Flashcards in Adrenal Cortex Hormones Deck (46)
What are the 3 major hormones secreted by the adrenal gland?
1. aldosterone (mineralocorticoid)
2. cortisol (glucocorticoids)
3. dehydroepiandrostenedione (DHEA- androgens)
**all made from cholesterol
What is StAR?
Steroidogenic acute regulatory protein and mediates the uptake of cholesterol into the mt. There are different types of StAR depending on zones of the adrenal gland
What is the StAR enzyme of the zona glomerulosa?
CYP 11AS (P450c11AS) aka 11BHSD
What is the StAR enzyme of the zona reticularis?
sulfatransferase and 17,20 lyase, 17BHSD
What is the StAR enzyme of the zona fasciculata?
P450c17 (17a-hydroxylase) CYP17
How much cortisol, DHEA and aldosterone is produced daily?
- approximately 100x more cortisol and DHEA than aldosterone.
- DHEA is the steroid hormone with highest plasma concentrations
How is cortisol carried in the blood?
It has a specific carrier (CBG-cortisol binding globulin) and nonspecific carrier albumin. Pretty stable and a lot is bound to the carrier (4% unbound) so therefore a longer half life.
Is the active portion of the hormone bound or unbound to the carriers?
How is aldosterone carried in the blood?
has only nonspecific carrier to CBG and albumin. A much larger percentage is unbound and therefore has a much shorter half life.
How is DHEA carried in the blood?
only nonspecific carrier albumin. Is extremely stable and almost all is bound to the carrier, therefore has a really long half life.
What happens to levels of DHEA through out life?
increases during fetal development, then decreases shortly after birth as the adrenal gland matures. Increases again during puberty, plateau at 25 years of age and then gradually falls through out life in both males and females (higher levels overall in males)
What happens to cortisol levels through out life?
increases after birth and then stays at a constant basal level for the rest of life.
What is the correlation of ACTH and cortisol?
ACTH rises and shorty after cortisol also rises. ACTH released from the anterior pituitary and causes the adrenal to release cortisol. There is a direct symmetry between ACTH levels and cortisol levels.
Describe pathway to cortisol secretion
1. hypothalamus stimulated by stress or time of day etc
2. hypothalamus releases AVP and CRH
3. AVP and CRH cause the anterior pituitary to release ACTH via POMC expression and proteolytic processing
4. ACTH acts on adrenal gland binding to the MCR-2 G protein receptor.
5. This activates GaphaS system leading to increase in cAMP and PKC and increased StAR
6. increased StAR means more cholesterol delivery to the mt to initiate the synthesis pathway for cortisol
7. Get increasing amounts of cortisol that can negatively inhibit further cortisol release by acting on the anterior pituitary and the hypothalamus.
**in zona fasiculata and directly stimulated by ACTH
What is AVP and CRH?
AVP=arginine vasopressin (different from water regulator and involved in augmenting CRH when stress is a stimulator)
CRH=corticotropin releasing hormone
What is POMC?
pro-opiomelanocortin. Is the precursor for ACTH, B lipotrophic hormone, melanocyte stimulating hormone (MSH), B-endorphin and enkephalin. POMC is cleaved proteolytically into these different products.
What do all POMC derivatives have in common?
All have the common melanocortin receptor (MCR). So ACTH can bind to all derivatives of POMC.
Besides activating release of cortisol, what is another role of ACTH?
ACTH plays a role in maintenance and homeostasis of the adrenal gland. Deficiency leads to atrophy of the gland, overabundance leads to hypertrophy of the gland.
Helps promote production of NO which leads to vasodilation of vasculature facilitating delivery of products into the blood stream
Describe the pathway to aldosterone secretion
1. Angiotensin II binds to receptor on glomerulosa cells in the adrenal.
2. GalphaQ pathway activated leading to more PLC/DAG/IP3/Ca release.
3. Increased intracellular Ca activates CAM* so more StAR is made
4. More StAR=more cholesterol to mt
5. K+ is also able to induce aldosterone synthesis
**ACTH indirectly stimulates aldosterone. If ACTH deficiency, can still have aldosterone.
What is the GR hormone receptor?
- glucocorticoid receptor binds cortisol and ONLY cortisol
- is a ligand-activated transcription factor present in the cytoplasm bound to heat shock proteins
- expressed all over the body
- when ligand binds (cortisol) then dimerization, nuclear translocation, binds to hormone response elements (HRE) in the promoter region
- can alter gene regulation by either activation or inhibiting it.
What is the MR hormone receptor?
- mineralocorticoid receptor binds aldosterone AND cortisol with similar affinity
- ligand-activated TF in the cytoplasm with heat shock proteins
- expressed only in the kidney, colon, salivary and sweat glands
- ligand binds, dimerization, nuclear translocation, HRE bound in promoter region and alters gene regulation
Describe tethering and how GR can inhibit gene expression?
- GR dimer can bind to either an activating or inhibiting hormone response element.
- tethering is thought to be the main mechanism of anti-inflammatory drugs. GR dimer binds to other different transcription factors and inhibits them.
- tethering differs from direct in that in tethering, GR doesn't come in contact with DNA, in direct the GR do come in contact with DNA
How does prolonged taking of cortisol lead to hyperglycemia?
GR receptor can bind to HRE that are both activating and inhibiting. When high glucocorticoids in the blood, high GR. GR binds to +GRE elements leading to increased blood glucose. Also there are nGRE- elements before all the insulin genes, so GR also responds here therefore inhibiting insulin production, so blood glucose can continue to raise in someone taking glucocorticoids for a long period of time at high dosage.
What is the overall role of cortisol?
To increase blood glucose
What actions does cortisol have on fuel metabolism?
- increase blood glucose
- increase lipolysis (adipose tissue)
- increase proteolysis (muscle)
- increase gluconeogenesis (liver)
- increase glucose storage (liver)
- increase glycogen synthase (liver)
What are some other physiological effects of cortisol?
-fetal lung development (alveoli maturation and surfactant)
- normal BP and CO
- mental well being
- suppress immune response and inflammation
- inhibit bone remodeling and formation
- decrease Ca absorption/reabsorption
How do glucocorticoids provide anti-inflammatory actions?
- GR binds to HRE and induces iNF-KB which binds to NF-KB and inhibits normal production of inflammatory elements like COX2, cytokines, prostaglandins, iNOS, etc.
- Interrupts positive feedback of inflammatory pathway.
- Main inhibition via tethering mechanism and its ability to increase expression of the inhibitor molecule which keeps NF-KB in cytoplasm so it isn't able to bind to DNA and cause inflammatory production.
- prevents generation of arachiodonic acid and any of its corresponding lipids.
What are the symptoms of hypercortisolemia?
1. obesity (central deposition of fat)
2. thinning of arms and extremities (proteolysis)
Is cortisol responsible for weight gain?
- cortisol is not responsible for weight gain. Obese people do not have increased levels of cortisol in their blood, however if we look just at visceral adipose cells, there is a localized increase of cortisol. Shows that cortisol has local production in visceral fat which leads to increased fat production only in the visceral fat (?).