Endo: 2:00-3:00Scribe: Hunter Neill

Tuesday, November 10, 2009Proof: Taylor Nelson

Dr. GalinHormonal Control of Calcium HomeostasisPage1 of 6

I.Intro [S1]

  1. Going to talk about the following
  2. Salt and Water Retention
  3. Glucose Metabolism (pancreas lectures will help)
  4. Fight or Flight Response
  5. All of this comes from the adrenal gland

II. Adrenal Anatomy [S2]

  1. Quite Small
  2. 3cm in diameter
  3. 4-6 grams
  4. Essential for life – you must have them

III.Adrenal (Suprarenal) Gland Location [S3]

  1. Adrenal gland lie superior to each kidney
  2. Are small but have one of the highest blood flow rates of any tissue or organ in the body
  3. Need the hormones coming from the adrenal gland to survive stressful situations – Physical, emotional, etc
  4. You need an immediate response and therefore has one of the highest blood flow rates of anywhere in the body

IV.Diagram [S4]

  1. Cortex and the medulla derived from the mesoderm and neural crest (ectoderm) respectively
  2. The derivation will help you to remember the stimulus for the secretion of the hormones in the cortex and medulla
  3. Cortex will have hormonal input whereas the medulla will have neural inputs

V.Anatomy and Histology [S5]

  1. Background review of histology: Cortex with 3 zones
  2. Zona Glomerulosa – Uppermost or outermost layer
  3. Aldosterone production - Water Retention
  4. Zona Fasiculata
  5. Largest
  6. Cortisol - Sugar regulation
  7. Zona Reticularis – innermost cortex
  8. Wont talk much about today
  9. Androgens – cant substitute for estrogen and testosterone, but are important if you are deficient in some of those
  10. Females – where you get some of the estrogen and testosterone needed post-menopausally
  11. If in excess can cause women to get hair
  12. One of the famous things – Androgens that increase Libido!
  13. Medulla – Innermost layer
  14. Derived from neural crest cells and therefore a neural input – sympathetic nervous (Acetylcholine – Ach)
  15. Ach is responsible for giving you the catecholamines that come from the medulla

VI.Cholesterol [S6]

  1. Hormones that are produced in the cortex (working from outermost to innermost)
  2. All steroid hormones coming from the cortex are derived from cholesterol
  3. That is why you have to have some in your diet
  4. Cholesterol is then converted Pregnenolone via P450 Scc (side chain cleavage) enzyme – part of the CYP450 family – this is your rate limiting step for all adrenal cortex biosynthesis
  5. Pregnenolone will then enter the 3 pathways
  6. Zona Glomerulosa – to produce aldosterone
  7. Fasiculata to produce cortisol
  8. Reticularis to produce androgens
  9. Don’t have to know all the enzyme
  10. Please know the common ones
  11. P450 Scc enzyme
  12. 21 Alpha hydroxylase or 21 hydroxylase
  13. Accounts for 95% of all CONgenital defects associated with adrenal hormone biosynthesis
  14. Pregnenolone in Glomerulosa will go to progesterone
  15. In the Fasiculata 17-Hydroxyprogesterone
  16. Both of the precursors must then be acted upon by 21 hydroxylase to go further in the hormonal biosynthesis
  17. If you are lacking this enzyme what will happen? Answer towards end of lecture

VII.Adrenal Cortex: Zona Glomerulosa [S7]

  1. Skipped

VIII.The Juxtaglomerular Apparatus [S8]

  1. The site of action of aldosterone is on the cortical collecting duct
  2. Review of the Juxtaglomerular Apparatus
  3. Blood enters via afferent Arteriole
  4. Gets seen by cells in the macula densa
  5. Exits via the efferent arteriole
  6. The cells of the Macula Densa are recognizing sodium and blood volume
  7. If it detects low sodium or blood volume than renin is immediately produced
  8. Then angiotensin (Ang) is made and converted to Ang II
  9. And the number one signal for aldosterone production is Ang II
  10. Potassium is the other player
  11. Therefore a rise in Ang II or a rise in potassium can increase Aldosterone production
  12. Ang II binds to a Gq coupled receptor and a IP3, DAG pathway to get an increase in intracellular Ca2+. Remember that most of the endocrine hormones have to do with an increase in intracellular Ca.
  13. High levels of potassium, if your hypercalemic, can increase the expression of voltage sensitive Ca channels on cells of the Zone Glomerulosa and can then increase intracellular Ca
  14. The rise in intracellular Ca will start the pathway of the of cholesterol to pregnenolone, through P450, and ultimately gets aldosterone production that then leaves the cell

IX.Aldosterone [S9]

  1. The site of action is the cortical collecting duct. What happens when aldosterone get there? Aldosterone, a steroid hormone, enters the cell and binds its receptor leading to 4 actions
  2. Remember - Peptide hormones have membrane bound receptors while steroid hormones have intracellular receptors – remember that
  3. It will increase Na channels on the apical membrane– want to retain sodium
  4. Increase Na/K ATPase on the basolateral membrane to allow the calcium to leave the cell
  5. Stimulate mitochondrial production for ATP for the Na/K ATPase
  6. Even though Agn II is the number one regulator of Aldosterone, Potassium can be as well
  7. If you are hypercalemic you want to excrete potassium so regardless of whether the stimuli is Ang II or potassium ultimately you are going to excrete potassium
  8. As Na channels go into the apical membrane, so to K channels

X.Cortisol to Cortisone [S10]

  1. If you look at the steroid hormone biosynthesis, there is some structural similarities between cortisol and aldosterone because the come from the same precursors
  2. The cortical collecting ducts have a back up system so that when you are in a high stress situation you don’t start messing with a Na/K balance
  3. It has enzyme 11-hydroxydehydrogenase that will convert cortisol to corticosterone (which cannot act on the aldosterone receptor)
  4. This is a backup system. It also shows that even though these are very similar the body has ways of preventing one hormone from acting on other receptors

XI.Review for Aldosterone[S11]

  1. Going to be measuring either Na or Blood Volume to the macula densa
  2. If either is low it will turn on rennin and ultimately get AngII, which will then act on the Zona glomerulosa to make aldosterone
  3. Don’t forget that K cant be a regulator for this too – ultimately K will be excreted and increase Na retention with water following. Therefore Na will increase as well as blood volume.

XII.Adrenal Cortex: Zone Fasiculata [S12]

  1. Where Cortisol production occurs

XIII.Hypothalamic-Pituitary Adrenal Axis [S13]

  1. How Cortisol is produced
  2. The Hyporthalamus produces Corticotropin Releasing Hormone (CRH)
  3. Acts then on the Anterior Pituitary (corticotrophs) to product ACTH
  4. ACTH acts on the adrenal glands
  5. Then you get Cortisol Production
  6. Both of them are through a Gs Coupled receptor so you get adenylate cyclase, increase cAMP, etc
  7. Rise in intracellular Ca
  8. Hormone production

XIV.Negative Feedback for Cortisol [S14]

  1. Also has a very fine tunes negative feedback loop (Short and Long)
  2. CRH will then act on the pituitary to give you ACTH which then acts on the adrenal to give you cortisol
  3. Short loop: ACTH acts back on the Hypothalamus to shut the system down
  4. Long loop: cortisol acts at either the pituitary or or the hypothalamus
  5. You have 3 tiers of neg feedback – important because you are messing with glucose metabolism
  6. You want to have glucose for your brain
  7. Things that can regulate this (pos or neg)
  8. Stress – Physical or Emotional
  9. Circadian Rhythm – sleep wake cycle – pineal gland and melatonin
  10. Hypoglycemia

XV.Effects of ACTH on Zona Fasiculata [S15]

  1. Binds via Gs coupled receptor that increases adenylate cyclase and cAMP, PKA and ultimately start making various proteins etc
  2. P450 Scc (rate limiting step)
  3. Can then start converting cholesterol to pregnenolone
  4. LDL receptors are highly upregulated by ACTH
  5. You want to bring the LDLs in to give you a constant supply of cholesterol to make the cortisol that is needed to deal with the stress whether it is acute or chronic

XVI.Circadian Rhythm of ACTH release [S16]

  1. What you see with ACTH as well as growth hormone (GH) and catacholamines are diabetagenic hormones because they have an opposing action to insulin
  2. Good that we have them because,
  3. If you look at the circadian rhythm for ACTH (peaks 15-17 times/day)
  4. The largest cycle and the highest amount is just before you wake up
  5. ACTH needs to go up just before you wake up because cortisol ultimately increase gluconeogenesis
  6. Providing the body with energy
  7. This is important because you are fasting and not eating (really starts to follow your food cycle)
  8. Goes up to make sure that you are providing glucose for the brain

XVII.Actions of Cortisol [S17] – not just glusose metabolism

  1. 3 Sites of Action: Muscle, Fat, Liver
  2. Liver - Increase gluconeogenesis and increase glycogen storage
  3. Sounds counterintuitive, but reason for both is so that you don’t deplete the system
  4. In order to have gluconeogenesis you have to break down muscle so that you get the amino acids needed and increase glycolysis
  5. If you understand what insulin does than understanding cortisol is pretty much the opposite
  6. Need to understand that glycogen will go up because you don’t want to deplete the system
  7. Under normal circumstances is increases glycolysis so that you get FFA for gluconeogenesis
  8. In excess of Cortisol, you will increase glycogenesis – in some of these patients you can see wasting in the arms and legs but not have a huge belly
  9. Why would you store fat differently centrally than peripherally
  10. It signals the omentum to start really increasing glyogenesis
  11. Only occurs in excess of cortisol
  12. Why you see transplant patients on excess of cortisol that have central obesity (Cushings-like scenario)

XVIII.Arrow Diagram [S18]

  1. Cortisol has many other affects not only on glucose metabolism but elsewhere
  2. Bone: estrogen normally inhibits the paracrine factors that go from the osteoblasts that signal the osteoclasts for reabsorbtion. Corticoids actually increase that. This is the reason a transplant patient may suffer bone fractures because the increased amount of steroids are signally the osteoclasts – Steroid Induced Osteoporosis
  3. Decreases muscle mass – increasing proteolysis so you are breaking down muscle to get the amino acids for gluconeogenesis
  4. Modulates Wakefulness and Emotional Tone (Clarity of Mind)
  5. Why you must be careful of the amount of steroids you give an elderly patient cause it might affect their lucidity
  6. GFR Glomerular Filtration Rate – by affecting ADH (anti-diuretic hormone) affects the babies
  7. Affects Cardiac Tone
  8. Decreased Collagen Synthesis
  9. Once the patients start gaining weight, coupled with increased collagen destruction in the skin, causes striations that you can see (like stretch marks)

(Don’t have to know all of them but they should make sense so that you should know them)

XIX.Cortisol and the Immune System [S19]

  1. One of the reasons for steroids is inhibition of the immune system
  2. Affects Bcell and Tcell formation so that you wont get Ab or cytokine production, or cell mediated immunity
  3. Will also inhibit neutrophil and basophil migration to the site of inflammation
  4. It is a global inhibitor or suppression of immunity
  5. Why it is so good to give to transplant patients, but must be monitored

XX.Adrenal Cotex: Zona Reticularis[S20]

  1. Not going to go into because we will talk about androgens in the reproductive lectures

XXI.Adrenal Medulla [S21]

  1. Site of action of the Chatecholamines
  2. The majority of what comes out of the adrenal medulla is Epinephrine not the NorEpinephrine
  3. You get NE from many places so that’s not an issue

XXII.Chatecholamine [S22]

  1. Precursor is Tyrosine
  2. Central nervous system or Ach as a neurotransmitter turns on Tyrosine hydroxylase which give you Dopa - rate limiting step
  3. Once Dopa is formed it goes to Dopamine
  4. Adrenal medulla is not really a source of Dopamine
  5. When Dopamine is formed in the cytoplasm of the adrenal medulla it is immediately taken into a secretory granule
  6. Once take into the granule it is converted into NE
  7. NE then passively leaves the secretory granule where it is then acted on by Phenylethanolanine N-Methyltransferase (PNMT) and will then give you Epinephrine
  8. That is back in the cytoplasm. Epinephrine must be actively put back into the secretory granules for release
  9. This is the reason the Epi is the primary catecholamine that you will get from the adrenal medulla due to the shifting between compartments. Once NE is made it, typically passively diffuses. What is release is Epi because it is actively put back in.
  10. Two enzymes that you should pay attention to are tyrosine hyrdoxylase and PNMT
  11. PNMT is important because you can increase the amount of PNMT and its activity through glucocorticoids

XXIII.Diagram [S23]

  1. If we look at the structure, blood comes from the cortex to the medulla. In a stressful situation (fight or flight), you will definitely turn on cortisol, and as much Epi as you can put out, so as blood is coming in it will pic up cortisol from the fasiculata and carry it to the medulla and increase the conversion from NE to Epi so that you can have that immediate response.

XXIV.Summary Slide: Medulla [S24]

  1. Neural impulses will cause an increase in the sympathetic activity (Ach being the primary NT) - Acts on the Adrenal Medualla to produce primarily Epi that will then enter the body and alter metabolic activity
  2. Increase Cardiac Output and blood flow
  3. Turns everything on

XXV.Disorderos of Aldosterone Secretion [S25]

  1. Aldosterone deficiency
  2. Aldosteron is important for salt and water retention
  3. Going to be natriuretic – salt wasting (and needing Na)
  4. Can get metabolic acidosis
  5. Dehydraded – if you cant retain Na than you cant retain water
  6. Can lead to orthostatic hypotension
  7. Aldosterone Excess
  8. Too much Na retention and too much water
  9. Going to be the opposite
  10. HypoKalemic – secreting way to much K
  11. Alkalosis
  12. Expansion of ECV because you are retaining so much water
  13. Hypertension due to Na and water retention

XXVI.Thomas Addison [S26]

  1. Disorders of Cortisol – can have 2 (too little or too much)
  2. Addison’s Disease (described in 1855 by Thomas Addison)
  3. “The constitutional and local effects of disease of the suprarenal capsules”
  4. Too little cortisol

XXVII.Cortisol Deficiency [S27]

  1. Can be primary or secondary
  2. Primary affects the adrenal gland itself
  3. 60-70% autoimmune destruction causing Addison’s Disease
  4. Secondary affects ACTH
  5. Symptoms are
  6. Weakness and Fatigue – not providing glucose to the body
  7. Anorexia and Weight loss –
  8. Nausea and Vomiting
  9. Hypotension and Shock
  10. Hypoglycemia
  11. Hyperpigmentation (only if primary) –
  12. Due to adrenal insufficiency – When the levels of ACTH are very high trying to get the fasculata to make cortisol
  13. Because of Pro-opiomelanocortin (POMC), the precursor of ACTH. The more ACTH you have the more Alpha-melanocyte stimulating hormone you have

XXVIII.Addison’s Disease [S28]

  1. One of the first places that you will see hyperpigmentation is the gums because of the structure

XXIX.Hyperpigmentation in Primary Adrenal Insufficiency [S29]

  1. Skipped – just for fun

XXX.POMC Processing [S30]

  1. POMC actually gives you multiple peptides (proteins) – once being ACTH and beta endorphins so that’s why once you are in a stressor you get ACTH to help with glucose metabolism and the endorphins to help you feel better
  2. In the cleavage process from POMC to ACTH, there is one cleavage site that gives you Alpha-melanocyte stimulating hormone that acts on melanocytes causing pigmentation
  3. Since 60-75% of the cases are primary, it will be the first things and dentists are one to notice it first

XXXI.Cortisol Excess [S31]

  1. Know as Chushing’s Syndrome
  2. ACTH dependent is really the disease
  3. ACTH independent is just the syndrome
  4. Both will result in high cortisol
  5. Primary (at the level of the adrenal gland) or Secondary
  6. Secondary hypercortisolism is Cushings disease
  7. Because of the amount of precursors that are flowing into the pathways to make cortisol, some can trickle over and increase androgen production. These cell are right next to one another, and the precursors are the same for all three.
  8. Hypertention due to the increase in aldosterone production
  9. Gonadal disfunction
  10. Hirsutism - Hair where is shouldn’t be due to the increase in androgens
  11. Truncal obesity – cortisol in excess will affect the trunk differently than the periphery
  12. Platelet activate
  13. Osteoporosis due to the effects of glucocorticoids on bone breakdown
  14. If you are giving steroid therapeutically you can induce a Cushing’s like condition
  15. Usually once you do that you will get a decrease in ACTH – turning off that whole system
  16. Your body is not contributing anymore that what you are given
  17. Another way this can happen is an ACTH secreting tumor (secondary). These neoplasias of the cortictrophs can cause hypertension and everything else just the same as if overproducing cortisol on its own in the body.

XXXII.Cholesterol [S32]

  1. Back to the question asked earlier
  2. We have our different pathways
  3. If you have Cushing’s Syndrome (you’re making all of this cortisol) – remember that the precursor pregnenolone is the same for all 3
  4. Plus progesterone can make hydroxyprogesterone and eventually (DHEA)
  5. If you have an excess in one it can affect all the rest cause you making so many of the precursors
  6. For both the Glomerulosa and the Fasiculata they need 21 AlphaHydroxylase
  7. What would happen if you were missing that? What would happen to your androgens? They go sky high!
  8. The #1 congenital defect is 21 Hydroxylase (95% of adrenal congenital disorders of a newborn)
  9. So if this is a newborn female, and you are making your androgens, what would you foresee? Following slide

XXXIII.Cogenital Adrenal Hyperplasia [S33]

  1. The 4 month old girl
  2. The clitoris has received signals from this excess androgens to promote penis formation
  3. Going to get an intersex child that is female has female external and internal genitalia but also has rudimentary male genetalia
  4. Due to the excess androgens
  5. If you don’t take care of this and recognized early – most of the infants die and never see the sexual effects
  6. They are not making aldosterone or cortisol to make
  7. Shows the hyperplasia if it is not treated immediately

XXXIV.Picture [S34]

  1. What if it’s a boy? – 4 yr old boy
  2. Can cause precocious puberty –

[END 44:45]