Growth Hormone Flashcards
1
Q
Where is growth hormone releasing hormone (GHRH) released from?
A
- Hypothalamus (PVN)
- GHRH or somatocrinin
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
3
Q
What is the target tissue for growth hormone?
A
- Liver (IGF-1)
- Muscle and bones
- Adipose tissue
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
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
6
Q
How is GH transported in blood?
A
By GH-binding proteins (GHBPs)
7
Q
How does Ghrelin impact GH secretion?
A
- Ghrelin released during fasting
- Enhances GH secretion (acts as a secretagogue)
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
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
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
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
12
Q
Explain the JAK-STAT pathway.
A
JAK2 phosphorylation (due to binding) -> STAT activation -> promoting transcription of target genes
13
Q
Explain the MAPK pathway.
A
Activates RAS/REF/MEK/ERK cascade -> important for cell growth and division
14
Q
Explain the P13K-Akt pathway.
A
- Involved in protein synthesis, anti-apoptotic responses, and metabolism regulation
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
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
- Liver: stimulates IGF-1 production, promoting glucose metabolism and gluconeogenesis
- Muscles: increases amino acid uptake and protein synthesis, enhancing muscle growth
- Adipose tissue: stimulates lipolysis, reducing fat stores and increasing free fatty acids in circulation
- 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
- Resting zone: contains inactive chondrocytes
- Proliferation zone: chondrocytes divide and align in columns, producing new cartilage
- Hypertrophic zone: chondrocytes enlarge and begin secreting factors to calcify the matrix
- Calcification zone: cartilage matrix becomes calcified, and chondrocytes die
- 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
