Pituitary Hormone Function (GH/PRL) Flashcards

1
Q

The Growth Hormone/Prolactin Family of Hormones

A

a. Prolactin (PRL) and growth hormone (GH) are members of the same family of hormones, and both are ~22-23 kD polypeptides of slightly less than 200 amino acids containing 2-3 disulfide bonds.
i. PRL and GH are ~16% similar at the level of primary sequence.

b. This class of hormones is also referred to as the somatomammotropin family.
c. A third member of this family is placental lactogen (hPL or chorionic somatomammotropin), which has 83% amino acid identity with GH.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Prolactin (PRL) Secretion from the Ant Pituitary

A

a. This hormone distinguishes itself by the fact that the hypothalamus tonically inhibits the secretion of PRL via PIH (prolactin-inhibiting hormone), or DA (dopamine).

b. If the hypothalamic influences to the anterior pituitary are prevented, the adenohypophysis will secrete much larger amounts of PRL, whereas the secretion of the other anterior pituitary hormones will not increase
i. Ant Pituitary will secrete large amounts of prolactin unless the hypothalamus stops it with PIH or DA

c. In some instances of hypersecretion of prolactin, administration of a dopamine agonist, such as bromocriptine, is effective in reducing the excess release of prolactin.

d. DA reduces release and synthesis of PRL, inhibits lactotroph cell division and DNA synthesis and increase destruction of PRL containing secretory granules (crinophagy).
i. Inhibition of cAMP formation appears to be involved in mediating these effects.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Prolactin Function

A

a. The cells that secrete PRL, lactotrophs, comprise 30% of the adenohypophysis (anterior pituitary)
b. The breast is the principal target of PRL action, where PRL plays a role in the production of milk.

c. In cases where there are prolactin-secreting tumors, there will be inappropriate milk secretion.
i. Reproduction is impaired, because high levels of prolactin inhibit pulsatile secretion of GnRH by hypothalamic neurons.

d. PRL is transported in the blood unmodified and has a short half-life of 20-30 min.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

External causes that lead to increased Prolactin secretion

from the anterior pituitary

A

a. In females, suckling of the breast is an effective physiological stimulus leading to release of prolactin.
b. In addition, prolactin is released in both males and females in response to stress. Prolactin interacts with specific receptors found in the breast, liver, ovary, testis and prostate; the main site of action is the mammary gland

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Prolactin receptors are members of the growth hormone/cytokine receptor families.

A

a. The long form of PRL receptors and the growth factor receptors are about 620 amino acids in length
i. They are single chain proteins crossing the membrane only once.

b. Upon ligand binding, receptors dimerize, leading to the activation of the JAK/STAT pathway.
i. Just as prolactin and growth hormone share structural homology, so do their receptors.

c. Human PRL receptors are well stimulated by GH.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Growth Hormone (GH)

Large Summary

A

a. Growth hormone is fundamental for postnatal growth, stimulates somatic growth and regulates metabolism.

b. GH is a peptide hormone as well as a secretory protein.
i. The principal and biologically most important form consists of 191 amino acids.

c. Similar to many other hormones, GH is synthesized as part of a prohormone.
i. Once the signal peptide is cleaved, GH is stored in secretory granules of somatotrophs of the adenohypophysis.

d. The synthesis of GH is evidently a major activity of the anterior pituitary, since 10% of the dry weight of the anterior pituitary is contributed by GH!

e. Secretion of GH is under the influence of the hypothalamic hormones GHRH and somatostatin.
i. GHRH and somatostatin stimulation of somatotrophs have opposing actions on cAMP levels; GHRH stimulation increases them, whereas somatostatin decreases them.

f. The majority of GH circulates in an unbound form and has a half-life of 20-45 min.
i. There is some evidence suggesting that a portion of plasma GH is bound specific binding proteins (GHBP), which are cleaved N-terminal peptides of its receptor.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Growth Hormone is a very specific peptide for its species

A

a. Human or primate GH are the only GH’s that are active in humans.

b. Previously, human GH isolated from cadavers was used therapeutically.
i. In 1985, it was noted that several individuals who had been treated with “cadaver” GH acquired Creutzfeld-Jacob disease, a devastating form of spongiform encephalopathy caused by prions.

c. Recombinant GH is now available and has become the sole source of GH replacement therapy.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What type of receptors Growth hormone interacts with

A

At a cellular level, GH interacts with GH receptors in the plasma membrane of target cells. Both GH receptors and their signaling mechanisms are similar to that of PRL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Direct actions of Growth Hormone-

These are metabolic effects (Counter-regulatory or diabetogenic)

A
  1. Adipose tissue- The net effect is to increase lipolysis and lead to mobilization of lipid and thus an increase in plasma free fatty acids (FFAs). Eventually, the effect of GH on fat metabolism will be evidenced by a loss in subcutaneous fat. In this action GH antagonizes the action of insulin.
  2. Muscle-GH has a strong anabolic action on muscle. Amino acid transport is increased, and protein synthesis is increased.
  3. Liver-Increased RNA, protein and glucose synthesis. Further, IGF-I will be secreted, which mediates the indirect effects.
  4. The increase in glucose levels is mainly due to an increase in gluconeogenesis and not due to glycogenolysis.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

General Effect of Growth Hormone

A

a. In general, GH’s effects are anti-insulin like, i.e. glucose uptake will be decreased and plasma glucose levels will rise.
i. Note that the increased plasma FFA is providing an alternate energy source and the increased plasma glucose is reserved for the CNS.

b. Importantly, protein is spared.
i. This contrasts with the actions of cortisol, the subject of another lecture.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Indirect Actions of Growth Hormone:

A

a. In addition to its metabolic effects, GH also has effects on muscle and skeletal growth mediated by another hormone-the Insulin-like growth factor (IGF).

b. There are two forms of IGF that have been shown to exist (IGF-I and IGF-II).
i. Of these, IGF-I is the predominant form in postnatal tissues.

c. The production of IGF requires both GH and insulin and occurs in a number of tissues (e.g. liver, bone marrow).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Insulin-like Growth Factor I (IGF-I):

summary

A

a. IGF-I is structurally related to proinsulin (hence its name) and has many insulin like actions (especially in adipose tissue and muscle).
b. IGF-I is a powerful mitogen and growth-promoting agent.
c. Elevated IGF-I levels increase slowly from birth until puberty, when there is usually a much more pronounced elevation.

d. Although growth hormone usually promotes secretion of IGF-I production, there are some stimuli that have different effects on GH and IGF-I levels.
i. For example, during fasting, GH levels are elevated, while IGF-I levels are depressed.

e. IGF receptors belong to the EGF/ Insulin receptor family.
i. These receptors contain an inherent tyrosine kinase activity and upon ligand binding can readily phosphorylate themselves (auto phosphorylation) and other proteins of the signal transduction pathway.

f. The major pathway activated by IGF receptors is initiated by the binding of Insulin Receptor Associated proteins 1 and 2 (IRS I&II). IRS in turn can bind to other molecules to activate either the MAP kinase pathway or transduction mediated by PI-3 kinase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

IGF receptors belong to the EGF/ Insulin receptor family.

A

a. These receptors contain an inherent tyrosine kinase activity and upon ligand binding can readily phosphorylate themselves (auto phosphorylation) and other proteins of the signal transduction pathway.
b. The major pathway activated by IGF receptors is initiated by the binding of Insulin Receptor Associated proteins 1 and 2 (IRS I&II).
c. IRS in turn can bind to other molecules to activate either the MAP kinase pathway or transduction mediated by PI-3 kinase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Growth Hormone actions mediated via IGF-I

A
  1. Bone/cartilage - Long bone growth is promoted by the stimulated proliferation of epiphyseal cartilage. After puberty, the epiphyses seal and IGF-I no longer has this effect on linear growth.
  2. Muscle - stimulates proliferation, differentiation and protein synthesis
  3. Adipose tissue - stimulates uptake of glucose and inhibits lipolysis. This action of IGF is insulin like and antagonizes that of GH.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Control of GH secretion by products of Intermediary metabolism:

summary

A

a. Other stimuli include hypoglycemia, amino acids (arginine), low free fatty acid levels, α-adrenergic agonists (clonidine), β-adrenergic antagonists (propranolol) and estrogens.
b. Conversely, hyperglycemia, high free fatty acid levels, obesity, α-adrenergic antagonists, β-adrenergic agonists as well as pharmacological doses of corticosteroids inhibit GH secretion.

c. In assessing GH levels and secretion, it is important to obtain measurements several times over the course of a day.
i. Stimulation of GH secretion by exercise or high doses of arginine is often used to assess GH status.
ii. In addition, measurement of IGF-I levels is very helpful, especially since its levels are subject to less diurnal variation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Hormones released from Hypothalamus to Anterior Pituitary

*Great list

A

Hormones released from the median eminence to the Ant. Pituitary

  • RH —> releasing hormone
    1. TRH
    i. only 3 amino acid size
    ii. works on Thyrotroph cells to cause TSH release
  1. CRH
    i. is 40 amino acid size
    ii. Works on Corticotrophs to release ACTH
  2. GnRH
    i. Works on gonadotrophs to release LH and FSH
  3. GHRH
    i. works on Somatotrophs–> will release growth hormone
  4. Somatostatin
    i. works on Somatotrophs—> will Decrease Growth hormone
  5. PIH (prolactin inhibiting hormone)–> Dopamine
    i. Decrease prolactin release

These hormones are all peptide hormones (except dopamine)

17
Q

Prolactin

A

a. Prolactin is a protein hormone that is released by Lactorophes in the anterior pituitary
i. released by Ca2+ dependent exocytosis

b. Prolactin is carried mostly freely in blood (still researched), short half-life due to proteases (30 min half life)

c. Prolactin Target: Will reach target cell membrane receptor (Prolactin Receptor). This receptor belongs to the Cytokine family
i. Cytokine family are large membrane receptors, will have 2 binding sites for prolactin

d. Binding of Prolactin to the Prolactin receptor (Cytokine receptor) will activate Janus Kinase
i. Janus kinase is a tyrosine kinase, will phosphorylate a bunch of signal transducers that lead to transcription inside the nucleus
ii. also Janus kinase will phosphoralte Activates of Transcription (STATS)
iii. Called JAK-STAT activation in total

18
Q

When Prolactin reaches its target-

Cellular Mechanism

A

a. Prolactin Target: Will reach target cell membrane receptor (Prolactin Receptor). This receptor belongs to the Cytokine family
i. Cytokine family are large membrane receptors, will have 2 binding sites for prolactin

b. Binding of Prolactin to the Prolactin receptor (Cytokine receptor) will activate Janus Kinase

c. Janus kinase is a tyrosine kinase, will phosphorylate a bunch of signal transducers that lead to transcription inside the nucleus
i. also Janus kinase will phosphoralte Activates of Transcription (STATS)
ii. Called JAK-STAT activation in total

d. JAK-STAT is the major tyrosine kinase pathway of cytokine receptors

19
Q

Prolactin effect on Mammary Gland

A

a. Primary function is to regulation milk release from mammary gland

b. Prolactin will cause 3 process:
1. Mammogenisis–> growth of mammary gland
2. Lactogenesis–> getting glands ready for milk production
3. Galacoporesis—> synthesis and release of milk

c. Dysfunction of prolactin–> dysfunction in milk production

d. Dopamine will inhibit the production of Prolactin
i. Dopamine will cause increased Gi protein function at Ant Pituitary, lower porlactin production

e. It appears TRH (thyroid releasing hormone) will cause increased prolactin release

f. Estrogen and Progesterone will modify the different functions of prolactin
i. They will increase the effect of Mammogenisis (mamillary gland devlopment)
ii. They will decrease lactogenesis and galacoporesis
* will allow breast to get ready for milk developing during pregnacy

20
Q

Main inhibitor of prolactin release

A

PIH (prolactin inhibiting hormone)–> Dopamine
i. Decrease prolactin release

Dopamine will inhibit the production of Prolactin
i. Dopamine will cause increased Gi protein function at Ant Pituitary, lower porlactin production

21
Q

Dysfunction of Prolactin

A

a. Hyper-Prolactin
i. Overgrowth of mamallary gland
ii. Amenorrhea (disruption of mentral cycle)
iii. Loss of Libido

b. Hypo-Prolactin
i. Sheehan’s Syndrome–> failure to lactate

22
Q

Growth Hormone

A

a. Growth Hormone is released by Somatotrophs in the Ant Pituitary

b. Growth Hormone will reach its target, the Cyotkine receptor family
i. Will undergo the JAK-STAT pathway (Janus kinase and its targets)

c. Two major effects of growth hormone: Metabolic and Growth
1. Will increase gluconeogenisis
i. create more glucose for growth
ii. Will decrease insulin effect (stop glucose uptake)
iii. Excess is diabetogenic

  1. Fatty Acids–> GH will increase serum fatty acids
    i. GH will activate hormone sensitive lipase
    ii. source of energy for growth
  2. Protein–> GH will stimulate amino acid uptake into muscle
    i. increase the amount of growth
23
Q

How Growth hormone affects metabolism of body

A

Summary: Increase glucose creation (but lower uptake), will increaes serum fatty acid, will increase protein uptake by cells

  1. Will increase gluconeogenisis
    i. create more glucose for growth
    ii. Will decrease insulin effect (stop glucose uptake)
    iii. Excess is diabetogenic
  2. Fatty Acids–> GH will increase serum fatty acids
    i. GH will activate hormone sensitive lipase
    ii. source of energy for growth
  3. Protein–> GH will stimulate amino acid uptake into muscle
    i. increase the amount of growth
24
Q

Growth Effects of growth hormone

A

a. The growing effects of GH is induced by IGF (insulin-like growth factor)

b. IGF will mediate the growth of cells
i. Growth hormone will increase IGF creation from liver and other tissues

c. Need GH + Insulin —> create Insulin-like Growth factor
i. need high amounts of both Insulin and growth hormone for creation of IGF

d. Target of IGF—> Will target EGF family receptors
i. EGF receptors have tyrosine kinase, will undergo dimerization and will activate Insulin Receptor Substrate (IRS)
ii. similiar to chemical pathway of insulin

e. Effect of IGF
1. Increase Long bone growth
2. Increase muscle growth
3. growth of other tissues

25
Q

Target and Effect of Insulin like Growth Factor

A

a. Target of IGF—> Will target EGF family receptors
i. EGF receptors have tyrosine kinase, will undergo dimerization and will activate Insulin Receptor Substrate (IRS)
ii. similiar to chemical pathway of insulin

b. Effect of IGF
1. Increase Long bone growth
2. Increase muscle growth
3. growth of other tissues

26
Q

Regulation of Growth Hormone

*Important Slide

A

Hypothalamus——> Anterior Pituitary—> Growth Hormone

a. Hypothalamus secretion:
1. Hypothalamus releases GHrH
i. will increase GH release from anterior pituitary

  1. Hypothalamus releases SST (somatostatin)
    i. will decrease GH release from ant pituitary

b. Growth Hormone will lead to Negative feedback on the Hypothalamus
i. It will cause lower GHrH to be released, and it will increase the SST release to the anterior pituitary
ii. less growth hormone will be released

c. Hypoglycemia–> increased Growth hormone release (by increased GHRH from the hypothalamus)
i. Increase glucose creation (but lower uptake), will increaes serum fatty acid, will increase protein uptake by cells
ii. GH hormone is acting as a stress hormone in this case

d. High amino acids in serum—> increased Growth hormone release (by increased GHRH from the hypothalamus)

27
Q

In a well-fed state

Growth Hormone..

A

a. Well fed state means high insulin in serum, and high amino acids in serum
i. means there will be high amount of Insulin-like Growth Factor
GH + Insulin—> IGF
ii. can make cells and tissues larger

b. In low fed state, low amino acids and insulin
i. will NOT make Insulin-like growth factor
ii. no need to make cells larger

28
Q

Dysregulation of Growth Hormone

A

Hyper-Growth Hormone
1. Diabetogenic–> will lead to high serum glucose (be in a diabetes state)

  1. Gigantism–> high amounts of IGF
    i. typically die by 20s due to heart problems
    ii. high GH before puberty
  2. Cardiac hypertrophy
  3. Acromegaly
    i. excessive GH post-puberty
    ii. will see enlarged jaw, hands, ect (due to loss of liner growth)
    iii. less severe than gigantism

Hypo-Growth Hormone

  1. Dwarfism
    i. can be due to low GH, or due to mutation in GH receptor
  2. Laron’s Dwarfism- GH receptor issue
  3. African Pigmie–> Poor IGF response