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Flashcards in Breast Development and Physiology Deck (30)
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1

Basic physiology of breast

  • Breast contains many lobes
  • Lobes contain lobules
  • Lobules contain segmental lobules
  • Segmental lobule contains many terminal ductal lobular units (TDLU)
    • TDLU composed of acini + terminal duct
  • Terminal ducts drain into segmental ducts
  • Major ducts drain into lactiferous sinuses
  • Lactiferous sinuses drain into ducts in the nipple
  • Usually 9-10 ducts in average female

2

Cell types lining ducts and lobules

  • Contractile myoepithelial cells
    • Surround glandular components
    • Assist in milk ejection during lactation
    • Contain myofilaments on basement membrane
  • Luminal epithelial cells
    • Overlay MECs
    • Only cells capable of producing milk
  • Whole unit encased in adipose tissue

3

Non-lactating breast: composition of tissue

  • Glandular (20%)
  • Subcutaneous fat (24%)
  • Retro fat (7%)
  • Intragland fat (49%)

4

Non-lactating breast: cellular characteristics

  • Myoepithelial cells
  • Luminal epithelial cells
  • Surrounded by increase in adipose fat

5

Non-lactating breast: functional organization

  • TDLUs that change throughout cycle with progesterone

6

Lactating breast: composition of tissue

  • Composition (left, right)
    • Glandular (62%, 64%)
    • Subcutaneous fat (24%, 22%)
    • Retro fat (7%, 9%)
    • Intragland fat (7%, 6%)
  • Fat is depleted from cells --> energy for milk production
    • Synergistic 

7

Lactating breast: cellular characteristics

  • Glandular architecture increased
  • Lobule proliferation
  • Adipose tissue decreases

8

Lactating breast: functional organization

9

Stages of breast development 

  • Embryonic development
  • Neonatal
  • Infancy
  • Puberty
  • Mature
  • Pregnancy
  • Lactation

10

Embryonic development: defining feature and key hormones

  • Defining feature
    • Nipple morphogenesis
    • Developed by invagination of ectoderm into mesenchyme
  • Key hormones
    • Parathyroid hormone related protein (PTHrP)

11

Embryonic development: mechanism

  • PTHrP (secreted by epithelial cells) --> condensation of mesenchyme
  • Mammary mesenchyme:
    • Maintains mammary fate of epithelial cells
    • Triggers morphogenesis of mammary gland
    • Stimulates nipple formation
  • In absence of PTHrP signaling:
    • Dermal mesenchyme fails to differentiate to mammary mesenchyme
    • Epithelial cells revert to epidermal fate 
    • Blomstrands chondroplasia (amastia - no gland present)

12

Neonatal development: defining feature and key hormones

  • Defining feature
    • Induction of temporary milk secretion in both female and male neonates (witches milk)
  • Key hormones
    • Increased prolactin
    • Decreased progesterone

13

Neonatal development: mechanism

  • Maternal hormone influence at parturition

14

Development during infancy: defining feature and key hormones

  • Defining feature
    • Stimulation of branching and lobule formation
  • Key hormone
    • GnRH-driven increase in progesterone

15

Development during infancy: mechanism

  • Progesterone receptors present in glandular elements for up to 3 months after birth
  • Commences ~11 years old in girls
    • Similar to when growth spurt transpires

16

Development during puberty: defining feature and key hormones

  • Defining feature
    • Ductal morphogenesis
    • Glandular expansion and maturation
    • Increase in fat accumulation
  • Key hormones
    • Estrogen --> growth of ducts
    • Progesterone --> formation of alveoli
    • Estradiol - principal regulator
      • Required for initial outgrowth of gland
    • Estrogen + GH
      • Stabilize at end of puberty - no longer 'pressure' to alter structure

17

Development during puberty: mechanism

  • Increased estrogen + increased GH --> increased stromal IGF-1 production --> elongation and branching of ductal network
  • Progesterone secretion during luteal phase of menstrual cycle --> side branching and TDLU development

18

Mature development: defining feature and key hormones

  • Defining feature
    • Partial functional differentiation
    • Expansion and regression --> stimulates stem cells to grow
  • Key hormones
    • Increased progesterone = increased TDLU
    • Decreased progesterone = decreased TDLU
    • Changes throughout cycle

19

Mature development: mechanism

  • TDLU regress at end of luteal phase unless pregnancy occurs

20

Development during pregnancy: defining features and key hormones

  • Defining feature
    • Secretory differentiation
      • Extensive lobule formation
      • Differentiation of alveolar cells
      • Minimal or no milk secretion
  • Ovaries and placenta
    • Estrogen
    • Progesterone
  • Pituitary
    • Prolactin

21

Development during pregnancy: mechanism

  • Secretory differentiation / Lactogenesis I:
    • Initiation of milk protein expression due to prolactin 
    • Development of secretory capacity due to progestin
  • Lactogenesis II:
    • Copious milk production

22

Development during lactation: defining feature and key hormones

  • Defining feature
    • Copious milk secretion
    • Coordinated production of diverse milk components
    • Increased density of glandular units
  • Key hormones
    • Pituitary - prolactin, oxytocin

23

Development during lactation: mechanism

  • Milk secretion initiated by decrease in progesterone when placenta is delivered
  • Increased prolactin maintains milk synthesis and secretion

24

Hormonal basis of common developmental breast abnormalities

  • Pituitary defects
    • Defects in mammary gland formation
    • Tumor --> increase PRL --> galactorrhea
    • Decrease in FSH/LH --> decreased estrogen/progestin --> abnormal function and development
  • Girls with impaired gonadal maturation in puberty
    • Decreased estrogen --> decreased development
    • Treat with estrogen
  • Boys with breast development who are obsese
    • Decreased testosterone + increased estrogen
    • Puberty: increased testosterone --> galactorrhea regresses

25

Neural & hormonal mechanisms regulating lactation

  • Copious milk secretion - coordinated and regulated by pituitary hormones
    • Prolactin
    • Oxytocin
  • Production of PRL/oxytocin require "suckling stimulus"
  • Progesterone keeps secretion in check
  • Lactation activates PRL, oxytocin production
    • PRL partially regulated by milk removal

26

Phases of lactation & hormonal control

  • Initiation phase
    • Decreased progesterone due to placenta removal
    • If placenta left behind - milk might not come in
  • Maintenance of milk synthesis 
    • Prolactin
  • Secretion phase
    • Prolactin, milk removal
  • Ejection phase
    • Oxytocin, suckling

27

Feedback loops that control lactation

  • Prolactin
    • Suckling inhibits DA release --> enabling pulsatile PRL release --> stimulates milk product synthesis and secretion
    • Prolactin normally under tonic control of DA
    • Bromocriptine inhibits lactation
  • Oxytocin
    • Suckling stimulates synthesis/release of oxytocin from posterior pituitary
    • Causes contraction of myoepithelial cells of gland and letdown response

28

Cellular pathways involved in milk secretion

  • Classical pathway
    • Secretory vesicles fuse with apical membrane
  • Apocrine secretion
    • Lipids get engulfed by apical membrane, then secreted into milk 
  • Transcytosis
    • Endocytosis at basolateral membrane --> exocytosis at apical membrane
  • Paracellular transport
    • Between 2 cells

29

Progression of lactation

  • Colostrum important for immunity
  • Just after birth:
    • Epithelial tight junctions open
    • Milk at this point = colostrum
      • Rich in immunoglobulins, lactoferrin
  • Around day 2:
    • Decreased progesterone --> closure of tight junctions
      • Increased volume of milk
      • Decrease in IgA from maternal circulation
      • Decrease in lactoferrin from maternal circulation
      • Milk removal, suckling, increase in volume important for closing tight junction
  • Overall: breast milk changes from having immune function to nutritional function
    • Volume increases over time
    • Nutritional, ion, oligosaccharide content increases over time
    • Secretory processes increase coordinately with milk volume post partum decrease

30

Physiological factors that affect lactation

  • Breastfeeding = conditioned/psychological response
    • Milk letdown can occur when one hears a baby cry
    • Not only suckling can initiate --> also a psychogenic component
  • Anxiety/stress
    • Stress inhibits oxytocin production
    • Delayed lactation initiation
    • Enter the lactation consultant
  • Pituitary disorders/damage - can cause issues with prolactin and oxytocin
  • Excessive weight --> weight beyond IOM recommendations
    • Includes obese women, normal weight women who gain too much during pregnancy
    • Unable to initiate breast feeding
    • Unresponsive to suckling stimulus
    • Decrease in duration of breastfeeding
    • Decrease in ability to mobilize energy for milk production
    • Similar problems can occur in underweight women as well