Biology of Lactation 342-460B

Lactogenesis

Lactogenesis
Definition of Lactogenesis (initiation of lactation)
is a series of cellular changes whereby mammary epithelial cells are converted from a
nonsecretory state to a secretory state. This process is normally associated with the end of
pregnancy and around the time of parturition. Lactogenesis is a two-stage process.
Biochemical changes occur in the mammary gland as it turns from inactive to an active
stage. There is a marked increase in the RNA level of the epithelial cells. This causes the
RNA:DNA ratio, which is less than 1 during late pregnancy, to over 2:1 during
secretion(RNA is an index of protein secretion while DNA is an index of cell numbers).
The change in the ratio indicates a marked increase in the secretory activities of the cell at
time of parturition.

Stages of Lactogenesis
1. Stage I (Cytologic and enzymatic differentiation of alveolar epithelial cells). This
coincides with very limited milk synthesis and secretion before parturition when specific
milk components (e.g. fat droplets and proteins) make their first appearance in the
mammary gland. Stage I of lactogenesis coincides with the formation of colostrum and
immunoglobulin uptake. Lactose synthesis does not begin until stage II of lactogenesis.
Enzymatic changes include increased synthesis of acetyl CoA carboxylase, fatty acid
synthetase and increases in uptake of amino acids, glucose and other substrate for milk
production. Length of stage I of lactogenesis varies considerable among mammalian
species. For example, in goats, (5 month pregnancy) stage I begins 3 months prepartum,
whereas in rats (3 week pregnancy), stage I begins only 30 hours prepartum.
2. Stage II (Copious secretion of all milk components). In the cow this begins about 0-4
days before parturition and extends through a few days postpartum. Stage 2 of
lactogenesis is usually shorter than stage I. Copious milk secretion begins when the
release of the inhibitory effects of progesterone on lactogenesis and the stimulation by the
very high blood concentrations of prolactin and glucocorticoids associated with
parturition occur. During late pregnancy the mammary gland develops the capacity to
make milk, but copious milk secretion does not take place until near parturition.
At parturition, coincident with the onset of stage II, not only is milk flow rapidly
enhanced, but also the glands absorb increased quantities of metabolic substrates from the
blood. A marked transition in secretory composition , from colostrum to milk generally
occurs over a period of a few days. Stage I of lactogenesis may thus be characterized as
due to gradual chemical and morphological changes (such as closure of tight junctions),
and stage II as the result of abrupt cardiovascular, metabolic and secretory changes
In women the drop in the concentration of blood progesterone does not occur until
parturition. Therefore the impact of stage II of lactogenesis does not occur until about 2

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days postpartum. In pigs and mice, stage II of lactogenesis occurs immediately prior to
and at the time of parturition. It is difficult to get any mammary secretion out of a sow
until parturition, whereas in the cow, substantial mammary secretion volume can be
collected up to several days prepartum.

Hormonal changes during lactogenesis

A number of hormonal changes are occurring in the mother's blood around the time of
parturition. Since the nutritional needs of the neonate is become even greater, at a time
when its umbilical link is cut, it would be anticipated that the endocrine control of
parturition and lactogenesis would be closely integrated. Two types of hormonal changes
can be identified;
1- Release from inhibition by factors which decline in activity at parturition
2- Stimulation by factors, the activity of which is enhanced at parturition
Some of these hormonal changes are specifically involved in lactogenesis. Progesterone
decreases starting a few days prepartum. Estrogen starts to peak prepartum, which in turn
stimulates the periparturitent prolactin secretion. The periparturitent prolactin peak is
very important to the entire process of lactogenesis, especially in initiating copious milk
secretion (stage II of lactogenesis). Glucocorticoids also peak at parturition and, there is a
growth hormone peak associated with parturition.

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Role of Prolactin in Lactogenesis

Prolactin plays an important role in lactogenesis in many species. The hormone exerts a
direct effect on the mammary gland through the prolactin receptors, which are located on
the plasma membrane of the secretory cell. Numbers of prolactin receptors initially
increase in mammary tissue coincident with initiation of the first phase of lactogenesis.
Numbers of receptors remain constant until the second phase of lactogenesis in the
immediate periparturient period, when they increase again. Such changes in receptor
numbers are very likely involved in the mechanism of lactogenesis. It has been suggested
that both the availability of prolactin and the responsiveness of the mammary epithelial
cells (receptors for prolactin) are important for the switch over from the first to the
second stage of lactogenesis. Prolactin is important for lactogenesis in a permissive sense
since inhibiting its release prevents lactogenesis, but elevation of its blood levels does not
seem to elicit milk secretion.
Prolactin increases milk protein biosynthesis, particularly caseins. The initial response to
the binding of prolactin to its receptors in an increase in ribosomal RNA and the
accumulation of casein mRNA. Thus, prolactin controls expression of casein gene and
probably other genes as well.

Role of Progesterone
Secretion of the corpus luteum inhibits lactogenesis. Progesterone, which is very
important in stimulating lobuloalveolar development in pregnancy, seems also to be the
principal factors holding both parturition and lactogenesis in abeyance. Removal of
corpus luteum or other means of reducing progesterone leads to initiation of lactation and
abortion. However, reducing progesterone in adrenalectomized or hypophysectomized
animals does not result in lactogenesis. Thus the major concept is that positive, as well as
negative factors work in concert to control initiation of lactation.
The primary role of progesterone in lactogenesis is the inhibition of the process. Injection
of progesterone during pregnancy prevents lactose, -lactalbumin and casein synthesis.
Progesterone also blocks prolactin-induced increase in these milk constituents. It also acts
directly on the mammary tissue to decrease the ability of prolactin to induce secretion of
-lactalbumin.
Progesterone binds to progesterone receptors in the cytoplasm of the secretory cells and
also competes with glucocorticoids for binding on the glucocorticoid receptors. It also
inhibits the ability of prolactin to induce synthesis of prolactin receptors and reduces the
synergism between prolactin and glucocorticoids. These are antilactogenic effects.

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Role of Estrogen
Estrogen induces lactogenesis in many species with well-developed mammary glands.
The role of estrogen in lactogenesis is indirect one. Estrogen stimulate secretion of
prolactin and possibly other hormones from the pituitary gland. Since estrogen and
glucocorticoids increase the number of prolactin receptors on the mammary membranes.
This explains the synergetic effects among prolactin, glucocorticoids, and estrogen on
lactogenesis at the mammary cell level. It has also been suggested that estrogen stimulate
synthesis of casein and -lactalbumin in bovine and mouse.

Role of Adrenal Steroids (Glucocorticoids)

Adrenal gland secretions play a major role in lactogenesis. Although administration of
glucocorticoids will initiate lactogenesis in pregnant cows, in most species a combination
of glucocorticoids and prolactin is more effective. Cortisol induces differentiation of
rough endoplasmic reticulum and the Golgi apparatus of the mammary epithelial cells.
This differentiation is essential to permit prolactin to induce synthesis of milk proteins.
This indicates the essential synergism between prolactin and the glucocorticoids to
induce lactogenesis.

Role of Insulin and Growth Hormone

The role of insulin and growth hormone on lactogenesis is not known. Both insulin and
insulin-like growth factor (IGF) may be involved in glucose up take which is critical for
lactose biosynthesis. Insulin may also be involved en expression of milk protein genes.
Growth hormone may have an indirect effect of lactogenesis by increasing the secretion
of IGFs

Role of Local Factors in Lactogenesis

Stage II of lactogenesis depends on factors arising in the mammary gland as well as on
systemic factors. Prostaglandin (PGF2) is synthesized in the uterus and the mammary
gland. PGF2 inhibits milk secretion, therefore at parturition, it must be removed or
inactivated. In the mammary gland, PGF2 is inactivated few days prepartum. Milk
removal by the suckling young, immediately following parturition, also helps in
removing PGF2 from the mammary gland. If the number of suckling young is less than
the number of glands, the unsuckled glands will clearly regress rapidly as unremoved
PGF2 continues to exert its inhibitory effect. Suckling also elicit secretion of lactogenic
hormones.

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Role of Lactose in Lactogenesis

Decreasing progesterone and increasing glucocorticoids and prolactin secretions initiate
the synthesis -lactalbumin. The -lactalbumin protein 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 -lactalbumin in the mammary tissue is an indicator of lactogenesis

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Galactopoeisis
Definition
Galactopoeisis is defined as the maintenance of lactation once lactation has been
established. The changes in mammary cell numbers (by growth or by cell death) and in
milk yield per cell are regulated in part by galactopoietic hormones and in part by local
mammary factors. The role of milk removal complicates interpretation of the hormonal
requirements for milk synthesis. Without frequent emptying of the mammary gland, milk
synthesis will not persist in spite of adequate hormonal status. Conversely, maintenance
of intense suckling or milking stimulus will not maintain lactation indefinitely.
Nevertheless, suckling or actual removal of milk is required to maintain lactation.

Role of Hormones
The maintenance of lactation is at least partly controlled by a group of hormones
collectively known as galactopoeitic hormonal complex. The hormonal complex includes
prolactin, growth hormones, Thyroid hormones, and glucocorticoids.
Role of Prolactin
Prolactin is generally a galactopoeitic hormone. However, considerable variations exist
among species regarding the role of prolactin on galactopoeisis. The importance of
prolactin (alone) in maintaining lactation has been established in some nonruminants
such as rabbits. However, in most nonruminants and ruminants, prolactin is only one
component of a hormonal complex that regulates galactopoeisis. The role prolactin in
cows is ambiguous. Inhibition of prolactin in cows and goats had little effects on milk
yield especially when compared with about 50% reduction in rodents and a near complete
failure of lactation in rabbits.
There is a milking-induced or nursing-induced release of prolactin. However, this surge
of prolactin is small compared with the peripartum prolactin surge associated with
lactogenesis. The milking-induced prolactin surge is a direct link between the act of
nursing (or milk removal) and the galactopoeitic hormones involved in maintaining
lactation.

Role of Growth Hormones

Growth hormone is essential for maintaining lactation (galactopoeitic). Growth hormone
coordinates changes in body tissues and physiological processes that support increase in
synthesis of lactose, protein, and fat in the mammary gland. Bovine somatotropin (BST
or bovine growth hormone) is now commercially produced and has been used in many
dairy herds in the USA. An increase in milk yield of between 10 and 40% has been
reported. The BST-treated cows adjust their nutrient intake to support the increased in

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milk output, at least in the case of long term administration. The use of BST is not
permitted in Canada due to concerns with cows health.

Role of Adrenal Corticoids

Intact adrenal gland is essential for maintaining lactation. Glucocorticoids at
physiological levels is galactopoeitic, however, at high doses it inhibits lactation. In rats,
physiological doses of adrenal corticoids increased litter growth rate by increasing the
milk obtained by young during suckling period.

Role of Thyroid Hormones

Thyroid hormones are galactopoeitic. Injection of thyroid hormone into cows increases
milk production for a short period of time (several weeks). Administration of thyroid
hormones for more that 7 weeks had no effect on milk yield. Thyroprotein (iodinated
casein) is a commercial product that increases milk yield in cows by about 10% in early
lactation and by 15-20% in late lactation. However, the positive effect only lasts for 2-4
months and subsequent yield is below normal. There are generally no benefit in feeding
thyroprotein over the entire lactation.

Role of Ovarian Hormones

Estrogen administered in very low doses in galactopoietic. However, higher doses have
inhibitory effects. A combination of estrogen and progesterone is more inhibitory than
estrogen alone. Progesterone alone has no effect on galactopoeisis because there are no
progesterone receptors in the mammary gland during lactation

Role of Milk Removal in Galactopoeisis

Control of lactation is clearly regulated by hormones, however local factors such as milk
removal is also important. 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.
The greater the nursing intensity the more mammary growth and the more milk produced.
Nursing intensity means the number of nursing young (litter size), especially in litter-

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bearing species. Although it is less well documented, this effect of stimulation intensity
also probably means the vigor with which the young nurse, perhaps involving the degree
of gland emptying which occurs at each nursing or the intensity of stimulation of the
nipple.

Autocrine Control of Galactopoeisis

Autocrine control refers to the local factors within the mammary gland that affects milk
production. Rate of milk secretion increases as milking frequency (removal) increases.
Cows milked three times a day produced more milk than cows milked twice daily. The
response to milk removal is not likely the result of decreased intra-mammary pressure. It
has been suggested that a milk constituent acts as an inhibitor of milk secretion and that
removal of this inhibitor at milking regulates the rate of milk secretion.
A milk whey protein has been identified as a Feedback Inhibitor of Lactation (FIL). The
inhibitor is thought to be synthesized by the mammary secretory cell and in turn inhibits
further milk secretion as its secretion increases. The balance between systemic
(hormonal) and local (FIL) control of milk secretion can be summarized as follows:
Each time milk is removed:
- Prolactin release is stimulated
- Intra-mammary pressure is relieved
- FIL is removed from the alveoli
If milk is not removed:
- There is no stimulation of PRL release
- There is an acute accumulation of milk in the gland, resulting in:
- Increased intra-mammary pressure
- Activation of sympathetic nerves
- Decreased mammary blood flow
- Decreased availability of hormones and nutrients to the gland
- Rate of milk secretion declines
The gland is under the influence of the systemic factors shortly after milking and
maximal secretion rate is achieved. This gradually slows, as the role of the local factors
becomes dominant. If milk is not removed, then the secretion rate will eventually drop to
zero. However, under normal nursing or milking intervals the secretion rate does not go
to zero. Once milk is removed, the cycle begins again.

Milk Secretion Rate

Milk yield is dependent of the amount of secretory tissue and the rate of milk secretion
(per unit of time). Secretion rate is affected by the accumulation of milk in the alveolar
lumen. Accumulation of milk in the lumen increases the intra-mammary pressure. Once

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the intra-mammary pressure reaches a certain level, secretion rate declines. If the pressure
increases enough (~70 mm Hg in the cow), then the secretion stops and milk starts to be
reabsorbed. In the dairy cow secretion rate reaches zero at about 35 hours after the last
milking. The inhibition of milk secretion that accompanies increasing intra-mammary
pressure is probably caused by a chemical inhibitor rather than the increased pressure of
the fluid itself.

Milking Frequency
In dairy cows, milking 3 times a day increases milk yield compared with milking twice
daily, although the increase is variable. The increase in milk yield can be up to 25%. It
should be pointed out that only about 1/3 of that increase can be attributed to a decreased
intramammary pressure, the rest is likely due to better feeding and management. In
switching from 2X to 3X/day milking, the cows response in thought to occur in stages
with each stage reflecting a different mechanism: 1) there is an immediate (hours to days)
increase in milk secretion due to removal of chemical feedback inhibitor (FIL). 2) There
is a short term (days to weeks) increase in milk secretion due to stimulation of cell
differentiation. 3) there is a long term (weeks to months) increase in milk secretion due to
stimulation of cell proliferation.

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