Breast Development and Physiology

Question 1

Basic physiology of breast

Answer 1

• 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

Question 2

Cell types lining ducts and lobules

Answer 2

• 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

Question 3

Non-lactating breast: composition of tissue

Answer 3

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

Question 4

Non-lactating breast: cellular characteristics

Answer 4

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

Question 5

Non-lactating breast: functional organization

Answer 5

• TDLUs that change throughout cycle with progesterone

Question 6

Lactating breast: composition of tissue

Answer 6

• 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

Question 7

Lactating breast: cellular characteristics

Answer 7

• Glandular architecture increased
• Lobule proliferation
• Adipose tissue decreases

Question 8

Lactating breast: functional organization

Question 9

Stages of breast development

Answer 9

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

Question 10

Embryonic development: defining feature and key hormones

Answer 10

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

Question 11

Embryonic development: mechanism

Answer 11

• 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)

Question 12

Neonatal development: defining feature and key hormones

Answer 12

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

Question 13

Neonatal development: mechanism

Answer 13

• Maternal hormone influence at parturition

Question 14

Development during infancy: defining feature and key hormones

Answer 14

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

Question 15

Development during infancy: mechanism

Answer 15

• 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

Question 16

Development during puberty: defining feature and key hormones

Answer 16

• 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

Question 17

Development during puberty: mechanism

Answer 17

• 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

Question 18

Mature development: defining feature and key hormones

Answer 18

• 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

Question 19

Mature development: mechanism

Answer 19

• TDLU regress at end of luteal phase unless pregnancy occurs

Question 20

Development during pregnancy: defining features and key hormones

Answer 20

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

Question 21

Development during pregnancy: mechanism

Answer 21

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

Question 22

Development during lactation: defining feature and key hormones

Answer 22

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

Question 23

Development during lactation: mechanism

Answer 23

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

Question 24

Hormonal basis of common developmental breast abnormalities

Answer 24

• 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

Question 25

Neural & hormonal mechanisms regulating lactation

Answer 25

• 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

Question 26

Phases of lactation & hormonal control

Answer 26

• 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

Question 27

Feedback loops that control lactation

Answer 27

• 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

Question 28

Cellular pathways involved in milk secretion

Answer 28

• 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

Question 29

Progression of lactation

Answer 29

• 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

Question 30

Physiological factors that affect lactation

Answer 30

• 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