Studydroid is shutting down on January 1st, 2019

by mtoom

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What are the 3 layers of the adrenal and what hormones do they produce?
  • Zona glomerulosa: Aldosterone (outer layer)
  • Zona fasciculata: Cortisol, androgens (middle layer)
  • Zona reticularis: Cortisol, androgens (inner layer)

Just remember that glomeruolsa secretes aldosterone (makes sense, right? and the other 2 secret both cortisol and androgens!)
  • Pneumonic: GFR 
Give examples of each of the following:
  • Mineralocorticoid (1)
  • Glucocorticoid (1)
  • Adrenal androgens (2)
  • Mineralocorticoid:
  • Glucocorticoid:
  • Adrenal androgens:
What are the functions of cortisol on intermediary metabolism? (8)
  • ↑ gluconeogenesis
  • ↑ glycogen synthesis
  • ↑ blood glucose
  • ↑ protein catabolism
  • ↑ lipolysis
  • ↓ glucose utilization
  • ↓ protein synthesis
What are the functions of cortisol on blood pressure? (7)
  • ↑ GFR, ↓ water resportion
  • At high concentrations, may bind to mineralocorticoid receptor in kidney
  • ↑ angiotensinogen synthesis by liver
  • ↑ vascular reactivity to vasoconstrictors
  • Required for synthesis of epinephrine
  • Inhibits kinins and prostaglandins
  • Promotes movement of sodium out of cells leading to ECFV expansion
What is the function of 11β-HSD2 enzyme?
  • Inactivates cortisol: Converts cortisol to cortisone
Note: HSD1 enzyme converts the other way (activates)
How does cortisol impact the immune system? (4)
  • Causes leukocytosis by decreasing movement of PMNs out of vascular space (impairs diapedesis)
  • Causes lymphocytopenia, monocytopenia, and eosinophilia
  • Suppresses inflammatory response by:
    -inhibiting interleukins and interferons
    -stabilizes lysosomes
    -inhibits phagocytosis
What is the impact of cortisol on growth?
High level of cortisol inhibits growth
What is the impact of cortisol on bone and calcium?
  • Inhibits bone formation and increases resorption
  • Net negative calcium balance 
What is the impact of cortisol on gondal function? (2)
  • Inhibits reponse of pituitary to GnRH
  • Decreased gonadotropins and gonadal steroids
What is the impact of cortisol on the CNS?
  • Initially causes euphoria
  • Prolonged increased exposure leads to:
    -memory loss
    -decreased libido
    -increased appetite
  • Low cortisol can cause apathy, depression and decreased appetite
What is the impact of cortisol on thyroid?
Increased cortisol may inhibit TSH secretion
Review the effects of cortisol action by part of body (11)
  • Brain/CNS:
  • Eye:
  • Endocrine:
    -LH, FSH release
    -TSH release 
  • GI tract:
    -peptic ulcerations 
  • Carbohydrate/lipids:
    -hepatic glycogen deposition
    -peripheral insulin resistance
  • Cardiovascular/renal:
    -salt and water retention
  • Adipose tissue distribution:
    -promotes visceral obesity 
  • Skin/muscle/connective:
    -protein catabolism/collagen breakdown
    -skin thinning
    -muscular atrophy 
  • Bone/calcium metabolism:
    -bone formation
    -bone mass/osteoporosis 
  • Growth/development:
    -linear growth 
  • Immune system:
    -anti-inflammatory action
Name the functions of aldosterone? (4)
  • Regulates ECFV through effects on sodium resorption (at DCT)
  • Regulates potassium metabolism
  • Promotes sodium resportion in exchange for excretion of potassium
  • Weak glucocorticoid (and concentration too low)
What are the adrenal androgens? (3)
  • DHEAS, DHEA, androstenedione (may only have indirect effect through conversion to testosterone)
What proportion of androgens are adrenal in men/women?
  • Men: 5%
  • Women: 50%
  • What is the function of adrenal androgens?
  • What happens if adrenal androgens are low
  • Necessary functions are not well defined (although may enhance immune system)
  • Low concentrations are associated with:
    -Many causes of death
What happens to adrenal androgens throughout life?
  • Increases in adrenarche
  • Peaks at age 30
  • Production falls off as we age
What is the rate limiting step for all steroid hormone synthesizing glands?
Conversion of cholesterol to pregnenolone
  • ACTH stimulates this step in ZF and ZR
What enzyme system hydroxylates steroid molecules?
Cytochrome P450 oxygenases
What is the immediate precursor to testosterone?
  • Does the zona glomerulosa express 17 hydroxylase?
  • What is the consequence?
  • No
  • Cannot synthesize cortisol 
  • What proportion of cortisol is usually free?
  • What is non-free cortisol bound to? (2)
  • 5-10% of cortisol is free (also the active form)
  • CBG (cortisol binding globulin) binds 80% and albumin binds the rest
What factors affect total cortisol levels? (4)
  • Circadian rhythm
  • Eating
  • Stress
  • CBG concentration changes
What factors can alter normal regulation of cortisol? (8)
  • Physical stress secondary to major illness, surgery, trauma, starvation
  • Altered sleep pattern or eating times
  • Psychologic stress (anxiety, depression, mania)
  • Pituitary and adrenal disorders
  • Liver and renal disease
  • Alcoholism
What are the major factors that control release of aldosterone from the zona glomerulosa? (3)
  • Renin-angiotensin system
  • Potassium (increased levels stimulate aldosterone)
  • ACTH (minor short term effects)
What are some minor factors that control release of aldosterone? (2)
  • Postural changes (renin increases in upright position)
  • Natriuretic peptides (ANP, BNP) released by myocardial cells to inhibit renin and aldosterone
  • What is the primary regulator of adrenal androgens? (1)
  • What other factors may affect adrenal androgens? (4) 
  • Primary: ACTH
  • Other:
    -Age (gradual fall after 30)
    -Illness (decrease) 
In several illness, what happens to cortisol and DHEA?
  • Cortisol
  • DHEA
Can DHEA replacement be useful?
Some evidence shows that women with adrenal insufficiency will benefit:
  • Psychological well-being
  • Sexuality
  • IGF-1
  • ↓LDL
Which 4 factors determine the physiological effects of a hormone?
  • Tissue-specific expression of receptor
  • Number of receptors expressed per cell
  • Receptor sensitivity
  • Mutational changes in receptor structure
Where might an endocrine receptor be located (2)?
  • Cell surface
  • Intracellular
Which types of hormones typically bind these receptor types?
  • Nuclear receptor
  • Tyrosine kinase receptor
  • G-protein coupled receptor 
  • Nuclear receptor: Steroid
  • Tyrosine kinase receptor: Peptide
  • G-protein coupled receptor: Peptide
Regarding ligands for nuclear receptors, provide some of their properties.
  • Non-protein molecules (not encoded in genome), but rather from dietary, environmental or metabolic precursors
  • Small
  • Lipophilic
  • Cross plasma membrane passively or via transport proteins
  • Why are nuclear receptors highly conserved?
  • What part of nuclear receptors is highly conserved? **
  • Because structure dictates function
  • ** DNA binding domain is highly conserved **
Give 5 requirements of nuclear receptor structure.
  • Ligand-binding domain
  • Dimerization domain
  • Nuclear localization signal
  • DNA binding domain
  • Activation domain
  • What is the name of the sequence in the promoter of the target gene that is bound by a nuclear receptor dimer?
  • How is its specificity determined? (3)
  • Hormone response element
  • Nuclear specificity:
    -Sequence of hexameric half sites
    -# of bases separating the half sites
    -Adjacent DNA sequences 
What are the structural components of nuclear receptors? (3)
  • N-terminal region
  • DNA binding domain
  • Ligand binding domain
What motif binds to the hormone response elements in the DNA binding domain of nuclear receptors?

Zinc finger motif
Nuclear receptors play a major role in physiology. Despite binding chemically unrelated ligands, how are the receptors related?
Nuclear receptors are structurally related
Fill in the blank:

Nuclear receptors are essentially lignan-regulated __________ factors.
Nuclear receptors are essentially ligand-regulated transcription factors
  • Biological effects are occur through transcriptional regulation (gene regulation)
What are the 3 classes of nuclear receptors?
  • Class 1: Steroid receptor family
  • Class 2: Thyroid/Retinoid receptor family
  • Class 3: Orphan nuclear receptors
Name 5 classic steroid receptors (Class I)
  • Glucocorticoid receptor
  • Mineralocorticoid receptor
  • Androgen receptor
  • Estrogen receptor
  • Progesterone receptor
Describe the steps of steroids binding steroid receptors (About 6 steps)
  • Unbound steroid receptors are in cytoplasm, complexed with heat shock proteins (HSPs)
  • Ligand binding results in dissociation of the HSPs, exposing the nuclear dimerization domain
  • Dimerization of 2 steroid receptors occurs
  • The dimer then translocates to the nucleus and associates with the hormone response element
  • Receptor dimer associates with coactivator or corepressor molecules
  • Gene transcription is altered
For the Thyroid/Retinoid (Class II) receptors, describe the 2 states that dictate the mechanism of action.

The thyroid/retinoid receptor is within the nucleus
  • In the unliganded state, the unbound receptor is associated with a repressor complex that represses gene transcription:
    -gene transcription is repressed by histone deacetylation
  • In the liganded state, the bound receptor is associated with a coactivator complex, that promotes gene transcription:
    -gene transcription is activated by histone acetylation 
Name 4 of the metabolite activated receptors (Thyroid/retinoid receptor family)
  • Thyroid hormone receptor
  • Retinoic acid receptor
  • Vitamin D receptor
  • PPARs receptor
Describe receptors in the thyroid receptor family relative to the steroid receptors
About the thyroid receptors:
  • Unlike steroid receptors, they do not associate with HSPs in the cytoplasm 
  • They form heterodimers (in the absence of a ligand)
  • Unliganded receptors bind to HRE and act as repressor
  • Liganded receptors upregulate gene expression
What are Orphan nuclear receptors (Class III)?
  • Ligand is undefined or may not be required for activation
How do nuclear receptors relate to human disease? (give 4 examples related to the receptor classes discussed)
  • Glucocorticoid receptor: Mutations in GR receptor lead to reduced sensitivity of receptor for cortisol
    -hypertension, hypokalemia, virilization, sexual precocity 
  • Thyroid receptor: Mutations in TRβ gene lead to reduced binding of T3 to TRβ
    -symptoms of both hypothyroidism and hyperthyroidism
  • PPARγ receptor: Mutation in the LBD of PPARγ (heterozygous)
    -lipodystrophy, severe insulin resistance, hypertension, hepatic steatosis, early atherosclerosis, diabetes
    -PPARγ agonists used as oral antidiabetic agents that promote lipid storage and improve insulin resistance
  • Orphan receptor HNF4α: Leads to mature onset diabetes of the young (MODY)
    -Rare monogenic form of diabetes, onset age less than 25, non-obese, abnormal insulin secretion or β-cell mass
For each receptor/drug, list conditions that are targeted with therapies:
  • Glucocorticoid(GR):
  • Estrogens (ER)
  • Thyroid hormone (TR)
  • Fibrates (PPARα)
  • Thiazolidinediones (PPARγ)
  • Vitamin D (VDR)
  • Retinoic Acid (RAR)
  • Glucocorticoid (GR): anti-inflammation
  • Estrogens (ER): hormone therapy in menopause
  • Thyroid hormone (TR): hypothyroidism
  • Fibrates (PPARα): dyslipidemia
  • Thiazolidinediones (PPARγ): type 2 diabetes
  • Vitamin D (VDR): preventative for rickets, diabetes, cancer
  • Retinoic Acid (RAR): acne, acute promyelotic leukemia
  • Regarding glucocorticoid receptor (GR), where is it expressed and what does it activate?
  • What can be said about ligand specificity for GR
  • Expressed in almost all tissues, and activation of GR affects many tissues
  • Ligand promiscuity between receptor family members (cross talk with ligand for multiple receptors)
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