Week 3 Flashcards
Adrenal Cortex
- 75%
- Cortical Cells
- Adrenocortical H. synth.
Adrenal Medulla
- 25%
- Chromaffin Cells
- NE & E synth.
Cortical Cell types
- Z.Glomerulosa: Mineralocorticoids (15%)
- Z.Fasciculata: Glucocorticoids (75%)
- Z.Reticularis: Androgens (10%)
Mineralocorticoids
Affect the electrolyte composition of the body
- Aldosterone (glomerulosa cells)
- Deoxycorticosterone
- Cortisol (weak)
Glucocorticoids
Affect the metabolism of the organism
- Cortisol
- Corticosterone
- Synthetic mineralocorticoids
Androgens
Have no biological activity, just precursors for some androgens and estrogens
- DHEA
Common steps of all steroid hormone biosynthesis
1) CE moved into mitochondria from cytoplasm via STAR transporter (stereogenic acute regulator protein)
2) CYP 11 A1 removed side chains off cholesterol
= Pregnenolone
THESE ARE RATE LIMITING
How is Cortisol transported in blood?
- 90% bound to CBP (corticosterone bp)
- 7% bound to Albumin
- 2-4% free
Half life of Cortisol
60 - 90 mins
How is Aldosterone transported in blood?
- 60% bound to Albumin
- 40% free
Half life of Aldosterone
20 mins
Total Cortisol vs Aldosterone
Total Cortisol is 1000x higher
Free Cortisol vs Aldosterone
Free Cortisol is 100x higher
Rule to do with half-life and concentration of hormone
The smaller the free fraction of a hormone, the longer its half-life will be
Methylprednisolone
Glucocorticoid activity
Synthetic
10x more potent vs cortisol
Dexamethasone
Glucocorticoid activity
Synthetic
20x more potent vs cortisol
Hormone Receptors
- Steroids freely cross PM so we have intracellular-R
- Hormones bind MC or GC receptors
- Receptors bind Steroid Response Element (SRE) on DNA
Aldosterone Receptor
Mineralocorticoid Receptor (MCR)
(MCR can also bind Cortisol)
Aldosterone Target Cells
- Principal cells of Kidney (nephrons)
- Exocrine glands (duct cells sweat/salv)
- Colon (epithelial cells)
MCR affinity
- Binds both Aldosterone & Cortisol
- Coreceptor 11-B-HSD2 converts Cortisol to Cortisone
- Cortisone can not bind
Apparent Mineralocorticoid Excess syndrome (AME)
If 11-B-HSD2 is blocked then we have symptoms similar to hyperaldosteronism
Because more cortisol binds to same receptor
Effects of Aldosterone
- Increased Na+ Reabsorption
- Decreased Na+ Elimination
- ENaC expression
- Higher blood Na+ causes increased ADH so more H2O reabsorption
- K+ and H+ excretion
Aldosterone Escape
After prolonged Aldosterone exposure
- ANP released
- GFR increased
- RAAS blocked
Regulation of Aldosterone Secretion
- MC2-R = cAMP
- Increased e.c K+ = Ca2+
- Angiotensin II on AT1-R = Ca2+
- ANP inhibits
How is secretion of Cortisol
Follows ACTH’s pulsatile secretion (bursts)
- Largest burst 2 hours before waking up
Permissive effects of Cortisol
Doesn’t directly initiate a response but necessary to allow the response to occur
e.g: B1-AR (heart) & a1-AR (vessels)
Cortisol Receptor & Action
Glucocorticoid Receptor (GC-R)
- After Cortisol binds, GC-R dissociates from HSP and goes to Nucleus
Cortisol Target Cells
All cells, wide variety of effects
Effects of Cortisol
All effects are based on regulation of Gene expression due to intracellular receptors
(GC-R dissociates from HSP, then goes to Nucleus to reg. exp.)
Cortisol effects on Gluconeogenesis
- Increases expression of all enzymes in Gluconeogenesis
- Inhibits Insulin since it has an inh. effect on gluconeogenesis.
- Effect of insulin activating Glycogen synthesis is not stopped
Cortisol effects on Glucose usage of Peripheral tissues
- GLUT4 expression decreased (gluc. uptake to skeletal m. & adipocytes)
- Insulin-R signaling is attenuated to prevent cell uptake
Cortisol effects on Protein Metabolism
- Increased degradation of Proteins (mm, adipocytes, lymphoid tissue)
- Increased aa in plasma from degradation
- Increased protein synthesis in LIVER for enzymes
Cortisol effects on Lipid Metabolism
- Increased Lipolysis in adipocytes (for gluconeogenesis)
- Increased Appetite
- More lipid storage translocated to central body (central obesity)
Cortisol effects on Immunity & Inflamation
- Less membrane permeability for granulocytes
- Less fever
- Less cytokines & prostaglandins
- Less antigen presentation
- Less COX & PLA2 expression
- Less autoimmune & anaphylaxis
Cortisol effects on Ca2+ & Bones
- Less Ca2+ Absorption/Reabsorption
- Increased RANK expression in osteoblasts, activating osteoclasts = osteoporosis
- Bone resorption causes Hypercalcemia & increased PTH
Cortisol effects on Connective tissue
- Less Collagen synth
- Less Fibroblast proliferation
- Affects wound healing & causes skin striation
Cortisol effects on Fetal Development
- GC are required for normal organ development (GI, CNS, retina, lungs)
- In Lungs, for Surfactant prod.
Cortisol effects on Baby Delivery
- GC initiate the birth of the Baby
- Especially GC produced in the newborn (+ moms)
Cortisol effects on Adrenal Medulla
- Activation of methyltransferase enzyme
- NE to E
- E to B2-AR for bronchodilation, vasodilation,…
Cortisol effects on Adenohypophysis
- GH production increased
- IGF-1 inhibited to stop GH indirect effects (tissue repair)
Cortisol effects on Stomach
- Increased Gastric acid secretion
- GC inhibit prostaglandins which are inhibitors of GA prod.
Cortisol effects on CNS
- Acute: Increased memory, learning, motivation, arousal
- Chronic: Decreased attention, behavioral flex., & depression
Cortisol effects on Kidney
- Cortisol required for GFR maintenance
- Also causes impermeability of collecting duct so no water reabsorption
Cortisol Negative Feedback
- Inhibits CRH release from Hypothalamus
- Inhibits ACTH release from Pituitary
Regulation of Cortisol production
- Vasopressin (V1/2 Gq)
- CRH (CRH-R Gs)
+++ ACTH (MC2-R Gs)
cAMP increase in Fasciculata/Reticularis cells
Cushing’s Syndrome/Disease & Causes
Caused by long-term exposure to high Cortisol.
- Tumor in Hypophysis = high ACTH = high Cortisol (disease)
- Tumor in A.Cortex = high Cortisol = low ACTH (syndrome)
- Synthetic cortisol med = low ACTH (syndrome)
Conn’s Syndrome
Uncontrolled overproduction of Aldosterone (by tumor)
Addison’s Disease
Adrenal Insufficiency
- Destruction of the gland by inflammation, tuberculosis, autoimm.
- Low GC & MC production
- Lack of negative feedback can cause high ACTH, more a-MSH = pigmentation
Weight & Follicle size of Thyroid Gland
- 15 - 20g
- 200 - 300 μm
Thyroid Hormones & Structure
- Thyroxine (T4)
- Tri-iodothyronine (T3) needs 2 iodines on inner ring to be active
Main Synthesis Steps of Thyroid Hormones
1) Iodination: Tyrosine aa peptide bound (thyroglobulin) MIT/DIT
2) Coupling: 2 of MIT/DIT combine to form T3/T4
Pendrin
I/Cl antiporter that pumps Iodide into Colloid
What forms Iodine (I2) from Iodide (I-)
Thyroperoxidase with NADH oxidase
How do the free thyroid hormones leave the cell
Monocarboxylate transporter 8
(MCT-8)
Minimum Iodine requirement
50 - 100 μg / Day
Average Iodine intake
400 μg
Iodine content of Thyroid
7000 - 8000 μg
Inhibitors of NIS
- Thiocyanide (SCN-): glycoside rich foods like cabbage, broccoli, caulif.
- Perchlorate (ClO4-): Environmental polutant
Inhibitors of Thyroperoxidase
- Thiouracil
- Propylthiouracil
- Methimazole
What happens in Iodide excess
Wolff-Chaikoff effect
- If more than 2 mg of iodide consumed per day
- Inh. of iodination (preventative)
T4 Transport
- P.bound: 99.98%
- Free: 0.02%
T3 Transport
- P.bound: 99.8%
- Free: 0.2%
Transport Proteins for T4
- Thyroxine binding globulin (TBG): 80%
- Thyroixine binding pre-albumin (TBPA): 15%
- Albumin: 5%
Mechanism of T3/T4 action
1) T3/T4 diffuse and go to i.c receptor
2) Thyroid h.-R is dimer with Retinoid x-R
3) Together they bind a DNA sequence, Thyroid Response Element (TRE)
Type 1 5’Deiodinase
- Removes iodine from outer ring (5’)
- Forms T3 from T4, to blood
- Liver, Kidney, Skeletal Muscle
Type 2 5’Deiodinase
- Removes iodine from outer ring (5’)- - Forms T3 from T4, Stays in cell
- Pituitary, Hypothalamus, CNS, Brown adipose
Type 3 5’Deiodinase
- Removes iodine from inner ring (5’)
- Forms rT3 from T4
- Inactivation of Hormone
Thyroid Hormone Calorigenic Effect
- Basal metabolic rate inc.
- Heat production
- More O2 uptake
- ABSENT in Brain, Testes, Spleen
Thyroid Hormone Carb metab
- More glucose absorption
- More glycogenolysis
- More gluconeogenesis
Thyroid Hormone Lipid metab
- More Lipolysis
- Lower plasma cholesterol
Thyroid Hormone Protein metab
- More protein Synthesis
- Proteolysis (very high T3/T4)
Thyroid Hormone Cardiovascular effects
- Higher O2 demand increases CO & HR (+SV)
- Permissive effects through B1-AR
- Higher BMR causes vasodilation due to metabolites (functional hyperaemia)
- Lower TPR, widened Pulse p.
Thyroid Hormone Growth & Dev
- CNS development
- Bone Growth
Thyroid Hormone CNS effect
- Elevated thyroid h. causes restlessness, decreased reaction time, low focus
- Low causes decreased cognitive function, longer reaction time
What is used to directly screen thyroid?
Pertechnetate (TCO4-) gamma radiating isotope
- Taken in by NIS
- Used in Thyroid scintigraphy
Myxedema
- T3/T4 usually degrade glycoproteins and proteoglycans
- In hypothyroidism, low h. levels cause edema since these molecules aren’t cleared and bind water
Graves disease
Immune system produces antibodies that have TSH action
- Hyperthyroidism
