Endocrinology Lec 8
Catecholamine effects consistent with what kind of response? What are the effects on metabolism, CV, pain? What about learning?
"fight or flight" Metabolic similar to cortisol ¨Mobilize glucose ¨Much Faster effect Increases CV capacity does so by: ¨Heart - increased rate - increased force of contraction - increased blood flow ¨Lung - Relaxes bronchia - increased blood flow Inhibits pain & stimulates euphoria: "Adrenaline High" Connects learning to endocrine system
One cause of hypocortisolism is Addison's disease, which is caused by autoimmune attack on the adrenal gland. What are the effects of Addison's disease on hormone levels? A. CRH, ACTH and cortisol are all high B. CRH and ACTH are high, cortisol is low C. CRH is low, ACTH and cortisol are high D. CRH and cortisol are low, ACTH is high E. CRH and ACTH are low, cortisol is high
. CRH and ACTH are high, cortisol is low
Prednisone is an example of a corticosteroid, which is a drug that mimics the actions of cortisol. Which of the following is an expected from proper use of Prednisone? A. Suppression of inflammation B. Weight loss C. Hypoglycemia D. Addison's disease E. Nervousness and anxiety
A. Suppression of inflammation
How are cortisol and epinephrine complementary parts of the stress response?
Cortisol is slow due to its transcriptional effects, while epinephrine is fast. Both respond to complex inputs, but epi strictly to emotional treats; cortisol responds to a wider range of threats. Cortisol can up regulate epi response through transcription.
Chronically high cortisol: What is the disease name? What leads to it? What are the symptoms?
Cushing's Disease Stress leads to cortisol secretion ¨Cushing syndrome -Maladaptation to chronic stress -Corticosteroid abuse -Adrenal tumors ¨Cushing disease leads to pituitary tumors Many complex symptoms ¨Immune suppression ¨Metabolic effects -Hyperglycemia leads to diabetes -Muscle wasting from excessive protein catabolism -Lipids (Mostly catabolism..Selective anabolism causes visceral obesity)
Synthesis and release on adernal chromaffin cell: Explain the step by step and result: -What stimulates synthesis? -•What nerves release acetylcholine? •What causes epinephrine release? Is there HPA feedback?
Epinephrine synthesis releases are sympathetic nerve are so this is a target. -So epinephrine is synthesized from amino acid tyrosine. It's synthesis is stimulated by cortisol and ACTH, increasing transcription of the biosynthetic enzymes from tyrosine leading to Epinephrine, stored in vesicles int he chromaffin cells. -Upon receipt of a stress, AcH is release from this sympathetic neuron. It binds to AcH receptor on the surface of the adrenal chromaffin cell. This causes depolarization and calcium channels open and allow calcium into the cell. The release of epinephrine, which will then bind to a receptor on the cell and give you your stress response. Cortisol and ACTH stimulate synthesis •Sympathetic nerves release acetylcholine •Acetylcholine causes epinephrine release No HPA feedback
Does epinephrine & norepinephrine mediate the fast or slow response? What about half life? Is it mostly like a steroid or protein?
FAST Very short half-life: < 1 min Mostly like a steroid or mostly like a protein? BOTH.
Long-term use of high-dose corticosteroid drugs can cause Cushing's syndrome, while rapid withdrawal of these drugs can cause hypocortisolism. Explain the mechanisms.
High dose corticosteroids (CS) mimic cortisol, which in excess can cause Cushing's syndrome. Rapid withdrawal can cause hypocortisolism because CS feeds back to the anterior pituitary and hypothalamus to reduce ACTH and CRH synthesis; lack of ACTH causes adrenal atrophy, which severely impairs the body's ability to synthesize cortisol. Soon after the drug is withdrawn, ACTH levels will start to recover (slowly, because the ACTH producing cells in the anterior pituitary, the corticotrophs, also atrophy), then the adrenal gland will usually recover its cortisol synthesizing capacity over a period of weeks.
Hypocortisolism: Hypercortisolism:
Hypocortisolism -Glucocorticoid drug misuse -Addison's disease Hypercortisolism -Glucocorticoid drug misuse -Cushing Syndrome -Cushing Disease
If cortisol is high, _______ If cortisol is low, _______ This is how we understand endocrine disease, not just for cortisol. Concept is the same. MEMORIZE 3/4 QUESTIONS WILL BE ON EXAM
If cortisol is high, ACTH/CRH will be low If cortisol is low,ACTH/CRH will be high Unless something in the path of physiology either defeats this feedback (like a pituitary tumor) or is somehow outside the feedback.
Hormones of the adrenal cortex
Medulla Zona reticularis •Androgens •Sex hormone •Significant in females Zona Fasciculata (largest area) •Cortisol •Glucocorticoid (has effects on glucose metabolism) •Responds to stress Zona glomerulosa •Aldosterone •Mineral corticoid (has no metabolic effects) •K+ and Na+ balance *Only interested in cortex vs medulla blood flow goes from glomerulosa (outside) to the medulla (inside)
The adrenal medulla: origins
Medulla & cortex have different developmental origins Cortex: a true endocrine gland Medulla: modified sympathetic ganglion
How many inputs influence [cortisol]? Explain the levels throughout the day:
Multiple So this graph depicts the levels of cortisol all throughout the day. They peak at 8:00 AM. As we get to the evening, Circadian rhythms inhibit CRH at night- That inhibition is released during the day. -but it's when you're up late cramming for an exam that stress can override the circadian effect
Cortisol functions
Nearly all cells have glucocorticoid receptors -function is widespread: -It's best known for its effects on the immune system where it has an overall suppressive. -It targets the bone and it targets the bone to cause the release of calcium into the extracellular fluid. -It imposes psychological well-being, high levels of cortisol all make you feel better because that's part of the stress. - It has metabolic effects is where the term glucocorticoid comes from. And what that means is it targets the liver, the skeletal muscle, the adipose. -In the liver, it stimulates glycogenesis. In the adipose tissue, it stimulates lipolysis and in the skeletal muscle it stimulates protein catabolism. -Lipolysis gives you fatty acids, proteins produce amino acids for carbon, together that adds to gluconeogenesis -even though gluconeogenesis and glycogenesis are occuring at the same time, that's to cover a short term glucose needs and long term glucose needs both in service to the CNS in times of stress
Types of Cushing syndrome/disease
Primary Cushing syndrome can be caused by, say, an adrenal tumor that overproduces cortisol -Those very high levels of cortisol will cause strong negative feedback and keep CRH/ACTH levels below normal Secondary Cushing syndrome, this would be Cushing disease because this one's going to be due to a pituitary tumor over secreting ACTH, which increases cortisol. So strong cortisol response leads to very strong negative feedback, short negative feedback to CRH. However, the long loop, negative feedback to ACTH doesn't really work very well. -Common effect in endocrine cancers, where the origin is in the pituitary gland
What is stress? -What stress are
Stress = externally induced disruption of homeostasis Exposed to many stresses ¨Neurogenic (injury / infections / see chart from fear and below) ¨Psychogenic (fear, emotional depression) Often >1 at one time Endocrine system → homeostasis (: Requires ¨Integrated system (something that works at many levels) ¨Down regulation of stress response (esp. cortisol, cortisol RELIEVES stress.. not causing it)
Stress is largely externally generated, the function of the endocrine system is to: The endocrine stress response is controlled by: Since stress is a complex input, there is extensive involvement of the ______.
Stress is largely externally generated, the function of the endocrine system is to control stress and restore homeostasis. The endocrine stress response is controlled by: hormones from the adrenal gland. Since stress is a complex input, there is extensive involvement of the HPA.
Why does Cushing's syndrome/disease cause diabetes-like symptoms?
The books all use terms like "diabetes-like symptoms" which I hate because diabetes is defined by blood glucose concentration. To avoid confusion with Type 1 & 2 diabetes, I could see using a term like hyperglycemic (I know, it's my class, I can call it whatever I want). Enough of the rant. The hyperglycemia is due to Cortisol's catabolic activities in the liver (↑ gluconeogenesis), and to a lesser extent in muscle (↑ protein catabolism) and adipose (↑ lipolysis).
Do Catecholamines & cortisol work together?
YES! Fast: -SNS release of ACh from sympathetic ganglia ¨Epinephrine from adrenal medulla ¨Norepinephrine from SNS -Activities: short-term (quick) ¨Purpose is to Mobilize nutrients & O2 to high priority tissues through smooth muscle regulation ¨To enable Fast nutrient (esp. glucose mobilization -Short t½ -Little regulation Slow -Regulated through HPA → adrenal cortex -Regulates Synthesis of cortisol (takes a while through transcription) -Activities → stress adaptation (takes longer to develop) ¨Restore homeostasis ¨Immune suppression ¨Long term glucose mobilization ¨CNS effects -longterm well being as opposed to a short term adrenaline high ¨Stimulates Fast response - epi synthesis is increased as an adaptation to chronic stress -Long t½ -Extensive regulation Two responses that proceed at different rates
Epinephrine binds to what receptors? How many receptors are there? What kind of receptors are they? Explain What determines target responses?
adrenergic receptors 9 total adrenergic receptors ¨3 each of α1, α2, β ¨G-protein coupled They influence activator enzymes, the alpha one stimulates calcium release. α1 → Ca²⁺ release α2 & β ¨Regulate cAMP synthesis ¨Antagonistic (so one stimulates and another inhibits cAMP ) NE & Epi affinity for receptors not that different.. With the exception for β2: Epi>>NE ( has a much higher affinity for epinephrine) Receptor ID gives target responses
Catecholamine is best known to act on what?
blood vessels! -blood vessel effects depend on short-term emergency need High priority Blood vessels exist in places like the ones the skeletal muscle in the heart. epinephrine stimulates b2 vessel dilation to allow more blood to get to these all important tissues, Low priority What you don't really need in emergency are things like the G.I., the bladder and the spleen. Those have the a2 receptor epinephrine causes vasoconstriction in those receptors.
Hypocortisolism: How does it work? What happens as a result? What do we have to be careful with in regards to treatment/ adverse effects?
common consequence of fast corticosteroid withdrawal -cortico-steroid does the same thing as CRH/ACTH since it targets tissues -as a drug they last longer in your bloodstream -So use high doses, just corticosteroids to amplify this cortisol response. However, you're amplifying all causal responses, one of which is this low negative feedback. -one of which is a long loop negative feedback suppression CRH/ACTH which in turn suppresses naturals secretion of cortisol -The adrenal gland will begin to atrophy. Low ACTH leads to atrophy - Fast withdrawal of the drug leads to hypocortisolism -It takes time to recover, So now you're left without glucocorticoids at all. -THEY NEED TO BE WITHDRAWN SLOWLY TO GIVE THE ADRENAL GLAND TIME TO RECOVER AND RESUME NORMAL FUNCTION Leads to all sorts of problems •Stress sensitivity •Pain •Fatigue •Weakness •Fever •Hypoglycemia •Depression •Hypotension •GI disturbances
HPA integrates what kind of inputs? What is the flow from hypothalamus > target what are the short and long loops? where are the major inputs from
complex. -stress is a complex input So we have corticotropin releasing hormone > adrenocorticotropic hormone > cortisol short loop from ACTH to CRH and long look from Cortisol to ACTH and CRH The major inputs of psychogenic and neurogenic stress act on CRH and Circadian rhythms inhibit CRH at night- That inhibition is released during the day.
ACTH release tracks what?
cortisol So you're CRH is releasing a pulsatile fashion, stimulates the release of ACTH (protein hormone) -ACTH binds to a GPCR -amplifier activates CAMP -activates a kinase -kinase phosphorylates a biosynthetic enzyme to increase their activity -kinase also phosphorylates a transcription factor to increase the transcription of the biosynthetic enzymes (This gives two levels of control: short term through modification of existing enzymes and long term by synthesis of new ones)
The adrenal medulla secretes _______ -Give details about it
epinephrine §Amide §Secreted from chromaffin cell •These cells are Modified postganglionic sympathetic neuron •Therefore epinephrine is a NEUROHORMONE Amide means which means it has some aspects of steroids and some aspects of proteins.
Draw out the long & short feedback loops for CRH, ACTH, Cortisol, and epinephrine
epinephrine has no negative feedback.
Epinephrine works with the SNS through __________ Explain the step by step process for both: What are the 2 referred to as?
norepinephrine -It's integrated in the hypothalamus and the impulse is sent down to the spinal cord to a pre ganglia sympathetic nerve, which releases the AcH in the adrenal medulla. Which binds receptors on the chromatin cell. In response, it secretes epinephrine. - Now, these stresses also can stimulate Norepinephrine, which is induced by many of the same stresses -These stimulate a different pre-ganglionic sympathetic nerve, this time AcH activates post ganglionic sympathetic nerve, and that nerve secretes norepinephrine. Epinephrine + Norepinephrine = CATACHOLAMINES
CRH-ACTH-Cortisol is the _________ HPA system
prototypical -This is a mechanism common to other tropic & hypothalamic hormones
Stress response with cortisol is the ______ response. What is responsible for a fast stress response?
slow The adrenal medulla is responsible for a fast stress response
Adrenal anatomy: where are steroids and hormones made?
steroids are made in the cortex from cholesterol epinephrine is made in the medulla
Cortisol analogs as what? What are they called: What do they mimic: What do they do? What does it also control? Misuses is a major source of:
therapeutic drugs! Called ¨Corticosteroids ¨Glucocorticoids Mimic most actions of cortisol Anti-inflammatory ¨Runaway inflammation ¨Controls swelling & pain Also controls ¨Allergies (often given for allergies) ¨Autoimmune diseases At any given time, 0.5% of US population has a prescription → 1.5 million people Misuse major source of pathophysiology
Hypocortisolism from other causes
usually rare Addison's Disease → autoimmune attack → adrenals So this autoimmune attack on the adrenal glands makes it a poor producer of cortisol. The long loop, negative feedback is reduced Loss of feedback > ACTH & CRH levels increase This is an attempt to make more cortisol. unfortunately, nobody's home mean that the adrenal gland is compromised in its ability to make cortisol.
Misuse of cortisol: Don't let misuse fool you...
very important drugs! they can even help with COVID19 -It happens with seriously ill covered patients who are the ones who are in the ICU is frequently what is causing there is a phenomena called a cytokine storm, which essentially is an overreaction of the immune system to the COVID infection -Now, giving dexamethasone carried a certain amount of risk because it's a general immune suppressant. So the idea of giving the dexamethasone was to suppress the cytokine storm. -the risk was that you'd bring covid back,. which wasn't the case, and in seriously ill colored patients, dexamethasone treatment is now of the standard.
Cortisol: the prototypical steroid signaling Explain the steps
•Glucocorticoid (has effects on glucose metabolism) •Responds to stress Cortisol is a prototypical steroid hormone. -Cortisol signal has a binding protein Transcortin (aka Corticosteroid binding globulin CBG), enters the cell, binds to receptor, conformational change -It then binds to glucocorticoid receptor. then to the Glucocorticoid response element to regulate transcription (either activation or repression) -regulates specific levels of proteins
