3.3 Prolactin and other tropic hormones Flashcards

1
Q

Prolactin:
1. what type of hormone?
2. similar structure to which hormone? conserved what?
3. how many aa?
4. concentration high?
5. prolactin locus has how many genes?

A
  1. peptide hormone
  2. GH! conserved helix bundle protein
  3. 198 aa (vs 191 in GH)
  4. 0.1 mg/pituitary –> small compared to GH
  5. prolactin locus has 1 gene –> PRL
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2
Q

PROLACTIN:
1. circulates in which form? what is the most bioactive?
2. half life?
3. released in what fashion? + describe
4. sexual dimorphism
5. which type of cell in pituitary produces PRL?

A
  1. monomeric, dimeric or polymeric –> monomeric is the most bioactive
  2. 25-45 minutes –> fairly short
  3. episodic release: 4 to 14 pulses per day –> highest at 3-5am. lowest at 10pm-12am (?)
  4. females have more prolactin than males (levels reduce with age)
  5. lactotrophs
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3
Q

explain the primary regulation of prolactin
- what type?
- what proves it?
- explain functioning

A
  • primary regulation by inhibition!
  • destruction of median eminence increase PRL secretion, while decreasing pituitary hormones!
  • dopamine neurons from arcuate nucleus produce dopamine = acts as main inhibitor via dopamine D2 receptors on lactotrophs
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4
Q

does PRL have positive or negative effect on dopamine neurons? to complete feedback loop
- dopamine neurons express what receptor?

A

positive!
- dopamine inhibits PRL
- so to complete feedback loop, PRL will positively activate dopamine neurons through the prolactin receptor on dopamine neurons so that PRL synthesis/release is even more inhibited

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5
Q
  • what positively regulates prolactin production?
  • what role does estrogen have in prolactin regulation
  • does oxytocin inhibit or promote PRL? how? what stimulus?
A
  • Putative PRL-releasing factors –> PRF neurons have been identified in various parts of brain –> TRH, VIP and oxytocin –> positively regulate PRL
  • estrogen inhibits dopamine neurons and activates lactotrophs = promotes PRL
  • suckling stimulus activates oxytocin neurons –> inhibits dopamine neurons = promote PRL
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6
Q

prolactin signals through which pathway?
- 2 types of dimerization

A
  • through RTK with recruited kinase activity –> JAK2 pathway –> stat OR ERK OR PI3K pathways
  • ligand dependant dimerization (PRL binds to 1 part, then recruits 2nd half for dimerization) OR ligand-independent dimerization (already dimerized, then PRL binds to receptor)
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7
Q

where are prolactin receptors expressed?

A
  • in breast tissue!
  • but also in many other tissues like pituitary, liver, adrenal cortex, kidneys, prostate, ovary, testes, intestine, epidermis, pancreatic islets, lung, myocardium, brain and lymphocytes
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8
Q

what is prolactin’s main function?
- distinct from which other function?

A
  • PRL is essential for initiation and maintenance of milk production (hypophysectomy/ removal of pituitary gland) leads to immediate cessation of milk synthesis)
  • prolactin stimulates milk synthesis in alveolar epithelial cells –> DISTINCT from neural regulation of milk ejection (which is enabled by instantaneous release of oxytocin in response to suckling –> oxytocin stimulates alveolar smooth muscles that surround each individual alveoli)
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9
Q

regulation of mammary gland development: WHICH HORMONES FOR:
- alveolar growth (4)
- duct system development (3)

A

ALVEOLAR GROWTH (epithelial cells and smooth muscles):
- PRL
- estrogen
- progesterone
- adrenal steroids
DUCT SYSTEM DEVELOPMENT (exocrine gland portion):
- GH
- estrogen
- adrenal steroids

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10
Q

PRL levels rise within ___-____ minutes of _________ and remain elevated for ___-____ minutes

A
  • 1-3 minutes of suckling and remain elevated for 10-20 minutes (beyond the suckling)
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11
Q

describe coordinated effect of oxytocin and prolactin on milk production (gros schéma)

A

suckling –> positive effect on mechanoreceptors in nipple –> positive effect on hypothalamus:
1. nervous pathway to posterior pituitary –> increase oxytocin –> contraction of myoepithelial cells surrounding alveoli –> milk ejection
2. hypothalamus –> decrease prolactin inhibiting hormone (dopamine neurones) + increase prolactin-releasing hormone (TRH, VIP, oxytocin) –> positive effect on anterior pituitary which produces prolactin –> milk synthesis

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12
Q

normally PRL activates/inhibits dopamine neurons, but not during __________
- explain

A
  • activates dopamine neurons to inhibit its own secretion
  • negative regulation is slightly lowered –> sensitivity of PRLr on dopamine neurons is lower –> for continued milk availability (which explains why PRL levels remain elevated even after suckling cessation)
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13
Q

how does prolactin regulate reproductive system? explain

A
  • involved in (negative) regulation of reproductive system
    (hyperprolactinemic conditions associated with hypogonadism in males and females)
  • PRL = inhibition of ovarian cycle during pregnancy/lactation (especially in pigs! –> don’t resume estrus cycle until weaning (separation of young one from mother))
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14
Q

what are other functions of prolactin (apart from milk synthesis)? (4)

A
  1. regulation of reproductive system (inhibit ovarian cycle)
  2. immunomodulation: PRLr on B and T lymphocytes and macrophages
  3. PRL acts as a mitogen and promotes survival + promote proliferation and differentiation
  4. acts synergistically with many other hormones
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15
Q

what is ACTH and how is it synthesized?

A

adrenocorticotropin = ACTH
- derived by proteolytic cleavage of large precursor molecule pro-opiomelanocortin (POMC)
- POMC is a neurotransmitter –> cleaved to smaller peptides that become hormones –> ACTH is one of them –> all the smaller peptides/hormones are called POMC derived peptides OR ACTH related peptides

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16
Q
  • which 2 enzymes break down POMC to make POMC derived peptides?
  • name a few ACTH related peptides
A
  • prohormone convertases –> PC1 and PC2
  • CLIP (corticotropin-liok intermediate lobe peptide)
  • EP (beta-endorphin)
  • LPH (lipotropin)
  • MSH (melanocyte-stimulating) –> many isoforms!
17
Q

what are the genetal functions of
- beta-endorphin
- MSH
- ACTH

A

BETA-ENDORPHIN:
- morphine-like analgesic activity via u-opiod receptor (MOR) –> inhibits pain sensation
MSH (melanocyte stimulating hormones):
- protection against UV damage via melanocortin receptor (MCR1)
ACTH:
- adrenal steroidogenesis via MCR2

18
Q

explain the molecular pathway of tanning

A
  1. UV causes DNA damage –> stimulates local production of MSH by keratinocytes
  2. MSH from keratinocytes stimulate melanocyte to produce melanin (tyrosine derived pigment)
  3. melanin is transported back to keratinocyte to reduce UV damage –> melanin deposited on top of cell and protects DNA in cell
19
Q

significance of which 2 hormones by human pituitary is unclear?
- these 2 hormones produced by POMC neurons and used as _________ in brain

A
  • of MSH/endorphin production –> unclear
  • used as neurotransmitters
20
Q

explain the mechanism of action of ACTH
- what receptor? requires what?
- what pathway
- role?

A
  • ACTH binds to MCR2 (melanocortin receptor 2) in adrenal cortex
  • MCR-accessory protein (MRAP) dimer is needed for ACTH binding to MCR2
  • GPCR pathway –> ACTH activates Gsa protein –> cAMP-PKA pathway
  • PKA activates StAR enzyme –> enhances mobilization of cholesterol into mitochondria
  • then –> increased conversion of cholesterol to pregnenolone via CYP11A1
21
Q
  • which hormone controls ACTH secretion?
  • that hormone is induced by what? (4 ish)
  • that hormone’s action is potentiated by what?
  • ACTH is subject to feedback control by what?
  • ACTH levels: lowest when vs peak when?
A
  • controlled by hypothalamic hormone CRH (corticotropin releasing hormone)
  • CRH is induced by stress (pain, fever, fear, hypoglycemia)
  • potentiated by other hormones like vasopressin
  • subject to feedback control by cortisol (can regulate ACTH)
  • lowest around midnight + early morning peak + decline
22
Q

describe the hypothalamus-pituitary- adrenal axis with relevant hormones

A

stress + other stimuli –> positive effect on hypothalamus –> secretes corticotrophin releasing hormone (CRH) –> positive effect on anterior pituitary –> secretes ACTH –> positive effect in adrenal cortex –> which produces cortisol
- cortisol can have negative feedback on anterior pituitary and hypothalamus

23
Q

what is TSH?
- secreted by which type of cell?
- structure?

A
  • thyrotropin OR thyroid stimulating hormone (TSH)
  • by thyrotrophs
  • similar to all gonadotropins: common a-chain with FSH and LH BUT unique b-chain
  • a and b chain are joined with disulfide bonds + are glycosylated
24
Q

what are the 3 roles of TSH?

A

TSH = thyroid stimulating hormone
1. regulator of thyroid gland. receptor signaling via G-proteins (cAMP)
2. major factor controlling formation of thyroid hormones
3. stimulates metabolism of thyroid follicular cells

25
Q

_____ neurons in which nucleus stimulates TSH release in pituitary
- TSH stimulates synthesis of (2) in which gland?
- these 2 hormones have negative/positive feedback on (2)

A

TRH neurons (thyrotropin releasing hormone) in PVN nucleus stimulates TSH release in pituitary
- TSH stimulates synthesis of T3 and T4 in thyroid gland
- T3 and T4 have negative feedback on thyrotrophs and TRH neurons

26
Q
  • which (3) stimulate TRH neurons?
  • which (1) inhibits TRH neurons?
  • which nucleus integrates all these signals?
A
  • CRH (corticotropin releasing hormone), POMC neurons and temperature sensory inputs stimulate TRH neurons
  • NPY neurons inhibits TRH neurons
  • PVN nucleus!
27
Q

hypothalamic pituitary target organ axes:
- name the releasing factors, the cells that synthesize the hormone, the target organ, the target hormone and target action
1. ACTH
2. TSH
3. LH/FSH
4. GH
5. PRL

A
  1. ACTH:
    - CRH –> corticotroph
    - adrenal glands –> cortisol –> cell homeostatis and function
  2. TSH:
    - somatostatin + TRH –> thyrotroph
    - thyroid gland –> T3 and T4 –> thermogenesis + protein synthesis
  3. LH/FSH:
    - GnRH –> gonadotrophs
    - ovaries –> estradiol + progesterone –> ovulation
    - testes –> testosterone + inhibin –> spermatogenesis
  4. GH:
    - GHRH + somatostatin –> somatotroph
    - liver –> IGF1
    - chondrocytes –> linear and organ growth
  5. PRL:
    - dopamine –> lactotrophs
    - mammary gland –> lactation
28
Q

name the 6 main hormones produced by anterior pituitary gland?
- which one are positively regulated vs which one are negatively regulated?
- the hormones all have negative feedback on (2)

A
  • ACTH: adrenocorticotropin hormone
  • TSH: thyroid stimulating hormone
  • LH: luteinizing hormone
  • FSH: follicle stimulating hormone
  • GH: growth hormone
  • PRL: prolactin
    *ACTH, TSH, LH/FSH and GH are positively regulated
    *PRL and GH are negatively regulated
  • all have neg feedback on pituitary cell and hypothalamus (except prolactin