bound hormone induces what reaction in the target cell?
Gs - Adenylyl cyclase activity
Increased synthesis of the preprophormone, pro-opiomelanocortin.
Cleavage of POMC and release of hormones:
- Melanocyte stimulating hormone (MSH)
- ACTH adrenocorticotropic hormone
- lipotropin
What does ACTH bind to? What is the effect?
binds to Melanocortin-2-receptor in adrenal cortical cells
a Gαs-coupled receptor, therefore it elevates cAMP concentrations to initiate a signal transduction cascade involving PKA
Rapidly promotes side-chain cleavage enzyme (CYP11A=P450scc) synthesis in adrenal cortex.
This reaction enzyme is required for cholesterol conversion to pregnenolone.
THIS IS A RATE-LIMITING STEP in adrenal steroid synthesis.
What Glucocorticoid has the highest affinity and potency for Glucocorticoid Receptors?
Cortisol
Where are Mineralocorticoid Receptors found?
kidney, colon, sweat glands, heart, hippocampus, brown adipose
What Glucocorticoid has the highest affinity and potency for Mineralocorticoid Receptors?
Has ~ equal affinity for aldosterone and cortisol
(Although affinity might be the same, in mineralocorticoid-responsive tissues such as the kidney, cortisol is enzymatically converted to cortisone (can be prevented by liquorice), a metabolically inactive steroid so has no affect => selectivity for aldosterone)
What are the actions of the Glucocorticoids?
Cause a rise in circulating glucose levels
- Cortisol mobilizes amino acids from proteins which are utilized by the liver to make glucose (via gluconeogenesis)
- Deficiency can cause hypoglycemia
Cortisol is the primary active glucocorticoid
Bind to glucocorticoid receptors (GR)
What are the actions of the Mineralcorticoids?
Promote salt and water retention by the kidney
Aldosterone => Has little glucocorticoid activity
Bind to mineralocorticoid receptors (MR)
How does cortisol circulate through the body?
10% circulates free
90% circulates bound => 60% to CBG (corticotropin binding globulin=transcortin) + 30% to albumin
Where are Glucocorticoids metabolized?
Liver (CYP450)
What are the clinical findings in Cushing Syndrome?
Moon face
Fat pads (buffalo hump)
Thin skin
High BP
Red striae (abdomen)
Pendulous abdomen
Thin arms and legs (fat redistribution)
What is excess ACTH secretion usually due to?
usually due to pituitary adenomas = Cushing Disease
What are the blood profiles in Cushing Disease?
ACTH, Cortisol, Aldosterone
Increased ACTH (hyperpigmentation
Increased Cortisol
+/- Aldosterone
What is Cushing Syndrome? Blood profiles?
iatrogenic or due to primary glandular excess production or cortisol due to adrenal tumors
or tertiary causes: (morbid obesity, DM2, some psychiatric drugs, alcoholism)
Blood profiles: ↑ Cortisol, ↓ ACTH
What are the effects of the mineralcorticoid Aldosterone?
Stimulates kidney reabsorption of Na+ and water
Stimulates Na+ and water reabsorption in the colon, salivary glands and sweat glands
Enhances kidney K+ excretion
Hypersecretion of aldosterone can cause hypertension
What is the effect on CRH, ACTH and cortisol levels if there is damage resulting in no CRH secretion?
Everything is suppressed
What is the effect on CRH, ACTH and cortisol levels in Pituitary damage resulting in no ACTH secretion?
High CRH
No ACTH
No Cortisol
What is the effect on CRH, ACTH and cortisol levels in adrenal damage resulting in no corticol secretion?
High CRH
High ACTH
Low Cortisol
What is the effect on CRH, ACTH and cortisol levels in receptor damage resulting in no efficacy of cortisol?
Everything would be elevated
What is the effect on CRH, ACTH and cortisol levels in a tumor secreting excess CRH?
Everything would be elevated?
What is the effect on CRH, ACTH and cortisol levels in a tumor secreting excess ACTH?
Low CRH
High ACTH
High Cortisol
What is the effect on CRH, ACTH and cortisol levels in a tumor secreting excess cortisol?
Low CRH
Low ACTH
High Cortisol
Where is the only place you can make Aldosterone in the body?
Adrenal glands (18 Lyase (aldosterone synthase) is unique to adrenal glomerulosa)
What are the six important steps in Adrenocorticoid Synthesis?
- All steroids are synthesized from cholesterol
- CYP11A1 = Side Chain Cleavage-RATE LIMITING!
- CYP17 = 17-alpha-hydroxylase
- *CYP21A = 21-hydroxylase (defect accounts for 95% of genetic abnormalities; is a CAH congenital adrenal hyperplasia)
- *CYP11B1 = 11-beta-hydroxylase (next most common defect; is also a CAH)
- CYP11B2 = Aldosterone Synthase
What is Addison’s Disease? Cause? Effect?
congenital adrenal dysgenesis/hormone insufficiency
Cause = usually due to immune mediated destruction of adrenal cortex
Effect = ↓Cortisol (knockout) ↓Aldosterone Compensatory ↑ CRH, POMC hence ↑ ACTH, ↑ MSH
What are the symptoms of Addison’s Disease?
Mucous membrane pigmentation
Skin pigmentation, Vitiligo
Pigment accentuation of nipples and friction areas
Hypotension
Fatigue and weakness
Weight loss, emaciation, anorexia, vomiting, diarrhea
What is secondary Adrenal insufficiency (aka hypocortisolism/hypoadrenalism)?
Iatrogenic following sudden withdrawal of exogenous glucocorticoid
With exogenous cortisol, ↓endogenous ACTH
What are adrenal steroids synthesized from?
Adrenal steroids, like all steroid hormones, are synthesized by enzymatic modification of cholesterol
Most of the cholesterol used for steroidogenesis is acquired from dietary sources or synthesized in the liver. De novo synthesis is also possible.
What controls the rate limiting step of glucocorticoid production?
Side chain cleavage enzyme (CYP11A1) is under ACTH regulation making the production of pregnenolone a rate limiting step
What does Aldosterone regulate?
Aldosterone regulates sodium & K balance.
Aldosterone has no effect on ACTH secretion.
