96. Mammary gland development, lactogenesis

Question 1

Phases of mammary gland development

Answer 1

Mammogenesis • development of the gland Lactogenesis • milk synthesis, milk secretion Galactopoesis • maintenance of milk production Ejection • milk let down Involution • regressive transformation of the gland

Question 2

Mammogenesis

Answer 2

Mammogenesis: development of the mammary gland • Mammary development begins when the animal is an early fetus and proceeds beyond initiation of lactation. • The mammary gland is one of a few tissues in mammals, which can repeatedly undergo growth, functional differentiation, and regression.

Question 3

4 stages of mammogenesis:

Answer 3

1. Development before birth 2. Development from birth to pregnancy 3. Development during pregnancy 4. Development during lactation

Question 4

1. Development before birth:

Answer 4

• influenced by endocrinological mechanisms during early embryonal phase. • Androgens (testosterone, etc.) inhibit the process in male fetuses, which will regulate normal mammogenesis in females around puberty. • (Administering androgens to females during early embryonic phase will lead to the lack of mammogenesis at puberty.)

Question 5

2.Development after birth until first pregnancy:

Answer 5

Stages: 1.Isometric growth • mammary growth rate is similar to the body’s • Cow: during 2 - 3 months after birth • mostly fat pad and connective tissue growth. 2.Allometric growth • mammary growth rate is 3.5times higher than the body’s • Itbeginsjustpriortothefirstestruscycle.Lastsfor2-3 months following puberty (cow) • Mostlyductulargrowth. 3.Isometric growth • mammary growth rate is similar to the body’s • Cow:12-15months(untilconception) • furtherductulargrowth. 324

Question 6

3..During the period of pregnancy:

Answer 6

Further lobulo-alveolar development happens also due to endocrinological effects • PRL, Glucocorticoids, Placenta lactogen • Local factors are also playing important role (IGF, EGF, etc.)

Question 7

4. During lactation:

Answer 7

 Further alveo/lobular growth until peak lactation, then regression happens.  Mammary epithelial cells begin to secrete  During dry period: • Secretory cells go through on regression (involution), preparation for the next lactation phase. During Lactation • Continuous growth until peak-lactation. • Milk production is related to the number of secretory cells and secretory activity. • During lactation the number of dying cells is higher than the number of growing cells. • Mammary gland has more secretory cells at the beginning of lactation than at the end of lactation. -During dry period: • Secretory cells degenerate (involution) to prepare for the next lactation.

Question 8

Hormonal effects in mammogenesis (GH, Glucocorticoids)

Answer 8

Growth hormone • Development of parenchyma, expression of epithel receptors.  Glucocorticoids: • Important in the development of ducts + in the growth of lobulo-alveolar structure (jointly with GH,PRL, E2, P4)

Question 9

Hormonal effects in mammogenesis (Estrogen,progesterone)

Answer 9

Estrogen: • significant species differences • Stimulate development of parenchyma (it is a must in cow; but not essential in sheep (ie: ovaryectomy (ovx) will not inhibit the development). IGF is also important, as a transmitter of effect.  Progesterone: • Stimulating lobulo-alveolar development, especially during the later phase of pregnancy (beyond, it is the inhibitor of lactogenesis)

Question 10

Hormonal effects in mammogenesis (Prolactin, placenta lactogen,lacal factors)

Answer 10

Prolactin (PRL): • species differences • It has permissive effect on steroids in cow,(an essential factor of mammogenesis in rodents) Placenta lactogen: • GH- and PRL-like effect, influence the size (body mass) of calf, as well as the would be milking capacity. Local factors: • i.e. IGF is absolutely necessary for E2 & GH in order to influence mammary gland development. • IGF generally stimulate cell growth, cell differentiation, maintains cell functions, prevents from apoptosis.

Question 11

Lactogenesis

Answer 11

Initiation of lactation is a series of cellular changes whereby mammary epithelial cells are converted from a non-secretory state to a secretory state. This process is normally associated with the end of pregnancy and around the time of parturition. Two-stages • Stage I: Cytological and enzymatic differentiation of the epithelial cells. • Stage II: Intensive secretion of milk.

Question 12

Lactogenesis; Stage I:

Answer 12

Cytological and enzymatic differentiation of alveolar epithelial cells • very limited milk synthesis and secretion just before parturition • specific milk components (e.g. fat droplets and proteins) make their first appearance in the mammary gland. • Formation of colostrum (and immunoglobulin uptake).  P4 + E2 inhibit the real milk production in Phase I.  The few drops of milk before parturition is also called pre-colostrum • Lactose synthesis does not begin until stage II of lactogenesis.  Stage I of lactogenesis may thus be characterized as due to gradual chemical and morphological changes (such as closure of tight junctions), and

Question 13

Lactogenesis; Stage II:

Answer 13

Copious secretion of all milk components • Stage 2 of lactogenesis is usually shorter than stage 1  In the cow this begins about 0-4 days before parturition and extends through a few days postpartum. • Copious milk secretion begins when the inhibitory effects of progesterone on lactogenesis decreases and the stimulation by the very high blood concentrations of prolactin and glucocorticoids (associated with parturition) occur. • Colostrum and then milk synthesis and secretion occur during Lactogenesis II stage II as the result of abrupt cardiovascular, metabolic and secretory changes

Question 14

Hormonal effects in lactogenesis

Answer 14

 Progesterone  Prolaktin  Glucocorticoids  Estrogen  PGF2alpha

Question 15

Hormonal effects in lactogenesis  Progesterone:

Answer 15

antilactogenic • Mechanism of inhibition of lactogenesis: Inhibits synthesis of α-lactalbumin and casein. Decreases the ability of prolactin to induce protein synthesis Competes with glucocorticoids for binding receptors Reduces synergism between prolactin and glucocorticoids.

Question 16

Hormonal effects in lactogenesis  Prolactin:

Answer 16

• Lactogenic • Both the availability and the responsiveness of PRL receptors in the mammary gland are important for lactogenesis. • PRL increases milk protein synthesis. • Controls expression of genes necessary for casein synthesis. • High PRL level is a must for all species in order to maintain the permanent milk production except the cow, where milk production can be maintained even if PRL decreases (GH takes over the role) 339

Question 17

Hormonal effects in lactogenesis  Glucocorticoids:

Answer 17

• lactogenic hormones. • They induce differentiation of rough endoplasmic reticulum and Golgi apparatus. • The differentiation is necessary for prolactin induced protein synthesis. • There is a synergy between prolactin and glucocorticoids for lactogenesis.

Question 18

Hormonal effects in lactogenesis  Estrogen:

Answer 18

 Estrogen: • (Indirect) lactogenic hormone • Increases secretion of PRL and other lactogenic hormones from the pituitary gland. • Increases the number of PRL-Receptors in the mammary cells. • Stimulates synthesis of casein and alfa- lactalbumin.

Question 19

Hormonal effects in lactogenesis Local factors in lactogenesis • PGF2α

Answer 19

produced by uterus and mammary gland. Inhibits the milk secretion, therefore it has to be inactivated/or eliminated at parturition. PGF2a is further reduced during suckling. In case the number of newborns are lower than the active glands, then the inactive glands are going through on regression due to the inhibitory effect of PGF2a. Suckling, on the other hand, further stimulates the secretion of lactogenic hormones.

Question 20

Lactose in lactogenesis

Answer 20

 Decreasing P4 and increasing glucocortiociods and PRL secretions initiate the synthesis of α-lactalbumin. • α-lactalbumin interacts with galactosyltransferase in the Golgi apparatus in synthesis of lactose.  Synthesis of lactose osmotically draws water into the Golgi and secretory vesicles. This process allows for secretion of large amounts of milk and is the most obvious manifestation of stage 2 of lactogenesis.  At the same time, synthesis of other milk components is increased. (The content of α- lactalbumin in the mammary tissue is an indicator of lactogenesis).

Question 21

Role of colostrum

Answer 21

Colostrum (and precolostrum) is produced in lactogenesis phase  Role: • Maternal immunity • Nutrient role • Laxative effect

Question 22

1. Maternal Immunity

Answer 22

 The colostrum is produced during lactogenesis stage 2  It has several functions: • Immunoglobulins are transmitted from the maternal body into the fetus (passive immunity). Several antigens (bacteria, viruses and other pathogens) are specific to a certain herd. The newborn has to be raised in the same environment where the mother was exposed to these antigen stimulations (this way it can be avoided that the infant meets such pathogens against which it is not have immune globulins).  There are two ways of getting immunoglobulins into the fetus: • Transplacental transport: dependent on the number of placenta layers, so it is typical of primates and rodents. • Absorptionthroughthedigestivetract.

Question 23

2. Nutrient Role:

Answer 23

• Compared to the milk, colostrum contains more protein, lipids and minerals; and less lactose (except in mare). • Water, fat soluble vitamins (mainly vitamin A, the transport of which through the placenta is limited) and essential amino acids are also present in a significant amount.

Question 24

3. The laxative effect

Answer 24

is caused by the mucus-like components, which cover the wall of the intestines and help the passage of nutrients. Mucous components in the colostrum also help to remove the meconium (embryonal faeces).

Question 25

Galactopoeisis

Answer 25

Maintenance of lactation once lactation has been established. It is regulated: • galactopoietic hormones • local mammary factors Milk removal: Without frequent emptying of the mammary gland, milk synthesis will not persist in spite of adequate hormonal status

Question 26

Hormonal factors (galactopoiesis)

Answer 26

The hormonal complex – maintaining galactopoesis - includes prolactin, growth hormones, thyroid hormones, and glucocorticoids. Prolactin is the most important hormone of galactopoesis • (except Cow, where GH takes over the role) • Due to the suckling stimulus the secretion of dopamine decreases (which is a PRL secretion inhibitor) while the secretion of VIP (stimulating PRL secretion) increases altogether elevating the PRL secretion.

Question 27

Hormonal factors (galactopoiesis)

Answer 27

Local factors • The nursing or milking stimulus triggers release of galactopoietic hormones (especially prolactin) which may stimulate the next round of secretory activity. • If milk removal is not maintained there is no stimulation for prolactin release. Acute accumulation of milk in the gland causes an increase in intra-mammary pressure. This increase in pressure activates the sympathetic nerves in the gland, which acts peripherally to decrease mammary blood flow. As mammary blood flow declines the availability of hormones (e.g. prolactin) and nutrients to the gland is reduced. If milk is not removed, the Feedback Inhibitor of Lactation (FIL) accumulates in the alveolar lumen, inhibiting further synthesis and secretion of milk

Question 28

Milk ejection

Answer 28

The transfer of milk from the lobulo-alveolar spaces into the ducts as a result of the contraction of the myoepithelial cell surrounding each alveolus. Milk ejection is a two-component neuro- hormonal reflex: • Neural component = afferent component • Hormonal component = efferent component

Question 29

Oxytocin

Answer 29

 Oxytocin can be released without mechanical stimulation of the udder. Visual and auditory signals can result in milk let down.  Oxytocin concentrations peak with 1-2 minutes following stimulation.  Oxytocin has a short half-life in blood (0.6 – 3.6 min).  Sensitivity of the neuro-hormonal reflex declines as lactation progresses.  Amount of oxytocin released declines as lactation progresses. 357

Question 30

Mammogenesis: (picture)

Answer 30

Question 31

Inhibition of milk ejection : (picture)

Answer 31

Question 32

Lactationg cycle of cows (picture)

Answer 32

Question 33

Milk production of the cow (picture)

Answer 33

Milk production of the cow is extending to a 305 day period (this is the lactation period). Milk production depends on the genetic background and environmental conditions, thus it is different throughout the whole world. The “highly productive” Holstein-Freezian cows produce an average of 8000-10000 l in one lactational period. Records of 15 000 l in one lactational period or above are also registered.

 At the beginning of lactation milk production increases suddenly.

 At this time the rumen is not yet adapted to the digestion of bigger amounts of nutrients, thus the need of energy is higher than the energy supply. By this

moment the cow is in a negative energy balance (its

body weight decreases).

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 The cattle reaches the peak of the lactation approximately on the 3rd - 4th week after calving.

 At this time the energy balance is still negative.

 After 4 weeks milk production slowly decreases.

 The energy balance is zero at this time (according to the ruminal adaptation), then energy balance turns positive.

 Just after the cattle went through a negative energy balance, she can be fertilized artificially (2-3 months of milking).

 Note: fertilization is only possible after refilling the energy stores (lack of energy inhibits pregnancy).

 When the lactation decreases to a low level, one stops milking the cow which becomes dry (conventionally at the 305th day of the lactation). During this period the accumulating milk creates a rise of the pressure in the mammary gland, thus secretion stops. In the dry standing cow the parenchyma atrophies (involution, 40 days). The lactation begins with the next pregnancy.