Growth Hormone

Front 1

What is the term for excess growth hormone? What is the term for GH deficiency (esp. signaling pathway, low IGF1)?

Back 1

Agromegaly – giganticism
Laron dwarfism

Front 2

Where is growth hormone produced and released? What type of cells produce GH and what proportion of the gland constitute these cells?

Back 2

GH comes from somatotrophic cells in the anterior pituitary gland, which constitutes 50% of the hormone secreting cells of the pituitary

Front 3

In what fashion is GH released and when is does maximum and minimum release occur?

Back 3

Released in a pulsatile fashion roughly every 2 hours, with maximum release in the first 1-2 hours of sleep (slow sleep wave), minimum release during REM sleep and in-between daytime bursts (undetectable).

Front 4

How much GH is secreted per day in men and women? What is the half-life of GH?

Back 4

Women: 500 μg/m2/day
Men: 350 μg/m2/day

Half-life: 25-30 min

Front 5

What is GH binding protein? Where does it come from? What proportion of GH is bound to the binding protein? What are the consequences for GH?

Back 5

GH binding protein binds and circulates with GH. GHBP is made up of a portion of the extracellular domain of the GH receptor, which breaks off when GH binds then recirculates. 45% of GH in the body is bound to GHBP. When GH is bound to the binding protein, the half-life is increased and clearance is reduced.

Front 6

What organ is responsible for GH elimination?

Back 6

Liver

Front 7

Give an overview of the GH feedback system.

Back 7

GH inhibits Growth Hormone Releasing Hormone in the hypothalamus and stimulates somatostatin in the hypothalamus.

IGF1 does the same thing as GH at the hypothalamic level and also inhibits the stimulatory action of GHRH at the pituitary.

Front 8

Does the GHRH G-coupled mechanism involve cAMP or IP3 as its second messenger? What is the end result? Describe Somatostatin’s G-coupled mechanism.

Back 8

GHRH acts via BOTH an adenylate cyclase and phospholipase C mechanism (so both cAMP and IP3). The end result is an increase in GH gene transcription, synthesis and secretion.

Somatostatin acts via a Gi (inhibitory) adenylate cyclase mechanism that decreases intracellular Ca2+. It DOES NOT affect synthesis, but rather relates to timing and amplitude of GH bursts (it tonically inhibits bursts).

Front 9

Sleep, Exercise, Stress, Glucose, Amino Acids, Fasting. Among these, which inhibit and which boost GH levels?

Back 9

Glucose inhibits. Everything else stimulates.

Front 10

By what means do glucose, fasting, and amino acids increase or decrease GH levels?

Back 10

Acute increase in glucose suppresses GH in healthy people; may be via increase in somatostatin.

Fasting: Increases GH secretion by inhibition of somatostatin. Increases the number of amplitude of the GH bursts.

Amino acids: Increase GH secretion by inhibiting somatostatin

Front 11

What do adrenergic and cholinergic inputs do to GH secretion?

Back 11

Decrease somatostatin, increase GH. Cholinergic are especially important during sleep.

Front 12

How does exercise affect GH secretion (by what mechanism)? Is this a long-term effect?

Back 12

Major mechanism may be increase in α2 receptor adrenergic input to hypothalamus, which lowers somatostatin. This leads to an acute increase in GH (magnitude of bursts proportional to exercise intensity). In the long-term, though, GH bursts go down with trainings, so athletes do not secrete more GH than average people.

Front 13

What pharmacologic agents can be used to stimulate growth and how do they act?

Back 13

L-dopa and Clonidine stimulates GHRH.

Insulin (via hypoglycemia), Arginine, and Pyridostigmine inhibit somatostatin.

Front 14

___(#)____ molecule(s) of GH bind(s) to ___(#)____ receptor(s). Signal transduction follows which leads to the production of _____. This signaling occurs via the ______ family of intracellular tyrosine kinases and the ______ family of transcription factors.

Back 14

1
2
IGF1
JAK
STAT

Front 15

What is the predominant source of IGF1 synthesis?

Back 15

Liver

Front 16

What is grelin?

Back 16

A hormone produced in the stomach that plays some kind of a role in GH secretion (unclear what that role is). It also stimulates the appetite.

Front 17

What are the actions of IGF1?

Back 17

MANY!!! Mediates the major anabolic and growth-promoting effects of growth hormone, as well as the cellular responses to growth.

It also has an insulin-like effect, independent of GH (hence its name).

Front 18

What effect of GH is NOT mediated by IGF1?

Back 18

IGF1 does not mediate the lipolytic effects of GH.

Front 19

Besides GH, list four other factors that control IGF1 levels.

Back 19

Nutritional status (caloric deprivation = lower IGF1)
Age (highest in puberty, decrease with age)
Genetic factors
Binding proteins (need to be present, so factors that control their secretion will also control IGF1)

Front 20

What two major proteins bind IGF1? What proportion of IGF1 is bound?

Back 20

IGFBP-3 and Acid Labile Subunit (ALS)

90% of circulating IGF1 is bound to a binding protein.

Front 21

Compare GH to IGF1 in terms of half life and % bound to binding protein.

Back 21

GH has a much shorter half-life than IGF1. IGF1 is bound to binding protein in greater proportions (90%) than GH (45%).

Front 22

What is the half-life of IGF1?

Back 22

>24 hours. So inject GH, you’ll see a burst of GH, but IGF1 will stay elevated for much longer.

Front 23

What is used to measure GH status?

Back 23

IGF1 – because it stays in the blood for much longer. GH bursts are quick and therefore more difficult to measure. So IGF1 is used as the preferred marker.

Front 24

Besides GHRH and grelin, what is another major hormonal regulator of GH/IGF1 secretion? How does it work?

Back 24

Estradiol – increases GH, decreases IGF1

Like exercise, it acts on α2 receptors in the hypothalamus to inhibit somatostatin. It also acts STAT proteins in the liver to decrease IGF1 production. Lower levels of IGF1 means less negative feedback, and therefore higher GH levels. This is why women have higher GH levels than men, though IGF1 levels are similar.

Front 25

If women have higher GH levels than men, why aren’t women huge?

Back 25

Estradiol increases GH secretion, but also simultaneously inhibits STAT proteins, which decreases IGF1 production in the liver. (The elevated GH in women compensates for the decrease IGF1 caused by estradiol, so that IGF1 levels are similar in men and women.)

Front 26

What do you do in GH replacement therapy for a woman taking estrogen pills?

Back 26

Need to increase the dose in order to make up for the lowered IGF1 production caused by the estrogen.

Front 27

Describe the GH effects mediated DIRECTLY by GH.

Back 27

Insulin antagonist

*Anabolic (builds) bone
*Lipolytic (burns) fat (releases free fatty acids and prevents FFA uptake, which potentiates insulin resistance)
*Insulin resistance in muscle (decreased glucose transport into myocytes)
*Anabolic and nitrogen retaining in muscle
*Insulin resistance in liver (increased glucose output)

Front 28

Describe the GH effects mediated by IGF1.

Back 28

Insulin agonist (acts on same receptor)

*Anabolic (builds) bone
*Insulin sensitizing in liver (decreased glucose output)
*Insulin sensitizing in muscle (increased glucose transport into myocytes)

Note: IGF1 itself doesn’t play a huge role in normal glucose homeostasis, but IGF1 deficiency causes severe insulin resistance.

Front 29

In a nutshell: How would an injection of GH or IGF1 affect glucose levels?

Back 29

An injection of GH will raise glucose levels.
An injection of IGF1 will cause hypoglycemia

Front 30

How does GH initiate lipolysis?

Back 30

1.) Enhances lipase synthesis, which reduces FFA and triglyceride accumulation in adipose tissue.
2.) Also enhances catecholamine lipolysis.
3.) Inhibits the α subunit of Gi in adipocytes, which reduces tonic inhibition of lipolysis.

(She says we don’t need to know this …)

Front 31

Overall, GH and IGF1 act to _____ amino acid uptake, ____ nitrogen retention, and _____ energy expenditure.

Back 31

Increase for all three.

Front 32

What are the effects of a pituitary tumor?

Back 32

These are benign tumors (don’t metastasize), but may cause increased GH secretion (acromegaly) and if they grow large may impair vision via encroachment on the optic chiasm. Also can cause headaches.

Front 33

What physiological results do you see in acromegaly?

Back 33

*Large hands and feet and coarsening of facial features – this is how it’s often presented in adults: soft tissue hypertrophy (b/c long bones no longer growing)
*Hypertension and heart disease (b/c GH has salt-retaining properties, also hypertrophy)
*Sleep apnea (b/c enlarged tongue and pharyngeal hypertrophy)
*Impaired glucose tolerance [DIABETES] (unclear why, but you only see insulin resistance effect of GH in acromegaly, but not insulin sensitizing effect o IGH1, even though both GH and IGF1 are high)
*Arthritis
*Headaches (b/c of tumor and vascular effects)
*Gigantism → ONLY IN CHILDREN (in adults, epiphyseal plates are not affected)

Front 34

Besides tumor removal, what other medical treatments are available for acromegaly?

Back 34

Somatostatin analogs (directly inhibits GH secretion)

Growth Hormone Receptor antagonist (a mutated GH molecule that blocks the GH receptor (prevents dimerization), negating effects of GH in periphery and inhibiting IGF1 secretion)

Front 35

What is pegvisomant? What does it do to GH and IGF1 levels?

Back 35

A Growth Hormone Receptor antagonist.

GH levels remain the same (i.e. elevated in acromegaly, but the metabolic effect of GH is reduced). IGF1 levels fall.

Front 36

What are lanreotide and octreotide?

Back 36

Somatostatin analogs, given as monthly injections for people with acromegaly.

Front 37

What are some sites for sources of growth deficiency?

Back 37

Hypothalamic Disease: GHRH deficiency
Pituitary Disease: Failure to Secrete GH
Peripheral blockade of GH action that leads to impaired IGF1 production.

Front 38

In an adult, what are some clinical consequences of GH deficiency? What are some causes of GH deficiency in adults?

Back 38

*Elevated cholesterol
*Increased central body fat (abnormal body composition)
*Decreased bone density

Usually caused by non-secreting pituitary tumor (50%), hypothalamic tumors (ex: craniopharyngioma) or other CNS tumors, head trauma, surgery or irradiation for other pituitary diseases.

Front 39

What is treatment of GH deficiency?

Back 39

Daily injections of human growth hormone leads to modest improvements.

Front 40

Besides the etiologies of GH deficiencies seen in adults, what can cause it in children?

Back 40

Genetic causes:

*GH1 gene mutations
*GHRH receptor mutations
*Pit-1 (pituitary specific factor important for expression of pituitary hormone genes)
*GHD mutations
*Prop-1 mutation (transcription factor for early pituitary development)

Front 41

What would be the effect of a mutation in GH signaling that results in low IGF1 and extremely high GH?

Back 41

Short stature (b/c GH does not directly cause growth)

Front 42

What is Laron syndrome? How is it treated?

Back 42

IG1 deficiency caused by a defect in the extracellular domain of the GH receptor. It can be treated by administering recombinant IGF1. Supplemental GH would NOT work in this type of growth deficiency.

Front 43

Besides GH deficiency, what are some other causes of growth problems in children?

Back 43

Peripheral problems:

IGF1 deficiency: defects in GH receptor (Laron syndrome) or defects in proteins involved in the cascade leading to IGF1 synthesis.

Also … IGF1 resistance: defects in IGF1 receptor, post-IGF1 signaling problems, or defects in IGF1 binding proteins. Or other defects in regulatory proteins necessary for bone growth.