Growth hormone, growth factors, & growth-related diseases

Question 1

Growth hormone

Answer 1

Growth hormone: a specific polypeptide hormone released into circulation by ant. pit.
somatotroph cells, acts on target cells in the periphery (e.g., in adipose, muscle, bone, liver)

Question 2

Growth factors

Answer 2

a broad/general term often used to mean secreted factors that stimulate
growth (cell proliferation and/or differentiation)

Question 3

Cytokines

Answer 3

a broad/general term for small proteins with cell signaling functions. They have a
fundamental role in the immune system; are typically short-lived and act locally; and a specific
cytokine may often be produced by multiple cell types

Broad range of functions (which may include promoting growth), but historically
categorized as cytokines when exerting immunological or hematopoietic responses

Question 4

Hormones, growth factors, and cytokines: …

Answer 4

all chemical messengers/signaling molecules that bind to specific receptors, initiating signal transduction pathways and biological responses

Question 5

Growth factors and cytokines have some similarities in structure to ___ hormones; they also act on cell ___ receptors (and receptors have structural homologies);
might share ____ signaling components

Answer 5

• Growth factors and cytokines have some similarities in structure to peptide hormones;
they also act on cell surface receptors (and receptors have structural homologies);
might share downstream intracellular signaling components

Question 6

Growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis

GH

Answer 6

191-a.a. polypep@de hormone
synthesized by anterior pituitary
somatotroph cells;
~ half in circulaNon is bound to
specific GH-binding proteins (GHBP)
(reduce oscillaNons, prolong half-life)
• High-affinity GHBP is the same as the
extracellular porNon of GH receptor

Question 7

Growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis

IGF-1

Answer 7

70-a.a. polypep@de hormone
synthesized by many Nssues
(paracrine/autocrine signaling), and most
IGF-1 in circula@on (endocrine signaling) is
produced by liver; bioavailability is
determined by specific IGF binding proteins

Question 8

Growth hormone (GH) signaling

• GH:

Answer 8

• GH: linked to nutritional status; promotes

↑ lean mass & using lipid/carbohydrate stores

Question 9

Most growth-promoting effects of GH are

mediated by IGF-1 (“indirect” effect of GH)

Answer 9

• GH stimulates liver to produce IGF-1 (into
  circulation), and stimulates local (autocrine
  /paracrine) IGF-1 production by most tissues
• Well-known effects in bone & skeletal muscle

Question 10

GH also has ____

Answer 10

GH also has metabolic effects

Question 11

Growth hormone (GH) signaling
Liver

Answer 11

Liver: stimulates glucose release (energy
source), in addition to release of IGF-1
• White adipose tissue: stimulates lipolysis and
release of fatty acids (energy source), while
inhibiting uptake of lipids from circulation
• w/IGF-1, promotes protein accumulation
(increases a.a. uptake & protein synthesis)

Question 12

GH: linked to nutritional status . fasting _____, potentially to mobilize lipids as an energy source & prevent protein loss

Answer 12

• GH: linked to nutritional status – fasting
stimulates GH secretion, potentially to mobilize
lipids as an energy source & prevent protein lo

Question 13

ghrelin

Answer 13

• e.g., via ghrelin, the “hunger hormone”
produced by enteroendocrine cells of GI tract,
which binds to receptors on somatotroph
cells and potently stimulates GH secretion

Question 14

• Rise in glucose or free fatty acids = ___ GH
• Protein-high meal or a.a. infusion = __ GH release
• Stress, exercise, and sleep all lead to ___ GH

Answer 14

• Rise in glucose or free fatty acids = ↓ GH
• Protein-high meal or a.a. infusion = ↑ GH release
• Stress, exercise, and sleep all lead to ↑ GH

Question 15

Age affects GH levels (___ levels in children,

drops in adulthood)

Answer 15

Age affects GH levels (high levels in children,

drops in adulthood)

Question 16

Growth hormone (GH) signaling – GH receptor is a Type 1 cytokine receptor

step 1

Answer 16

1. Different portions of a single GH associate with two independent GHR, leading to JAK2 recruitment

Question 17

Growth hormone (GH) signaling – GH receptor is a Type 1 cytokine receptor

step 2

Answer 17

2. JAK2 undergoes
autophosphorylation &
phosphorylates the GHR,
providing a docking site
for a STAT (signal
transducers and activators
of transcription).

Question 18

Growth hormone (GH) signaling – GH receptor is a Type 1 cytokine receptor

step 3

Answer 18

3. STAT is then
phosphorylated by JAK2,
and can form dimers that
translocate to the nucleus
and regulate transcription
of its target genes (e.g.,
stimulates IGF-1 gene
expression).

Question 19

Thyroid hormone:

Answer 19

promotes GH secretion and GH’s growth & metabolic effects;

Hypothyroidism in children leads to reduced growth after birth & developmental delays

Question 20

Gonadal sex steroids

Answer 20

• Gonadal sex steroids: important for puberty growth spurt

Estradiol stimulates IGF-1 production and also promotes GH secretion

Question 21

Glucocorticoids : high levels can
\_\_\_ growth (due to \_\_\_
endogenous levels/hypersecretion,

Answer 21

\: high levels can
suppress growth (due to excess
endogenous levels/hypersecretion,

Question 22

Synergistic actions of hormones
e.g., growth hormone (GH) &
thyroid hormone (TH)

Answer 22

Synergistic actions of hormones
e.g., growth hormone (GH) &
thyroid hormone (TH)

Question 23

e.g., Cushing syndrome,
or due to exogenous glucocorticoids,
e.g. steroid treatments);
Glucocorticoids \_\_\_\_
somatostatin secretion

Answer 23

e.g., Cushing syndrome,
or due to exogenous glucocorticoids,
e.g. steroid treatments);
Glucocorticoids increase
somatostatin secretion

Question 24

Acromegaly

Answer 24

• excess GH (and therefore high IGF-1) after puberty

- Most often because of excessive GH secretion (e.g., GH-secreting pituitary adenomas)

Question 25

Growth hormone axis deficiency

Answer 25

Abnormalities at various levels of the axis

Question 26

GH deficiency

Answer 26

(GH gene defect, pituitary defect, hypothalamic dysfunction) | – therefore, low levels of IGF-1

Question 27

Laron syndrome

Answer 27

: GH resistance, or deficiency in GH receptor (and GH binding protein), or IGF-1 or IGF-1 receptor defect – any could result from gene mutations

Question 28

GH levels are ___ under GH resistance, but IGF-1 levels are ____; low IGF-1 levels mean lack of ___ feedback inhibition, and ∴ ___ in circulating GH

Answer 28

GH levels are elevated under GH resistance, but IGF-1 levels are low or absent; low IGF-1 levels mean lack of negative feedback inhibition, and ∴ rise in circulating GH

Question 29

Other factors that affect growth

Answer 29

Genetics affect height in adulthood • Nutritional and socioeconomic factors Malnutrition is a major player that can cause significant endocrine changes e.g., elevated GH levels but GH resistance (e.g., ↓ GH receptors) and decreased IGF-1 • Chronic disease Many chronic systemic diseases interfere with growth • Psychological factors Psychological stress or psychiatric disease can affect endocrine function or nutrition

Question 30

Placenta

Answer 30

: endocrine organ that is critical for fetal growth • Supplies nutrients and oxygen • Produces & releases many hormones and growth factors

Question 31

• Insulin-life growth factors (IGFs)

Answer 31

• Insulin-life growth factors (IGFs) are important for fetal growth, but IGF-1 in the fetus is regulated by metabolic factors other than GH (few GH receptors)

Question 32

IGF-2

Answer 32

• IGF-2 is more abundant during fetal life than IGF-1

Question 33

Insulin

Answer 33

• Insulin also has important stimulatory effects on fetal growth

Question 34

Growth factors

Answer 34

a broad/general term often used to mean secreted factors that stimulate growth (cell proliferation and/or differentiation)

Question 35

Growth factor receptor

Answer 35

: the enzyme tyrosine kinase is part of the receptor…

Question 36

_____ of tyrosine residues in receptor creates docking sites to recruit adaptor proteins & effectors (forming a ____); And phosphorylating docked proteins (e.g., other kinases) regulates their enzymatic activity, causing a ________

Answer 36

Autophosphorylation of tyrosine residues in receptor creates docking sites to recruit adaptor proteins & effectors (forming a signaling complex); And phosphorylating docked proteins (e.g., other kinases) regulates their enzymatic activity, causing a phosphorylation cascade

Question 37

Insulin-like growth factors (IGF-1 & IGF-2):

Answer 37

Both are in the same family of peptides as insulin (common ancestral gene) IGF-1 receptor and insulin receptor are highly homologous, with many similarities in downstream signaling pathways

Question 38

Too little growth factor might cause ____ (= children's weight or rate of weight gain is significantly below that of other children of similar age and sex)

Answer 38

Too little growth factor might cause failure to thrive (= children's weight or rate of weight gain is significantly below that of other children of similar age and sex)

Question 39

• Proto-oncogenes

Answer 39

normal genes that affect cell growth, but can become oncogenes (genes with the potential to cause cancer) when something goes awry • e.g., mutation in a growth factor gene, its receptor, or a component of its signaling cascade

Question 40

Therefore, one disease that is associated with too much growth factor is ___

Answer 40

Therefore, one disease that is associated with too much growth factor is cancer …and tumors can cause increased secretion of growth factors