Chapter 5 Cortisol

Hypothalamic-Pituitary Axis

• • Hypothalamus
  • Integrates signals in the CNS and releases appropriate trophic
  neurohormones

• • Pituitary

  • • Anterior Pituitary (Adenohypophysis)
    • Synthesize and store (mostly trophic) hormones
    • Release hormones in response to hypothalamic trophic hormones

    • • Different types of endocrine cells for specific pituitary hormones

      • • Corticotroph, Thyrotroph, Somatotroph, Lactotroph, Gonadotroph

    • • Endocrine Tissue

  • • Posterior Pituitary (Neurohypophysis)
    • Stores and releases neurohormones synthesized in the
    hypothalamus(not trophic)
    • Nervous tissue

Hypothalamic-Pituitary Axis

• Trophic Hormone
  • A hormone that stimulates the release of other hormones.

• • Portal System
  • Network of blood vessels that carries blood from one capillary bed to another.
  • Hepatic Portal System
  • Hypothalamic-Hypophyseal Portal System

HPA(hypothalamic pituitary) Axis

• hypothalamus doesn’t receive much of a negative feedback from cortisol, but Anterior pituitary is greatly affected)

• CRH amount is affected by circadian rythym

• long-term stress leads to cortisol accumulation

HP Axis Pathologies

• • Location: Primary(adrenal cortex), Secondary(anterior pituitary), Tertiary(hypothalamus)

  • Descends from originating signal area for tertiary to primary for where the cortisol is released

• • Issue: Hypersecretion, Hyposecretion

Cortisol Releasing Hormone

• Synthesized in the PVN(paraventricular nucleus) of the Hypothalamus

• • Peptide Hormone

  • • Translated to PreproCRH on ribosomes in the RER.
    • 196 amino acids total
    • Contains a signal peptide

  • • Converted to ProCRH by Signal Peptidase in the RER
    • Cleaves the signal peptide
    • 169 amino acids total

  • • Converted to CRH by multiple enzymes
    • Enzymes located in the Golgi apparatus and secretory granules
    • End product is 41 amino acids total

  • 196 > 169 > 41 AA’s

CRH Secretion

• • Stimulators of CRH Synthesis and Secretion

  • • Stress
    • Physical, Emotional, Metabolic (hypoglycemia)
    • SNS neurons from the locus coeruleus (LC) release NE onto the PVN
    • LC receives input from the amygdala, hippocampus, and other parts of the brain stem

  • • Circadian Rhythm
    • Suprachiasmatic Nucleus (SCN) releases glutamate onto the PVN (Morning, Light)

  • • Inflammatory Cytokines
    • IL-1, IL-6, and TNFα

• • Inhibitors of CRH synthesis and Secretion

  • • Cortisol
    • Glucocorticoid receptors on PVN neurons are activated by cortisol

  • • Circadian Rhythm
    • SCN releases GABA onto the PVN (Evening, Darkness)

  • • Endocannabinoid System
    • CB1 Receptor activation reduces release of glutamate and NE onto the PVN

Adrenocorticotropic Hormone

• • Peptide hormone
  • 39 amino acids in total
  • Binds to melanocortin 2 receptors (MC2R) on adrenal cortical cells.
  • Gs GPCR

• • Interacts with Zona Fasciculata cells to induce cortisol production

• • Also interacts with Zona Reticularis cells to induce production of DHEA
  and androstenedione
  • Less responsive compared to Fasciculata stimulation

• • Corticotrophs have Gs and Gq GPCR receptors for CRH
  • Gs activation stimulates ACTH synthesis
  • Gq activation stimulates ACTH secretiosecretion

Adrenal Cortex

• Zona Glomerulosa(top layer)
  • Produces and secretes mineralocorticoids (aldosterone)
  • Maintains blood volume and pressure
  • Reduces urine production and sodium excretion

• • Zona Fasciculata(middle and thickest layer)
  • Produces and secretes glucocorticoids (cortisol)

• • Zona Reticularis(bottom layer)
  • Produces and secretes sex-steroid hormone precursors(DHEA and androstenedione)
  • Converted to testosterone in peripheral tissues (liver, muscle, gonads if present/active)

Glucocorticoids

• • Class of corticosteroid
  • Named due to its role in glucose metabolism

• • Corticosterone
  • In humans/apes: Precursor to Aldosterone
  • In many other animals: Primary stress glucocorticoid

• • Cortisol
  • Primary stress glucocorticoid in humans

Cholesterol and Synthesis

• • Synthesized or obtained from diet(balance maintained between diet and cholesterol synthesis)

• • All cells can synthesize cholesterol, but it primarily happens in certain cells, including
  • Liver
  • Skin
  • Adrenal Cortex

• Synthesis:

  • HMGCR step is rate-limiting step for 1st cholesterol process

  • thiolase and HMGCS step happen in cytosol, HMGCR happens in peroxisome

  • rest of the cholesterol processes happen in the ER

Cholesterol Esters Process

• Cholesterol is stored in lipid droplets as cholesterol esters
  • Synthesized cholesterol is converted by a family of enzymes – ACAT1 (Acetyl CoA Acetyltransferase1, esterifies cholesterol) at the lipid droplet membrane
  • Brought in as esters from LDL or HDLs. (LDLR and SR- B1)

  • • Brought into the lipid droplet by NPC (Niemann Pick Type C Protein)

• • Cholesterol ester is de-esterified by cholesterol esterase, and cholesterol leaves via NPC

• • Cholesterol enters the mitochondrion via StAR (steroid acute regulatory protein), aided by a VDAC.

Cortisol Synthesis

• • Cholesterol is converted to pregnenolone in the mitochondrion

• • Pregnenolone is transported to the
  cytosol via StAR/VDAC

• • Pregnenolone is converted to deoxycortisol in the SER

• • Deoxycortisol is transported into the mitochondrion (both membranes) via StAR/VDAC and converted to cortisol

Cortisol Synthesis

• • ACTH binds to MC2R (a Gs GPCR)
  • Induces activation of StAR and Cholesterol Esterase

• • Via CREB activation, increases synthesis of key proteins
  • CYP11A, CYP17, CYP21, CYP11B1
  • StAR, LDLR, SR-B1
  • Requires more chronic activation

• [cortisol] does not rise until ~20-30 minutes following the acute stressor stimulu

Cortisol Transport

• ~90% of released cortisol binds to CBG (Cortisol Binding Globulin) in the blood for transport.

• • ~5% of released cortisol binds to albumin.
  • Lower affinity, but higher capacity
  • Contributes more when CBG becomes saturated due to very high cortisol levels.

• • ~5% of released cortisol remains unbound
  • At targets, cortisol releases from binding proteins and diffuses into target cells.

Cortisone

• • Kidneys can convert cortisol to its inactive form – cortisone

• • Cortisone can be stores in many cells (especially adipose and liver).

• • Can be converted back to cortisol

• • Cortisone storage occurs when cortisol concentration is high.

• • Long term high cortisol is associated with obesity, hypertriglyceridemia, and hypercholesterolemia.

Glucocorticoid Receptor

• • Cytosolic Receptor

• • Ligand-activated transcription factor

• • Expressed in almost all cells

• • Inactive State

• • In a complex with HSP90 (dimer 1), HSP70(dimer 2), and FKBP52 (a regulator protein)
  • Altogether called the ‘chaperone complex’
  • Chaperone complex covers Zinc Fingers

Glucocorticoid Receptor Activation

• Binding of cortisol causes dissociation of the chaperone complex
  • This exposes the Zinc Fingers
  • This induces folding of the receptor

Receptor Translocation

• • Zinc binds to the exposed zinc fingers

  • • Stabilizes the zinc fingers

    • • Critical for the zinc finger to bind to DNA response elements.

  • • Triggers dimerization of the receptor

• • Receptor enters the nucleus via nucleoporin

• • Receptor dimer binds to specific parts of DNA to influence gene transcription
  • Glucocorticoid Response Elements(GREs)

• Note: Dimerization and nuclear translocation are independent and can occur in either order
  Note: Dimerization may not occur if the GR binds to other transcription factors

Glucocorticoid Response(GR) Elements

• • Rather than DNA, GRs may bind to other transcription factors to stimulate/inhibit them.
  • GR may reduce transcription
  • GR may increase transcription (less common)

Activation of Other Receptors

• • Cortisol can bind/activate mineralocorticoid receptors
  • Traditional ligand is aldosterone
  • Cytosolic steroid receptor

• • Cortisol can bind to some GPCRs
  • Reduced cytokine release and immune cell activation
  • Increased neuronal excitability in the hippocampus (learning and memory)
  • Vasoconstriction

Cortisol Effects (Non-Metabolic)

• • Bone
  • Inhibits osteoblasts, stimulates osteoclasts
  • Results in decreased bone matrix formation and
  decreased bone density

• • Skin
  • Reduced collagen synthesis

• • CNS
  • Acute: enhances memory function
  • Chronic: impairs memory function and hippocampal
  function

• • Reproductive System

  • • Inhibition of GnRH secretion in the hypothalamus
    • Reduces testosterone/estradiol production and ovarian
    function

  • • Testes
    • Reduces Leydig Cell function (further reducing
    testosterone)
    • impairs spermatogenesis

  • • Ovary
    • Inhibits aromatase production
    • Impair follicular development

Cortisol Effects(Non-Metabolic) on some systems of the bodies

• Cardiovascular System
  • Upregulation of adrenergic receptors in blood vessels
  • Increased sensitivity to catecholamines
  • Binds to mineralocorticoid receptors, causing increased blood pressure and sodium retention

• • Immune System
  • Immunosuppressant
  • Impairs immune cell function/proliferation/action/chemotaxis and reduces cytokine production

• • Chromaffin Cells
  • Increased synthesis of VMAT and PNMT

Cortisol Effects(Metabolic)

• • General Effect: Increase availability of fuel sources (glucose, fatty acids, ketone bodies)

• • Liver
  • Increased lipolysis

  • • Increased [HSL]

  • Increased beta-oxidation
  • Increased ketogenesis
  • Increased gluconeogenesis

Cortisol effect on Skeletal Muscle

• • Reduced Insulin-Stimulated GLUT4 translocation • Reduces glucose utilization by SM, increasing glucose availability for other tissues

• • Decreased glycolysis • Increased [PDK4] (an enzyme that inhibits pyruvate dehydrogenase by phosphorylation)

• • Increased lipolysis and beta oxidation • Increased [HSL]

• • Increased protein catabolism • Provides more Amino Acids for liver gluconeogenesis • Decreased protein synthesis

• glucose stored selfishly by skeletal muscle for more buildup, cortisol forces skeletal muscle to undergo lipolysis for energy instead of glycolysis

• ISGU = insulin-stimulated glucose uptake

• PDH phosphatase activates PDH

Cortisol Effects on Adipose Tissue

• • Reduced Insulin-Stimulated GLUT4 translocation

  • glut4 is responsible for glucose intake by cells

• • Increased lipolysis • Increases beta oxidation for AT energy • Increases plasma fatty acid concentration

Cortisol effects on Pancreas

• • Decreased insulin synthesis from pancreatic β cells • Increased glucagon synthesis from pancreatic α cells

Stress Response Dilemma

• •Stress response is designed to respond to acute stress.

  • • Increased cardiac output, blood pressure, oxygen/nutrient delivery

  • • Increased blood glucose and fatty acids

  • •Suppression of non-essential functions (immune system, reproductive system, digestive system, etc

• •Stress is nonspecific

  • •Not well adapted for some forms of modern stress

  • •Eustress: stressor within control that can be resolved with the aid of the stress response
    •Distress: a stressor not within control that cannot be resolved with the aid of the stress response

• Stress response is out of control for humanity because we worry about future prospects such as rent

Chronic Stress

• Maladaptive stress response results in chronically high cortisol

  • • Hyperglycemia

  • • Fat redistribution: Increased deposition of visceral fat, leading to central obesity

  • Reduced muscle strength and muscle connective tissue

  • • Hypertension

  • • Immunosuppression and illness
    • Hippocampal atrophy":paired memory and learning

  • • Prefrontal cortex degradation(higher order thought degradation)

  • • Amygdala hyperactivity

  • • Reduced fertility, reduced libido, irregular or absent menstrual cycle • Osteoporosis

  • • Gastric Ulcurs • Reduced blood flow to stomach mucus-producing cells(zebras don’t have ulcers)

Chronic Stress in Early Life

• • Chronic stress during a developmental window in early life disrupts the ‘programming’ of the HPA axis

• • Reduced glucocorticoid receptor expression in the hypothalamus •

  • Epigenetic modification: Methylation of the NR3C1 gene (gene for glucocorticoid receptor)

  • methylation of the NR3C1 gene stops its activation to create glucocorticoid receptor

• • Reduces hypothalamus sensitivity to negative feedback • Exaggerated cortisol response • Prolonged cortisol response

• Cortisol is meant to be a negative feedback inhibitor for the hypothalamus