Slide Set 4: Lactogenesis Flashcards
Define Lactogenesis
Ø A series of cellular changes whereby mammary epithelial cells are converted from a non-secretory state to a secretory state.
Ø There is an increase in RNA:DNA ratio (from 1:1 during pregnancy to 2:1 in early lactogenesis)
Lactogenesis consists of two stages:
Stage I:
Cytologic & enzymatic differentiation of the epithelial cell
Stage II:
Copious secretion of milk
When does stage 1 of lactogenesis happen?
- Occurs before parturition (prepartum)
- In cows (9 mon.) 4 month, goats (5 mon), 3 month, rats (3 weeks) 30 h prepartum, women (9 mon) mid. pregnancy
What occurs during lactogenesis stage 1?
- Coincides with colostrun formation and immunoglobulin uptake
- Limited milk synthesis and secretion
- No lactose biosynthesis
Example of enzymatic differentiation in stage 1:
Ø Increased synthesis of enzymes necessary for synthesis of milk components
Ø Increased # of transport systems for milk precursors (e.g. amino acids & glucose)
What are some histological changes that occur in lactogenesis stage 1:
Ø Prominent rough endoplasmic reticulum
Ø Marked increase in the # of mitochondria
Ø Prominent Golgi bodies
Ø Lipid and protein granules accumulate in the lumen
Ø Increase in the size of the alveoli
Ø Closure of tight junctions
What happens during lactogenesis stage 2?
Copious secretion of milk:
Significant increase in mammary blood flow and substrate uptake
In cows, stage 2 of lactogenesis begins _____ and humans _____
pigs & mice _____
0-4 pre-partum and lasts for few days post-partum
2-3 post-partum
at parturition
What initiates lactogenesis stage 2
The pre-partum removal of secretion could initiate lactogenesis II
What are the changes in mammary secretion during lactogenesis?
Lactogenesis I (colostrogenesis) High concentrations of protein, immunoglobulins, Na, Cl Low concentrations of lactose, K, citrate
Lactogenesis II
High concentrations of lactose and K Low concentrations of protein, fat
What are lactogenic hormones?
- Prolactin
- ACTH (glucocorticoids)
- Estrogen
- Absence of progesterone
In most mammals, birth and ______coincide with the withdrawal of progesterone
lactogenesis II
When does the progesterone drop occur in humans?
In humans, the major fall in progesterone occurs after birth (30-40 h after birth)
How is lactogenesis 2 and human baby body weight related?
Human infants have significant fat reserves and slow rate of neonatal growth
How long does the lactogenesis 1 last for?
mid pregnancy to day 2 postpartum
What happens during lactogenesis 1 in hormonal and tissue level in humans
- Differentiation of secretory cells
- Prolactin stimulates mammary epithelial secretory cells
- Progesterone inhibits prolactin secretory activities during late pregnancy
What happens during lactogenesis 1 in hormonal and tissue level in humans?
- Differentiation of secretory cells
- Prolactin stimulates mammary epithelial secretory cells
- Progesterone inhibits prolactin secretory activities during late pregnancy
When does colostrum start forming in humans?
Mother will start making colostrum half way through pregnancy (endocrine control system)
When does lactogenesis 2 occur?
day 2 to day 5 pospartum
What happens during lactogenesis 2 in hormonal and tissue level in humans?
- The delivery of placenta results in sudden drop progesterone levels
- Triggered by rapid drop in mother’s progesterone and high prolactin levels
- Closure of tight junctions in alveolar cells
- Switch from endocrine to autocrine (local) control
What are the hormones involved in lactogenesis 2?
Major hormones: prolactin & glucocorticoids
Other hormones: growth hormones, insulin & thyroxin
Compare baby pigs and human babies in terms of birth weight and lactation
Pigs Ø Born with little body fat Ø Double its birth wt in the 1st week of life Ø Consumes 50-100 ml colostrum within 4 h after birth
Human
Ø Born with significant body fat
Ø May regain birth wt after the 1st week
Ø Consumes 30-40 ml of colostrum during the first 24 h of life
Ø Increase to 500-750 ml/d of milk, 5 days post-partum
How do prolactin and oxytocin control milk secretion/ejection
- Impulses arising in sensory terminals of the nipples (suckling) follow common pathways
- They activate different nuclei in the
hypothalamus
Why can be there a delay in lactation?
- Not all women experience lactogenesis phase II 3-4 post-partum
- Possible reasons: cesarean birth, obesity, placental retention, stress.
How can lactation be inhibited?
- Lactogenesis does not begin in humans until the rapid decrease in estrogen and progesterone 2-3 d post-partum
- Exogenous steroids (combination of estrogen & progesterone) can be used to maintain high circulating levels after or/at delivery
- Both hormones inhibit glucorticoid receptors (inhibit RER formation and protein synthesis)
- Bromocriptine can be used as a medical therapy for milk inhibition
- Highly effective in lowering prolactin concentration post-partum
- Cabergoline (prolactin lowering medication) can be given within 24-h after delivery
- Both medications are no longer recommended (major adverse reactions)
- Supportive measures can be effective: (use of breast binders, tight brassiere, use of ice pack, avoidance of coffee, tea and nipple stimulation)
What are the names of the 2 drugs that can be taken to inhibit lactation or treat hyperprolactinemia?
- Bromocriptine can be used as a medical therapy for milk inhibition
- Highly effective in lowering prolactin concentration post-partum
- Cabergoline (prolactin lowering medication) can be given within 24-h after delivery
What are the mechanical ways of inhibiting lactation?
use of breast binders, tight brassiere, use of ice pack, avoidance of coffee, tea and nipple stimulation
Where is prolactin secreted from?
Secreted by the anterior pituitary gland
What is the role of prolactin in lactogenesis and what is its mechanism of action?
Ø A lactogenic hormone
Ø Binds to prolactin receptors on the mammary epithelial cell
Ø Increases milk protein synthesis
Ø Controls expression of genes necessary for casein
synthesis
Ø Involves in the maturation of Golgi body and appearance of secretory vesicles
What are the roles of glucocorticoids in lactogenesis?
Ø Glucocorticoids (adrenal steroids) are lactogenic
Ø Glucocorticoids induce differentiation of rough
endoplasmic reticulum and tight junctions
Ø The differentiation is necessary for prolactin- induced protein synthesis
Ø Synergism between prolactin & glucocorticoids for lactogenesis
What are the roles of estrogen in lactogenesis?
Ø Lactogenic (indirect effect)
Ø Increase secretion of prolactin and other
lactogenic hormones from pituitary gland
Ø Increases in the # of prolactin receptors in the mammary gland
Ø Stimulate synthesis of casein and a-lactalbumin
Ø Synergetic lactogenic effect with prolactin, glucocorticoids and estrogen
What are the roles of progesterone in lactogenesis?
Ø Progesterone is anti-lactogenic
What are the roles of progesterone in lactogenesis?
Ø Progesterone is anti-lactogenic
TRUE/FALSE
Prolactin is anti-lactogenic in all mammals
FALSE
Progesterone is not anti-lactogenic in marsupials
What are some other lactogenic hormones that are indirectly involved in lactogenesis?
- placental lactogen
- prostaglandin
- insulin
- growth hormone
What are the roles of placental lactogen in lactogenesis?
Found in many (e.g. rats & mice) but not all mammalian species (e.g. rabbits)
Binds to prolactin receptors
What are the roles of prostaglandin in lactogenesis?
- Fatty acids produced by several tissues
- Luteolytic enzyme (lyses corpus luteum and reduces secretion of progesterone)
- Administration during pregnancy lead to abortion and lactogenesis
What are the roles of insulin and growth hormone in lactogenesis?
Ø Insulin & insulin-like growth factor (IGF) may be involved in glucose uptake by the mammary gland (precursor of lactose)
Ø Growth hormone increases the secretion of IGF
What is prolactin’s mechanism of action?
prolactin is a peptide hormone which means it cannot enter the epithelial cell
the binding will trigger a secondary messenger
cyclic amp CAMP
this will synthesize an enzyme called protein kinase. the function of this enzyme is the phosphorylation fo the amino acids - activating protein synthesis
the CAMP will also enter the nucleus of the epithelial cell to synthesize messenger RNA
- differentiation of the organelles
progesterone will inhibit the phosphorylation
How does accumulation of milk in the mammary gland act on the hormonal pathways?
accumulation of milk will inhibit lactogenesis 2
this is an example of what happens to the dairy cow
the second activity will stimulate the brain and initiate the prolactin synthesis by inhibiting dopamine synthesis
accumulation of milk will inhibit milk production there is an antilactogenic component found in the dairy cows thats called dihydroxyketoprostaglandinF (DHKPGF)
prostaglandin is synthesized in the mammary gland that inhibits milk production
DHKPGF is inactive and this will be activated by PGF
the removal of both components will activate the milk secretion but the most important thing is the milk removal
What does DHKPGF stand for? What is its function?
dihydroxyketoprostaglandinF
antilactogenic component found in the dairy cows
prostaglandin is synthesized in the mammary gland that inhibits milk production
DHKPGF is inactive and this will be activated by PGF
the removal of both components will activate the milk secretion but the most important thing is the milk removal
What is the role of lactose in lactogenesis?
Ø There is little synthesis of a-lactalbumin during stage I of lactogenesis.
Ø High concentrations of prolactin, glucocorticoids & low concentration of progesterone initiates synthesis of a- lactalbumin.
Ø a-lactalbumin important for lactose synthesis (very important for milk production)
TRUE/FALSE
Only the mammary gland can synthesize alpha lactalbumin
TRUE
This is the reason why lactose is only found in milk
How is milk protein synthesis controlled?
prolactin and glucocorticoids will synthesize 2 milk prtoeins: casein and other whey rpotein
in golgi the lactose will be synthesized by lactose synethase and that will draw water inside the golgi body
lactose is the main osmole of the milk
high concentration of lactose inside the mamma gland will draw water
the more lactose = the more water in the milk and that deteremines the quality of the milk
high volume and more milk
it is extremenly impo to sytnehsize alpha lactalbumin
determeines the volume of milk
animals that have very little amuont of milk haee very low lactose
What is the main osmole of milk?
lactose
high concentration of lactose will draw water inside the mammary gland
What molecule is extremely important in synthesizing lactose
alpha lactalbumin
What are the effects of hypophysectomy & hormonal administration on milk yield of goats?
the role of Thyroid Gland
they are synthesize inside the pit gland so if you remove it by hypophysectomy
- this will immediately inhibit lactation
- inject animals with glucocorticoids the milk production was not disrupted
- bovine growth hormones were added but it didn’t restore completely
What are the enzyme changes in lactogenesis?
For many mammals, removal of progesterone is a prerequisite for lactogenic enzyme activities
Ø The significant increase in lactogenic enzymes occurs at 1- parturition or 2- after parturition
Ø Example for group 1 is lactose synthetase
Ø Examples for group 2 are enzymes associated with
fatty acid synthesis (e.g. acetyl CoA carboxylase)
Ø Milk removal might be necessary for activities of other enzymes involved in lactogenesis
What is a group 1 enzyme and what is its function?
lactose synthetase synthesizes lactose
What is a group 2 enzyme and what is its function?
fatty acid synthesis (e.g. acetyl CoA carboxylase) synthesizes the fat components of milk
How can you induce lactogenesis in non-pregnant women?
ØTwo phases
1- Stimulation of mamogenesis by injecting high levels of estrogen & progesterone
2-1 Injection of prolactin
2-2 Injection of glucocorticoids
~ 3 weeks of treatments
Ø Not effective for all cows
Ø Milk yield is lower than from cows giving birth
