Glucocorticoids and Adrenal Androgens Flashcards
The zona […] of the adrenal cortex is unique in that it is the only layer of the 3 cortical layers that is not under ACTH control.
Glomerulosa (Mineralocorticoids)
What are some of the effects of cortisol on the body?
Once ATCH circulates to the adrenal glands, describe:
- The receptor it binds to
- The intracellular signaling pathway it utilizes
- The effects it produces in the cell
- Binds to MC2R receptor
- MC2R is GPCR, Gas –> results in increased cAMP and PKA stimulation –> gene transcription
- Immediate effects –> increase production of enzymes and proteins needed to produce steroid hormones
- Sustained effects –> increase production of proteins in the cells to sustain response to ACTH (LDL receptor, etc.)
- Long term effects –> increased size, number and complexity of organelles and cells leading to hypertrophy
Describe the process that the adrenal cortex uses to make steroid hormones.
All hormones produced by the adrenal cortex are steroid hormones, which are derived from cholesterol. Most of the cholesterol comes from circulating LDL, but the cells do have the ability to synthesize de novo cholesterol.
- Cholesterol entry into fat droplets inside cells.
- LDL binds to LDLR –> LDL endocytosed and fused with lysosome –> Lysosomal acid lipase (LPL) converts cholesterol esters to free cholesterol which is secreted into cytoplasm of cell via NPC (Nieman Peak protein) –> free cholesterol is re-esterified and put into faty droplet stored inside cell.
- AcetylcoA inside cytoplasm can be used to produce free cholesterol and ACAT can esterify cholesterol for entry into lipid droplet inside cell.
- Mobilization of cholesterol from fat droplet and entry into mitochondrion.
- When cholesterol is needed to produce hormones, hormone sensitive lipase (HSL) (signaled by ACTH) can remove cholesterol esters and produce free cholesterol again.
- Free cholesterol is moved across mitochondrial membranes via STAR protein.
- Conversion of free cholesterol to pregnenolone
- Free cholesterol in the mitochondrion is converted to pregnenolone by CYP11A1 and then pregnenolone is converted to various products that ultimately produce cortisol, aldosterone, and weak sex hormones depending on the layer of the cortex.
What is cholesterol ester storage disease (wolman’s disease)?
Mutation in lysosomal acid lipase –> large fatty lysosomes b/c can’t remove cholesterol
What is lipoid congenital adrenal hyperplasia?
How is it different from congenital adrenal hyperplasia?
LCAH = mutation in STAR proteins, results in inability to produce steroid hormones in response to ACTH b/c can’t get cholesterol into mitochondria. There is loss of negative feedback to higher brain centers, so ACTH is over produced and this results in long term hyperplasia of adrenal glands.
CAH = mutation in either CYP21A2 (more common) or CYP11A1 (less common) –> results in inability to produce steroid hormones in response to ACTH b/c can’t produce necesscary precursors. There is loss of negative feedback to higher brain centers, so ACTH is over produced and this results in long term hyperplasia of adrenal glands.
How is congenital adrenal hyperplasia due to CYP21A2 different from the same condition due to CYP11A1?
CYP21A2 is only important in formation of cortisol and aldosterone where as CYP11A1 is important in the formation of all steroid hormones produced by adrenal cortex.
- CYP21A2 mutation –> individual will not produce cortisol or aldosterone, but will over produce weak androgens (problem in female)
- CYP11A1 mutation –> individual will not produce any cortical hormones
How is cortisol transported in the blood?
Bound to proteins
- 90% bound to corticosteroid binding globulin (CBG)
- 5-7% bound to albumin
- Remainder is free / biologically active / feedback to HPA axis
The […] is the major site of cortisol metabolism.
Liver
What are the ways coritisol can be inactivated?
- Liver conjugates with glucuronide or sulfate for renal excretion
- Liver (adipose, skin, CNS) inactivate it by reversibly converting it to cortisone once it enters the cell via enzyme 11 beta HSD2
Glucocorticoid receptors and mineralocorticoid receptors share a lot of homology. GCs can bind to both GCR and MCR, but MCs can only bind to MCR. How do MC cells then protect themselves from GCs, considering that GCs are 1000x more present than MCs?
MC cells convert cortisol to cortisone, via 11 beta HSD2. Cortisone then enters blood and can be taken up by cells that utilize GCs and converted back into cortisol and used for signaling purposes.
What are the major metabolic effects of coritsol?
Maintain blood sugar levels during fasting
- Increase gluconeogenesis
- Increase muscle proteolysis
- Increase fat mobilization and redistribution
- Decrease peripheral glucose utilization to conserve for brain
What are the effects of cortisol on the immune system?
Decreases inflammatory signaling
Increases anti-inflammatory signaling
Inhibits immune response
What are the effects of cortisol on cardiovascular system?
What are the effects of cortisol on the kidney?
Mainly - inhibits ADH
What are the effects of cortisol on the bone?
Decrease Ca++ reabsorption in gut and kidney
Increase bone resorption –> osteoporosis
What are the effects of cortisol on the muscle?
Excessive proteolysis –> weakness and pain
What are the effects of cortisol on the connective tissue?
Scarring –> inhiits fibroblast proliferation and collagen formation
What are the effects of cortisol on the GI tract?
Stimulate appetite
Stimulate gastric acid and pepsin –> ulcers
What are the effects of cortisol on a fetus?
Induces differentitaion and maturation of type 2 pneumocytes (produce surfactant) in fetal lungs
What are the effects of cortisol on mental function?
In excess:
- Depression
- Insomina
Insufficient:
- Depression, apathy, irritability
When does the zona reticularis develop?
When does it start secreting hormones?
Develops after birth
During puberty (menarche, adrenarche)
Androgen levels produced by adrenal cortex increase during […], peak during […] and then […] with age
Childhood
20s
decline
Once weak androgens are produced by adrenal cortex and secreted into blood, what happens to them?
- Transported in blood bound to albumin (most) and other transport globulins (less)
- Tissues that express appropriate enzymes will convert them to more potent sex hormones (testosterone, estrogen, estradiol)
- Weak androgens can be excreted by kidneys
What are the physiological roles of weak androgens produced by adrenal cortex in men and women?
If a person has too much GCs, they have […], whereas if they have too little they have […]
Cushing’s syndrome
Addison’s disease
If a person has too much aldosterone, they have […]
Conn’s syndrome
If a person has too much cortisol in their system, this could be due to many factors (primary, secondary, tertiary). What are 5 tests you can do to look at the HPA axis function?
Why do you have to be tapered down off of a GC dose?
People who receive exogenous GCs have an atrophied zona fasiculata b/c the exogenous GCs are controlling feedback to the H & P. If you withdrew the person from GCs all at once, they would have no ability to produce cortisol and could die. The tapering is needed to allow time for the ZF to rebuild and start producing GCs again.
