Lecture Objectives- Adrenal Flashcards
Describe the Hypothalamic-Pituitary-Adrenal axis regulation
1) Hypothalamus releases CRH to Anterior Pituitary
2) Stimulates Ant. Pit. release of ACTH
3) ACTH binds Mealanocortin 2 receptor, stimulates adrenal cortex (zona fasciculata) release of cortisol
4) cortisol gives negative feedback to hypothalamus and pituitary via mineralcorticoid and glucocorticoid receptors
5) cortisol also gives negative feedback ( via GABA neurons) to hippocampus through MR/GR to hypothalamic CRH, giving a set point for overall negative feedback (chronic cortisol elevation will diminish MR/GR so more cortisol is needed to engage hippo inhibition of CRH, thus elevating set point)
Zones of the adrenal cortex and their major products
1) Zona glomerulosa (outermost): aldosterone
2) Zona fasciculata: cortisol
3) Zona reticularis (innermost): adrogens
CRH-driven biosynthesis of ACTH
-in anterior pituitary corticotrope
-from POMC (preproopiomelanocortin)
=cleaved in to ACTH (+ other peptides like MSH, co-released from corticotropes)
=cleaved into B-lipotropin –> B-endorphin (little released in humans)
Diurnal rhythm of cortisol
- ACTH peaks as waking
- cortisol peaks on waking (driven by ACTH peak)
- during day: irregular ACTH decrease, so overall cortisol decrease
Vasopressin Effects
- vasopressin from post pit (co-incident with CRH) induces ACTH release
- occurs at much higher levels of vasopressin than needed to regulate antidiuresis.
- so post. pit. not usually involved in ACTH/cortisol regulation
Cortisol activation and inactivation in tissues
bioactive cortisol –> inactive cortisone
- -via 11B-hyroxysteroid dehydrogenase 2
- -in kidneys: prevents cortisol from binding MR and disrupting aldosterone action
- -in placenta: prevents cortisol from inhibiting placental estrogen production
- -if defective 11B-HSD2: apparent mineralcorticoid excess from unconverted cortisol action in kidney
inactive cortisone–> active cortisol
- -via 11B-hydroxysteroid dehydrogenase 1
- -in fat: enhances local action on adipocytes (increased GR expression in abdominal visceral fat)
- -in liver: enhances local action
Adrenal Steroid pathways: zona glomerulosa
- -> Aldosterone (mineralcorticoids)
- controlled principally by ANGIOTENSIN II:
- stimulates conversion of cholesterol to pregnenolone (via 20,22 lyase)
- inhibits expression of 17a-OHase and 17/20lyase
- stimulates synthesis of aldosterone synthase
- *little ACTH regulation
- *highest AT1-R, lower ACTH-R
Adrenal Steroid pathways: zona fasiculata
- ->Cortisol
- ACTH drives the conversion of cholesterol to pregnenolone (via 20,22 lyase)
- 17a-OHase is present and has a higher affinity for 3b-HSD, so it outcompetes! (converts pregnenolone to 17a-Hydroxypregnenolone)
- 17/20 lyase is present but is inactive because cofactor cytochrome b5 is not present (so don’t make androgens)
- no aldosterone synthase, so even though small amounts of progesterone and deoxycorticosterone are made, no corticosterone or aldosterone are made
- **Highest ACTH-R, much lower AT1-R
Adrenal Steroid pathways: zona reticularis
- -> Androgens (DHEA/DHEAS/Testosterone)
- ACTH is the predominant driver of cholesterol to pregnenolone (via 20,22 lyase)
- does not fully develop until just before puberty, and also a decrease in expression of 3b-HSD in innermost ZR cells, so pregnenolone is converted to 17a-hydroxypregnenolone (via 17a-hydroxylase)
- cytochrome b5 is present for 17/20 lyase to create DHEA
- sulfotransferase is present for 3B-sulfotransferase to make DHEAS (used to measure the adrenal androgen output, separate from testis and other sources)
Effects of Stress (short and long term)
Short term stress: mediated by epinephrine
- glycogen breakdown, increased blood glucose
- increased BP, breathing rate, metabolic rate
- change in blood flow pattern, so increased alertness and decreased digestive and kidney activity
Long term response:
Mediated by Mineralcorticoids (aldosterone)
-retain Na+ and H20 in kidneys
-increased blood volume and BP
Mediated by glucocorticoids (cortisol)
- stimulate GNG, lipolysis
- anti-inflammatory
Metyrapone
- competitive inhibitor of 11B-hydroxylase (and of 11B-HSD1 and 11B-HSD2 in tissues)
- results in deficient cortisol production, loss of negative feedback, so high ACTH
Aldosterone effects
- acts on distal tubules and collecting duct in kidneys
- reabsorption of Na+, increases H20 reabsorption
- K+ secretion into filtrate
Chronically high aldosterone:
-hypernatremia, fluid retention, high BP, hypokalemia
Chronically low aldosterone:
-salt wasting, hyponatremia, hyperkalemia
Chronic cortisol effects
Liver:
-enhances GNG so increased glucose release and glycogen formation
Muscle:
- decreases insulin-mediated glucose uptake
- enhances protein turnover, so free aa’s into blood for GNG
Adipose:
- decreases insulin-mediated uptake of glucose and FFA’s
- enhances epinephrine and GH stimulation of lipolysis and SNS stimulation of FFA release
- enhances adipocyte formation/lipogenesis
Bone:
-decreases osteoblast formation and enhances apoptosis
-enhances osteoclast formation
-decreases bone formation, increases bone resorption
Overall: net loss of bone, release of Ca++
(relevant to cortisol excess and anti-inflammatory drugs binding to GR)
Congenital adrenal hyperplasia
- commonly from 21-hydroxylase deficiency
- Results in cortisol deficiency
- see high ACTH (from loss of cortisol negative feedback); low aldosterone, high DHEA
- -Common form from inadequate aldosterone: salt wasting, virilized girls
- -less common form sufficient aldosterone: simple virilization in girls
- **major discriminator is high levels of 17-OHP4 (cortisol precursor)
Cushing’s Syndrome
- excess cortisol
- can be ACTH dependent (pituitary adenoma) or independent (adrenocortical tumor)
- loss of limb muscle and fat
- accumulation of fat in abdomen and face
- insulin resistance
- loss of CT leading to thin skin
- osteoporosis
- depression
