Growth Hormone Flashcards

1
Q

Where is growth hormone releasing hormone (GHRH) released from?

A
  • Hypothalamus (PVN)
  • GHRH or somatocrinin
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2
Q

Where is growth hormone released from?

A
  • Anterior pituitary
  • Somatotrophs
  • Two forms: one derived from all five exons, one missing part of exon III
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3
Q

What is the target tissue for growth hormone?

A
  • Liver (IGF-1)
  • Muscle and bones
  • Adipose tissue
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4
Q

How is GH secretion regulated?

A
  • Hypothalamic hormones: GHRH stimulates and somatostatin inhibits
  • GHRH binds to its receptor GHRHR (GPCR) on somatotrophs -> increased cAMP -> increased synthesis
  • cAMP also stimulates opening of calcium and potassium channels -> secretion
  • GHRHR also expressed in pancreas and GI tract
  • GH secretion follows a pulsatile pattern (peaks at night) and aligns with circadian rhythms
  • Increased by sleep, stress, hormone related to puberty, starvation, exercise, hypoglycemia
  • Increases from birth to childhood
  • Peaks during puberty
  • Decreased by somatostatin, obesity, hyperglycemia, pregnancy
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5
Q

How is GH synthesized?

A
  • Peptide hormone
  • GH gene (GH1) on chromosome 17
  • Transcription and translation of GH1 -> prepro-hormone
  • Prepro-GH has an N-terminal signal peptide that directs it to rough ER
  • Signal peptide is cleaved off as the protein enters the ER -> pro-growth hormone
  • In ER and golgi, post-translational modifications -> remove any remaining inactive segments
  • Mature hormone stored in vesicles
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6
Q

How is GH transported in blood?

A

By GH-binding proteins (GHBPs)

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7
Q

How does Ghrelin impact GH secretion?

A
  • Ghrelin released during fasting
  • Enhances GH secretion (acts as a secretagogue)
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8
Q

How does IGF-1 impact GH secretion?

A
  • IGF-1 produced in response to GH
  • Feeds back to hypothalamus and pituitary to modulate GH levels
  • Elevated IGF-1 levels -> increase somatostatin release -> further inhibit GH
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9
Q

Explain the action of GH.

A
  • Crucial for body growth, cell repair, and metabolic regulation
  • Causes growth of almost all tissues of the body (that are capable of growing)
  • Increases cell size, mitosis, and cell numbers (and cell differentiation)
  • Impacts body composition, increasing lean muscle mass and bone mass (increases rate of protein synthesis)
  • Necessary for maintaining glucose and lipid homeostasis
  • Increases mobilization of fatty acids from adipose tissue, circulating free fatty acids in blood, and usage of fatty acids for energy
  • Decreases rate of glucose utilization throughout body
  • Enhances body protein, uses up fat stores, and conserves carbs
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10
Q

Explain the differences and similarities between GH and insulin.

A
  • Insulin and GH similar stages of protein synthesis (minus C-peptide)
  • Insulin: gets glucose into tissue and increases fat
  • GH: gets glucose out and decreases fat
  • Both can utilize P13K-Akt pathway
  • Tyrosine kinase receptors
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11
Q

GH receptors

A
  • GHR present mainly in liver (IGF-1), muscle, and adipose tissue (also present in bone, brain)
  • Tyrosine kinase
  • Activation of JAK2 (remember leptin) initiates downstream signaling pathways
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12
Q

Explain the JAK-STAT pathway.

A

JAK2 phosphorylation (due to binding) -> STAT activation -> promoting transcription of target genes

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13
Q

Explain the MAPK pathway.

A

Activates RAS/REF/MEK/ERK cascade -> important for cell growth and division

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14
Q

Explain the P13K-Akt pathway.

A
  • Involved in protein synthesis, anti-apoptotic responses, and metabolism regulation
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15
Q

Somatomedins

A
  • GH causes liver to synthesize and release small proteins called somatomedins (insulin-like growth factors)
  • Somatomedin C (IGF-1) produced in liver
  • GH can also stimulate local IGF-1 production in tissues, where it acts in a paracrine or autocrine manner to mediate local growth effect
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16
Q

What are the indirect effects of GH?

A
  • Mediated through IGF-1
  • Bone growth, muscle growth, tissue repair and regeneration
17
Q

What are the direct effects of GH?

A
  • On tissues
  • Increasing lipolysis (fat breakdown) and glucose production
18
Q

Explain the differences between IGF-1 and insulin.

A
  • IGF-1 and insulin structurally similar
  • IGF-1 is a single-chain protein (insulin is two chains)
  • IGF-1 and insulin have distinct receptors and functions
  • IGF-1 primarily promotes growth and cell proliferation
  • IGF-1 circulates in blood bound to IGF-binding proteins (IGFBPs) (comparison to T3 and T4)
  • IGF-1 binds to IGF-1 receptor (IGF-1R)
19
Q

How does GH impact carbohydrate metabolism?

A
  • Diabetogenic
  • Decreased glucose uptake in tissues (skeletal muscle at fat)
  • Increased glucose production by liver
  • Increased insulin secretion
  • GH-induced insulin resistance -> decreases insulin’s actions to stimulate the uptake and utilization of glucose in skeletal muscle and fat and to inhibit gluconeogenesis by liver
  • Leads to increased blood concentration and a compensatory increase in insulin secretion
20
Q

How does GH impact protein metabolism?

A
  • Anabolic
  • Directly enhances transport of most amino acids into cell
  • Increased amino acid concentrations -> increased protein synthesis
  • Stimulates DNA transcription and mRNA translation
  • Decrease in the breakdown of cell protein
  • Mobilizes large quantities of free fatty acids from adipose tissue that are used to supply most of the energy for the body’s cells (protein sparer)
21
Q

How does GH impact fat metabolism?

A
  • Ketogenic
  • Causes release of fatty acids from adipose tissue -> increasing circulating concentration of fatty acids in body fluids
  • Enhances conversion of fatty acids to acetyl coenzyme A (acetyl-CoA) and subsequent for energy
22
Q

What are the target tissues and actions of GH?

A
  1. Liver: stimulates IGF-1 production, promoting glucose metabolism and gluconeogenesis
  2. Muscles: increases amino acid uptake and protein synthesis, enhancing muscle growth
  3. Adipose tissue: stimulates lipolysis, reducing fat stores and increasing free fatty acids in circulation
  4. Bones: enhances chondrocyte proliferation and bone growth via IGF-1
23
Q

How does GH play a role with bones?

A
  • In embryonic stage, GH is responsible for differentiation and development of bone cells
  • Later stages, GH increases growth of the skeleton, it increases both the length as well as the thickness of bones
  • Primarily promotes longitudinal bone growth (length) during childhood and adolescence by stimulating: chondrocyte proliferation and activity in the epiphyseal growth plates of bones and osteoblast activity to enhance bone formation
  • Increases length until epiphysis fuses with shaft (puberty)
  • Also has role in bone remodeling throughout life, which involves a balance between bone resorption (breakdown) and formation
24
Q

Explain the organization and zones of the epiphyseal plate.

A
  1. Resting zone: contains inactive chondrocytes
  2. Proliferation zone: chondrocytes divide and align in columns, producing new cartilage
  3. Hypertrophic zone: chondrocytes enlarge and begin secreting factors to calcify the matrix
  4. Calcification zone: cartilage matrix becomes calcified, and chondrocytes die
  5. Ossification zone: osteoblasts invade the calcified cartilage and deposit bone matrix
25
Q

Somatotroph Adenomas

A
  • Noncancerous tumor
  • Pituitary tumor that produces too much growth hormone
  • Excess GH leads to abnormal growth of tissues (gigantism, acromegaly)
26
Q

Gigantism

A
  • Hypersecretion of GH in children before closure of epiphysis of long bone
  • Tall, large hands and feet, coarse facial features, delayed puberty, hyperglycemia
  • IGF-1 levels used for diagnostic
  • Treatments: surgical removal of tumor, radiation, SST analogs (inhibit GH), GHR agonist
27
Q

Acromegaly

A
  • Excess of GH in adults after fusion of epiphysis
  • No vertical growth but bones can become thicker and soft tissue can continue to grow
  • Lower jaw protrudes forward (prognathism), nose increases in size, large feet, thick fingers and hands, enlarged tongue, liver, and kidneys
  • Can lead to insulin resistance and T2D, colon polyps and colon cancer
28
Q

Dwarfism

A
  • Hyposecretion of GH leads to short stature, increased body fat, and reduced muscle mass
  • Deficiency in early childhood
  • Pituitary dwarfism, laron dwarfism, pygmy peoples
29
Q

Pituitary dwarfism

A
  • No GH secretion
  • Congenital or acquired
  • Due to: genetic defect, brain injury, absence of pituitary
  • Growth retardation in all parts proportionally
  • Normal mental activity
  • Plumpness and immature faces
  • Potential lack of sexual development
  • Treatment: hormone therapy
30
Q

Laron Drawfism

A
  • Growth hormone insensitivity syndrome
  • Congenital abnormalities of GH receptors
  • GH produced normally
31
Q

African pygmies

A
  • Population in Congo Basin
  • Average adult male height less than 150cm
  • decrease growth hormone receptors in tissue
  • Normal GH levels
  • Reduced plasma IGF-1