Breast Development and Physiology Flashcards by Justine Ahle

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

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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

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Non-lactating breast: composition of tissue

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

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Non-lactating breast: cellular characteristics

Myoepithelial cells
Luminal epithelial cells
Surrounded by increase in adipose fat

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Non-lactating breast: functional organization

TDLUs that change throughout cycle with progesterone

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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

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Lactating breast: cellular characteristics

Glandular architecture increased
Lobule proliferation
Adipose tissue decreases

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Lactating breast: functional organization

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Stages of breast development

Embryonic development
Neonatal
Infancy
Puberty
Mature
Pregnancy
Lactation

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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)

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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)

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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

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Neonatal development: mechanism

Maternal hormone influence at parturition

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Development during infancy: defining feature and key hormones

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

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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

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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

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

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

Mature development: mechanism

TDLU regress at end of luteal phase unless pregnancy occurs

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

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

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

Development during lactation: mechanism

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

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

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

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

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

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

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

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