Monday, March 12, 2012 CC-BY-NC
Prolactin's Biological Functions

Maintainer: admin

1Prolactin (PRL) Basics


  • there are structural variants. heterogeniety
  • residual modification
    • usually decrease activitity of PRL
    • glycosylated, phosphorylated, sulfated PRL
    • post translational
    • modification on residue differs among species
  • cleaved forms:
    • 16kDa and 8kDa (loop is destroyed)
      • cathepsin D-like protease does this.
      • it's a antiangeogenic factor
    • 22kDa. C-terminal s-s loop removed
      • by kallikren, a trypsin like serine protease
      • not well studied
  • native PRL: has a loop formed by disulfide bridge.

1.2synthesis and secretion

  • produced by lactotrophs:
    • comprise 20-50% of anterior pituitary cells, depending on the physiological state
      • 50% when it's lactation phase for the organism
    • also the last anterior pituitary cells to differenaite
    • adulthood prolactinomas: robust proliferative response.
      • no other pituitary adenomas produce the same effect
    • regulated by Pit1 (a transcription factor)
  • PRL are also expressed in extrapituitary (periphery) sites
    • ex: brain, thymus, lymph node, endometrium, mammary glands
    • they act as local growth factor and hormone.
    • account for ~20% of prolactin production


  • tonically inhibited by dopamine coming from hypothalamus

1.3.1Hypothaalmus-pituitary axis

  • hypothalamus controls ant. pituitary
    • hypophyseal portal artery branches into ME by primary plexus where many neurotransmitter/neuro peptides are released into.
    • secondary plexus then dumps into secondary plexus
    • tight control of hypothalamus over pitutiary because only a small amount needs to be secreted to affect pituiary (direct access instead of being diluted by systemic blood)
  • PRL is tonically inhibited by hypothalamus. Evidences:
    • PRL level increase when pituitary is detached and placed somewhere else like on top of adrenal gland.
    • stalk transection also leads to increase in PRL
    • lesioning of the ME also increases PRL.
    • (basically any interruption and disconnection)
    • reglulated by dopamine (inhibitor)


  • dopamin is converted from tyrosine by tyrosine hydroxylase and DOPA decarboxylase
    • rate-limiting enzyme: tyrosine hydroxylase
  • DA-nergic neurons:
    • TIDA : tuberoinfundibular dopaminergic neurons
      • to ME when primary pelxus is
    • THDA and DOPA: to short portal vessel
  • lactotrophs have DA receptors
    • in portal blood 80% of receptors are occupied
    • degree of inhibition of PRL release coorelates with degree of receptor occupancy
  • DA agonists make PRL decrease. DA antagonists make PRL increase.
  • suckling leads to decrease in DA and consequently increase in PRL

1.3.3prolactin short feedback

  • there's a negative feedback loop at ME or CNS.
    • prlactin gains access to CSF
    • stimulation on DA neruons, which have PRLR (prolactin receptor)
    • PRLR K mice have 30-100 fold increase in PRL.
  • feedback loop dimishes during lactation.


  • Suckling leads to :
    • increase in secretion of opiod peptide, endorphin in arcuate nucleus --> suppression of TIDA
    • dimished feedback control
    • increase in PRL release factors in hypothalamus
      • TRH, VIP, oxytocin, neuropeptide Y, neurotensin, histamine
    • release of adrenocorticotropin --> more glucocorticoids released into the blood.
    • increase in number of lactotrophs (~50% of ant. pitutiary cells)
    • suppression of tyrosine hydorxylase (the rate limiting enzyme of DA synthesis)


  • (has ~85 functions) Main outline:


  • lactation
    • alveolar growth
    • milk protein synthesis
  • luteotrophic function
    • increase progesterone synthesis
      • also inhibit progesterone degradation
    • potentiate sterodogenic effects of LH (lutenizing hormone)
    • PRLR KO : infertile, lack normal luteal function, decrease ovulation, aberrant oogenesis, implantation failure
      • restored by giving progesterone
  • parental behavior
    • nest building, nursing, etc.
    • PRLR KO female mice can't recognize pups (so PRL also has effects on nervous system)


  • immune function
    • restores thymic function in PRL-deficient dwardf mice (or Pit1-KO mice)
    • B and T cells have PRLR and PRL, suggesting autocrine and paracine functions of PRL
    • PRL potentiates IL2 mitogenic effects (mitosis-promoting) in T cells
    • PRL has overlapping functions with some pathways (may share signaling pathway with cytokines) because PRL KO mice do okay with their immune system.
  • osmoregulation
    • stimualtes solute movement for lactation
      • uptake of amino acid and glucose by mammary epithelial cells
      • also promote sodium, potassium and water retention by acting on kidney.

3Mechanism of Functions

3.1Hormonal control of Lactogenesis

  • estrogens act on lactotrophs to make them secrete PRL.
  • Progesterone inhibits lactogenesis (by inhibiting PRL)
    • after baby is born, progesterone level drops sharply
    • this sharp decrease in progesterone accounts for initiation of lactation
  • glucocorticoids or adrenocorticoropin (adrenal hormones) with PRL stimulates lactogenesis (synergistic)
    • right after baby is born there's a sharp increase of glucocorticoids
  • prolactin:
    • hypophysectomized mice don't make milk during pregnancy.
      • treated with PRL will restore functions
    • blocking of PRL surge before partuition by Da agonists inhibit lactogenesis
    • insulin, prolactin, hydrocortisol in combination induce cells to make milk proteins

3.2Mammaroy Gland Development

  • structure of alveolar:
    • lumen surrounded by a layer of epithelial cells, which secrete milk into the lumen
    • myoepithelai cells: muscles cells surrounded epithelial layer. contract upon oxytoxin stimulation -->milk ejection
  • prolactin
    • stimulates differentiation of termianl end buds in virgin state
      • acting through progesterone, which promotes differentiation
    • growth and differentiation of alveoli in pregnancy
  • during lactation, major cell type :alveoli
  • during involution, build up of milk in the gland initiates apoptosis of alveoli structure, which goes back to virgin-like state.

  • prolactin KO and PRLR KO have little terminal end buds

    • adding prolactin wouldn't restore structure in PRLP KO
      • because terminal end bud differentiation depends on indirect effect of PRL via progesterone.
  • PRLR partial KO have little alveolar growth/differentiation
    • halfploid insufficiency
    • therefore PRL won't restore the function. you need the receptor!

3.3Receptor Signaling Mechanism

  • PRLR is a Class I cytokine receptor
  • prolactin receptor have many homologies with receptors in this family : like GH receptor, IL2 receptor, etc
    • homologies include : Box1/2 (cytoplasm domain), disulfide bond, etc
    • act with JAK kinase, which interact with Box1/2 domains
  • STAT:
    • STAT is downstream of JAK. bind to JAK via SH2 domain
    • dimerize upon activation by JAK and go to nucleus to activate transcription via their TA domain (transcription activation)
    • There are 7 of them. Two of them are inhibitory (STAT4_beta and STAT1_beta)
      • inhibit action when dimerize with other STAT
  • activation mechanisms
    • JAK2 constitutively bind with PRLR via Box1.
    • activated receptor goes through confirmation change. they dimerzie and allow JAK to phosphorylate (thereby activate) each other
    • activated JAK2 recruits STAT and activate them
    • STAT dimerize and go into nucleus
    • STATs are also target of other pathways
  • experiment show tha tEGF don't activate JAK2 like PRL do
    • STAT5a is also not as upregulated when EGF is added.
  • JAK KO shows no terminal bud differentiation and has little alveolar structure.
  • Prolactin mainly activates JAK@ and STAT5, esp. in mammary gland. but cytokine can activate some pathways of prolactin (-->signal complexity&redundancy)
  • gain of function of JAK (with mutation at JH2) leads to lukemia : myeloproliferative disorders
  • STAT protein is also targets fr many other tyrosine kinase:
    • ex: target for SAR kinase, which plays a big role in tumoergenesis and metatesis as well.

4Breast Cancer and Prolactin

  • statistics show that women who breast feed have less chance of getting breast cancer
    • mostly those who breast feed for longer than 6 months get this protection of PRL.
  • therefore, even though prolactin is a growth factor for mammary cells, it promotes differentiation --> anticancer/antiproliferative
    • highly differentiated and polarized cells are less likely to turn into cancer cells
    • prolactin makes epithelial cells highly diffentiate (to make milk proteins) and polarized (to transport milk proteins to lumen)
      • factor that induces polarization is cancer-suppressing
      • polariztion comes with tight junction and adhesion molecules
        • PRL KO mice's mammary gland shows little staining of tight junction
        • blocking of JAK2 leads to loose structure. cells become more flat and loosely attached to each other due to less expression of adhesion molecule (Ecad)
  • therefore, dual role of PRL in breast carcinogenesis:
    • growth and differentiation
    • suppressor/anti-metastasis activity