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LACTOGENESIS

The term lactogenesis is used to describe the initiation of milk secretion after parturition (delivery

of the fetus), when the mammary glands have reached a suitable degree of development. The

process of lactogenesis at parturition encompasses the hormones involved in its initiation, milk

secretion by the epithelial cells of the alveolus, and removal of milk stored in the mammary gland.

It should not be confused with pharmacological hormone-induced lactation in barren, nonlactatingcows and heifers.

Secretions by the Epithelial Alveolar Cells

Alveolar cells of the lactating (postparturient) mammary gland synthesize and secrete milk proteins

(casein, serum albumin, alpha-lactalbumin, beta-lactoglobulin, immu-noglobulins, and

glycoproteins), fats, and lactose. Junctions between these cells enable them to carry on functions of

adhesion (desmosomes), occlusion (tight junctions), and communication (gap junctions).

At about midgestation, the epithelial alveolar cells begin to secrete appreciable quantities of specific

milk products, which frequently accumulate in the mammary gland as precolostrum. This

lactogenesis stage I is a prerequisite for lactogenesis stage II, which is the onset of copiouscolostrum and milk secretions at parturition.

Lactogenesis I

The onset of lactogenesis I, that is, secretory activity in the mammary alveoli, is marked by

production of fire-colostrum. The appearance of lactose in the precolostrum is of physiological

importance, since it indicates that the intra-cellular apparatus for milk synthesis is functionally

differen-tiated. It occurs at midgestation in goats, in the last third ot pregnancy in rabbits, a month

before parturition in ewes, 15 days before foaling in mares, at 10 days before calving in cows, and a

day before delivery in mice and rats. During this period of late pregnancy, when the mammary

gland remains unmilked, a local raccor maintains "leaky" tight junctions to keep the epithelial

paracellular pathway open, and the ducts permeable. Transfers between extracellular fluid and pre-

colostrum ar then possible. The precolostrum contains some large molecules such as

immunoglobulins, and its aqueous phase shows fluctuating levels of chloride, sodium, po-tassium,

and lactose. Eat globules, protein granules, desqua-mated epithelial cells, and leukocyces also

accumulate in the lumen of the alveoli. Disappearance of this factor, with removal of precolostrum

(sucking or milking), results in closure of the paracellular pathways in the alveolar epithelium and

duct system.

Lactogenesis II

Lactogenesis II usually begins shortly before parturition, when the mammary gland first releases

colostrum, then normal milk, which are not identical in all animal species. For instance, the

colostrum of some animals (cows, bitches, ewes, goats, mares, and sows) contains globulin

antibodies, which are essential for transmitting passive immunity to their offspring. The milk of

carnivores, with high-protein and low-sugar contents, is noticeably different from the milk of

equidae (protein-poor and sugar-rich).

Colostrum

Colostrum, the transitional fluid between precolostmm and normal milk, is the first food of the

neonate. In addition to its rich nutritive value, it transfers passive immunity, and it has a slightlaxative effect to aid in clearing the intestine of meconium (greenish mucilaginous material in the

intestine of the full-term fetus).


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Secreted and stored in the mammary gland during the last 2 co 7 days of gestation and the first 2 or

3 days poscpartum, colostrum contains more proteins (including immunoglobulins), lipids, and ash

(sodium, and chloride) and less lactose than milk (except in mares). It also contributes fat-soluble

and water-soluble vitamins and all the essential amino acids to the rapidly growing neonate (Table

59- 2). In the colostrum of sows, a trypsin inhibitor offers protection to the immunoglobulins in the

gut of piglets.

Colostrum is essential for supplying immunoglobulins to the neonates from females of species(cows, ewes, goats, mares, and sows) in which antibodies are not transferred from maternal to fetal

blood (Fig. 59 1). During their first 2 days of life, kittens and puppies need colostrum to

supplement the immunoprotection conferred through the placenta during gestation. A calf should

ingest about 6 percent of its body weight in colostrum within 6 hours after delivery. A dairy cow

produces about 50 Kg of colostrum during the first six milkings after parturition (the first milking is

the richest in immunoglobulins). After fermentation (souring), refrigeration, or freezing, colostrum

can be fed to calves until the age of 3 weeks, as a source of energy. Colostrum can be frozen in

cartons and kept for several months.

In the newborn lamb, bovine colostrum is a satisfactory substitute for natural ovine colostrum. A

synthetic ovine colostrum, adequate for its nutritive value but without protective antibodies, can be

made with one beaten egg, 1 teaspoon (10 ml) of cod liver oil, and 2 teaspoons (20 g) of sucroseadded to 750 ml of cow's milk. Commercial preparations containing concentrated immunoglobulins

are available for calves, lambs, and piglets.

Equine colostrum (300 to 500 ml) must be administered within 6 hours to foals born to mares with

anticipated lactogenesis II (running milk), that is, mares producing only milk, without any

colostrum, at parturition.

During the first 3 days of lactogenesis II, the composition of colostrum, far from being static,

changes, with the gradual modification of colostrum into normal milk (Table 59-3).

The immunological experiences of the mother determine the mix of antibodies available to the fetus

and the neonate. Domestic carnivores and primates deliver antibodies to their fetuses across the

placenta. Important additional immunoglobulins (Igs), mostly IgA, and lesser amounts ofIgG and

IgM, particularly significant for protection against viral diseases, are also provided in colostrum.

Domestic herbivores and swine have placentas that allow very little transfer of maternal antibodies

to the fetus. These species are very dependent upon the immunoglobulins in colostrum to provide

passive immunity to protect the newborn for the first few weeks of life. Their colostrum is

particularly rich in IgG (Fig. 592). Substantial amounts of IgA and IgM are also present. The

neonatal animal has little proteolytic activity in the gut, and colostrum contains trypsin inhibitors.

Consequently, the Igs pass intact to the ileum, where they are absorbed via pinocytosis for a limited

time only.

Permeability to and absorption of the Igs in the digesta is at a peak during the first few hours after

birth and starts to decline after about 6 hours. Often, by 24 hours, because of a phenomenon known

as "closure," little further absorption of proteins occurs. In species that have nearly protein-impermeable placentas, it is imperative that the newborn receive an adequate supply of colostrum

within the first 24 hours after birth.

For example, calves are born with very low plasma levels of Igs. These levels rise rapidly after a

colostrum meal, peaking during the first day. This rise is accompanied by a transient proteinuria,

resulting from renal filtration of smaller milk proteins, such as beta-lactoglobulin, that are also

absorbed. The plasma IgG levels persist for several weeks, providing passive immunity until the

young animal's immune system becomes activated. Some IgA is protected from digestion by a

protein called secretory component, which also reduces its absorption. Lymphocytes, which may

also be absorbed from colostrum, convey cell-mediated immunity, but also some infectious agents

such as viruses may be absorbed.

Normal Milk


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Normal milk contains proteins derived from amino acids taken up by, and synthesized in, the

alveolar epithelium of the mammary gland. In the lactating mammary gland, the entire duct system

is impermeable and acts as a storage region. The epithelium of the alveolus is also impermeable,

blocking all paracellular (between cells) transfers and all transport is via the transcellular route

across epithelial cells. This holds even for the aqueous phase of milk, which constitutes 88 percent

of cow's milk and contains the main ions (potassium, sodium, and chloride) and other substances(citrate, phosphate, calcium, urea) that make milk isoosmolar to blood plasma (Fig. 59-3). After

synthesis in the endoplasmic reticulum, milk proteins for secretion pass to the Golgi vesicles, where

caseins undergo phosphorylacion and associate with calcium to form micelles. The Golgi vesicles

move to the apical surface, and their protein contents are released by reverse pinocytosis

(exocytosis, exo-pinocytosis, merocrine secretion).

Lactose, the predominant milk sugar, is synthesized from glucose, enters the Golgi apparatus as a

complex (since the Golgi is impermeable to lactose), and is released into the alveolar lumen by

exocytosis, together with milk proteins. In humans, intolerance to lactose, a deficiency in lactase

(enzyme) within the small intestine mucosa, causes diarrhea and upsets the gastrointestinal tract in

certain populations (e.g., Eskimos, American Indians, blacks, Asians, and New Guinea and

Australian aborigines) after weaning.Triglycerides constitute over 95 percent of milk lipids. Fatty acids are either derived from the diet

or synthesized in the mammary gland. Lipid droplets migrate to the apical membrane, are

enveloped, and then extruded from the cell into the lumen of the alveolus.

The composition of milk varies with the animal species, and within a given species the composition

of secreted milk is not static but changes with the stage of lactogenesis and the level of nutrition.

Usually, toward the end of lactogenesis, when milk production is declining, the concentrations of

proteins, milk fat, and sodium (600 mg per liter) steadily increase, whereas lactose and potassium

(1450 mg per liter) decrease. In mare's milk, except for sodium and potassium, the concentrations of

calcium, phosphorus, magnesium, copper, and zinc decrease during the course of lactation. In 16

weeks, the content of total solids in mare's milk can pass from 12 to 10 percent, and that of ash can

be halved from 0.6 to 0.3 percent. Milk is isoosmotic to plasma and has a pH near 6.8 (Table 59-4).

Epithelial cells, macrophages, mononuclear leukocytes, and cell fragments are normal elements in

milk, but not polynuclear neutrophils associated with a diseased or infected mammary gland. The

number of cells considered as normal in average bovine milk (0.2 X 106 cells per milliliter) varies

with the time of day, the stage of lactogenesis, and the quarter of the udder. Equine milk usually

contains very few leukocyric cells (8,000 cells per milliliter). A high-quality bovine milk must meet

the major standards of low counts of somatic cells and of viable bacteria.

Certain plant alkaloids (colchicine, vincrisrine, vinblasrine) and some plant lecrins (concanavalin

A) interfere with the transport and discharge phases of the secretory process, and bring a retention

of the synthesized milk within the alveolar cells. Ergot derivatives (e.g., bromocriprine) can

depress or stop lactogenesis II in sows by inhibiting release of prolacrin (PRL) from theadenohypophysis.

Removal of Milk Stored in the Mammary Gland

Milk secreted into the lumen of the alveoli dilates and fills the alveoli, the duct system of the

mammary gland, and, depending on the species, the enlarged terminal portion of the ducts (the

sinus, or cistern). In ruminants, only the milk present in the larger ducts and sinus, or cistern, can be

removed by cannulation of the teat (Fig. 59-4). The mammary glands of the sow do not have a sinus

or cistern.

The bulk of the milk is retained in the alveoli and small ducts until the neuroendocrine milk-ejection

reflex occurs. The neurohumoral reaction is activated by sensory receptors in the teat, at sucklingor milking, and by conditioned responses to sound and sight at milking or suckling. The nervous

signals finally reach the neurohypophysis through still-unknown paths and result in oxytocin


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release. Oxytocin causes myoepithelial cells surrounding the alveoli to contract and to increase milk

pressure in the duct system and also causes scored milk to be forced down the galactophore (Fig. 59

5). Oxytocin, released in a single spurt, has a half-life of 2 to 3 minutes.

In lambs and kids, the tongue and mouth of the sucking ruminant acts on the teat like the hand of a

milker with suction added. The milk is trapped in the teat cistern by compressing the base of the teat

and is then expressed through the teat canal at the tip of the teat.

By cineradiography, with milk rendered radiopaque in the doe's udder, it has been possible to getthe following description of the sucking sequence in the kid's mouth.

The kid compresses the base of the teat between its upper gum and the tip of the tongue resting on

the lower gum. Then, it raises its tongue to indent the teat from the base toward (he tip, closing

the lumen of the teat sinus and expressing the milk to be swallowed. At the same time, it lowers

its jaw and tongue to allow the teat sinus to fill again with milk, and the cycle begins again.

Emotional stress, pain, fright, and epinephrine inter-fere with milk removal through inhibition of

oxytocin release from the neurohypophysis. The inhibitory effects of eo nephrine on milk ejection

are also mediated by vasoconstric tion of the mammary blood vessels, reducing access ofoxvtocin

to the myoepithelial cells, and by competition for receptor sites on the myoepirhelium. Some ergot

derivatives (alpha-ergocryptine, ergoramine, ergocornine) are also potent inhibitors of the milk-

ejection reflex.In postparturient sows, oxytocin administration may correct some forms of a condition of agalactia,

which is considered part of a syndrome also involving mastitis and metritis.

Hormonal Control

The initiation of lactogenesis is controlled mainly by lactogenic hormones from the

adenohypophysis (PRL and growth hormone [GH]) and the placenta (placental mammogenic

hormones or placental lactogens [PL] in cactle sheep, and goats). PRL, GH, and PL have similar

structures, but within a given species each hormone is believed to have a distinct biological role, not

yet precisely characterized. Adenohypophysial lactogenic hormones can partly replace their

placental counterparts in studies on initiation of lactogenesis, but they cannot do so completely. A

growing body of experimental evidence gives a role to PLs in the normal growth of the udder. The

metabolic hormones, such as adrenal corticoids (corticosteroids), insulin, and glucagon from the

pancreas, and thyroid hormones, also directly affect the mammary gland; these same hormones

exert an indirect effect on the metabolic precursors needed for milk synthesis.

In most periparturient females, the levels of progesterone and of PL decrease. These declines are

followed by a rise in levels of PRL, estrogens, PGF2a, oxytocin, and adrenal corticoids. Two basic

hormonal concepts are invoked to explain the triggering of lactogenesis stage II at parturition:

1. The release of the mammary gland from the inhibitory effect of progesterone, and

2. A rise in the levels of some lactogenic hormones (PRL and GH) to overcome the

progesterone inhibition.In beagle bitches, PRL levels rise steadily from mid-pregnancy to early lactation, decline slowly as

lactation progresses, and fall abruptly upon weaning. PRL levels are not significantly lower in

pseudopregnant (diestrous) bitches.

During the last week of pregnancy, the mare shows a major increase in plasma PRL concentration,

which fluctuates but stays high during early lactation, then declines to basal levels in 1 to 2 months.

If the foal dies shortly after birth, plasma PRL falls rapidly, and estrus occurs as early as 4 days

postparrum, rather than a week after parturition, as the usual "foal heat." PRL appears to be

important for the completion of mammary development and the initiation or milk secretion.

Suckling triggers increases in postpartum PRL secretion.

In ruminants, after lactation is established, PRL secretion can be completely suppressed without

arresting milk secretion. The release of PRL and GH, episodic in ruminants, is mostly spontaneousand due only in part to stimuli such as suckling or stress. In cows and goats, PRL plays a decisive

role only for establishment of milk secretion. Al-though PRL release is not related to the short


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ruminant sleep, and to circadian activity, morning and afternoon milkings cause an immediate

release of PRL and initiate a gradually decreasing chronic release of the hormone. The concen-

trations of PRL in blood, dependent on season (day length), are highest during summer and lowest

during winter in cows, goats, and sheep. This PRL periodicity is maintained from birch to maturity

in heifers and bulls, in rams, in pregnant cows, and in response to milking in cows and goats and to

suckling in ewes. Goats and ewes, pregnant during the winter months, have an increase in PRL

levels only a few days before parturition. Similarly, PRL levels rise sharply in the last 2 days ofbovine gestation and, because of seasonal variations, are higher in autumn calving than in spring

calving cows. PRL release is inhibited by PRL-inhibiting factor (PIF, or dopamine) and is

stimulated by a PRL-releasing factor (PRF), which may well be thyrotropin-releasing hormone

(TRF).

Growth hormone is more important than PRL for galactopoiesis in ruminants. Levels of GH are

low in pregnant ewes and cows but are somewhat higher and more fluctuating in ewes carrying

twins or triplets. Lactating or not, goats do not liberate GH in association with sleep, air

temperature, time of day or night, or husbandry routines, or in response to plasma levels of PRL,

insulin, glucose, or free fatty acids. The final release ofGH is thought to be the result of a balance

between the opposing effects of two hypothalamic peptides: GHRP (growth hormone-releasing

factor, or somatoliberin) and somatoscatin (growth hormone release-inhibiting hormone). BovineGH produced by biotechnology, that is, by fermentation in bacteria from recombinant DNA, is

known as recombinant somatotropin (rbST).

In lactating cows receiving supplemental bovine GH (bovine somatotropin, or bST), milk

production is increased by 10 to 25 percent, and the feed efficiency also becomes 5 to 15 percent

higher.

Sustained-release formulations have been developed that are effective for over 2 weeks.

Industrial production of bovine somatotropin made by recombinant DNA technology in bacteria

(rbST) has made possible the manipulation of bovine lactation physiology. It seems that bST

produces an increase in insulin-like growth factor I (IGF-I) and that this agent increases milk

synthesis. A large increase in milk production, on the order of 5 to 25 percent, depending on the

standard of herd management, occurs after the first 2 to 3 months of lactation. Given daily

injections of rbST, the increased yield persists throughout the remainder of the lactation. New

sustained-release preparations, lasting over 14 days, avoid the undesirable feature of daily

injections. The only negative effect ofrbST treatment is an increase in the average number of

services (from about 2 to 2.5) required to achieve conception, which causes the cows to remain

open (unbred) for about 21 days longer.

In one trial, the milk yield (x: 20 % = 3.7 kg per day) increased promptly (2 to 3 days) after

initiation of bST injection, at 9 weeks after calving (Fig. 59-6).

After a lag of about 8 weeks, dry matter intake increased by 1.7 kg per day. Feed efficiency

improved by 6 percent, because of the reduced contribution of the maintenance requirements per

gallon (about 4 L) of milk.In the treated cows, an initial negative energy balance was then compensated for, through the

delayed increase in food intake.

Plasma PL levels rise to a plateau of highest values during the last third of gestation in goats and

cows but only 10 days before full term in ewes. Concentrations of ovine PL in peripheral plasma

begin to fall 5 days before parturition and disappear rapidly after delivery.

GALACTOPOIESIS

The term galactopoiesis refers to the maintenance or stimulation of an already established milk

production (lactogenesis II). Galactopoiesis is related to the removal of milk from the mammary

gland by either milking or suckling. It is a commonly known fact that lactogenesis II slows orceases altogether if the frequency and the extent of milk removal is reduced. The secretory activity

of the mammary gland declines slowly and eventually ceases, even though milk is removed


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regularly. The natural decline in lactogenesis often coincides with weaning of the young. A

negative-feedback mechanism operating locally within the gland may participate in this slow,

direct, and gradual involution of the alveolar epithelium during the later stages of lactogenesis. In

marsupials, suckling is continuous during the first part of pouch life, which is equivalent to the fetal

period of placental animals (the "fetus" is firmly anchored to a nipple).

In some animals, milk is produced during a period far exceeding the weaning period of the

offspring. These main milk-producing species are the goat, water buffalo, sheep, reindeer, andcattle. As a result of genetic selection for milk-producing ability, the typical modern cow produces

more than four times the milk required to raise her calf, and top producers yield milk that would

suffice for more than 20 times the physiological needs of the normal calf. Posrpartum anestrus

occurs in cows and ewes. In ewes, the duration of the postpartum anestrus is related to the degree of

mammary stimulation during suckling. In cows, which are usually pregnant for most of the period

of lactation, the degree of udder stimulation does not influence the duration of postpartum anestrus.

In the absence of a new pregnancy, and with continual suckling or milking, lactation may be

prolonged far beyond the normal weaning period (e.g., as long as several years in cows).

Hormones

Prolactin (PRL), growth hormone (GH), thyroxine (T4), insulin, corricosteroids, and oxytocin are

the hormones recognized as also associated with maintenance of lactogenesis (galactopoiesis).

However, adenohypophysial release of PRL at milking or suckling is essential for galactopoiesis in

most animal species, except the goat and cattle. In these two ruminants, PRL has a decisive role

only in establishing lactogenesis II. The conditioned stimuli of events preceding milking, and the

tactile sensations at the udder and teat during milking or suckling, normally increase maternal

plasma prolactin and oxytocin levels in all species. In most dams, except the cow and the nanny

goat, failure to empty the milk from a producing mammary gland leads to lower levels of PRL and

consequent hypogalacna whereas inhibition of circulating PRL with an ergot alkaloid derivative

(bromocriptine) induces agalacria. Besides its classic role in the milk-ejection reflex, oxytocin also

influences lactogenesis and galactopoiesis. Oxytocin mjecred into lactating animals without

immediate milking generally inhibits lactogenesis, whereas lactogenesis is stimulated it th(. ejected

milk is removed immediately. Oxytocin would contribute to galactopoiesis by loosening the right

junctions between epithelial alveolar cells and by accelerating the transfer of milk constituents into

the alveoli.

Suckling or milking causes the release of growth hormone in nanny goats and rats but not in cows

and bitches. In nanny goats, the release of GH is unpredictable and may not be entirely related to

the tactile stimulation of the mammary eland. In contrast with the situation in nonruminants, in

which PRL is more important for lactogenesis, GH assumes a more prominent galactopoietic role in

ruminants (cows and goats). GH is required for maintenance of galactopoiesis in cows and goats

and increases milk yield in cattle without requiring a proportionate increase in food intake or aproportionate reduction in body tissue reserves in the short term.

A normally functioning thyroid gland is required for maintenance of lactogenesis. Lowered milk

yield and reduced milk fat percentage resulting from thyroid deficiency are reversed by prolonged

iodinated protein feeding. The role of thyroxine in maintaining ruminant lactogenesis is not clear,

since there is less hormone in lacrating cows than in nonlactating cows, and the levels are

negatively correlated with milk yield.

Insulin is recognized as essential for the maintenance of normal lactogenesis, but its exact

mammary gland action is difficult to distinguish from its general anabolic role. Insulin treatment

decreases milk yield and milk lactose in lactating cows and goats and increases milk protein and

milk fat. In goats, exogenous insulin favours synthesis of milk fat containing more Ciz to Cig fatty

acids.Intact adrenal glands are essential for the maintenance of lactogenesis in both ruminant and

nonruminant species, and replacement therapy is best effected by a combination of


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mineralocorticoids and glucocorticoids. In cattle, plasma cwticwteroids are higher in lactating

animals than in nonlactaring ones, and high-yielding cows have more corticosteroids than low-

yielding ones. A disagreement remains to be resolved on the relationship between plasma level of

corticosteroids and the stage of lactogenesis in cattle. Some claim that the basal postpartum level

increases as lactation progresses, whereas others support the opposite view, that is, a high

postpartum level that decreases with progressing lactogenesis.

Cessation of Calactopoiesis by Involution of the Mammary Gland

In animals, involution of the mammary gland may be "initiated" or "gradual." Initiated involution

refers to the regression of the gland as a result of sudden cessation of milk removal during

galactopoiesis. Gradual involution is the regression of the mammary gland during the normal course

of galactopoiesis. Initiated involution is of practical value in sows, since the production objectives

aim at increasing the annual number of piglets per dam, rather than the annual milk yield.

Regression of the mammary gland by early and sudden weaning of piglets (i.e., at 3 weeks instead

of at 6 weeks) is recommended in order to decrease the length of lactogenesis and the interval

between farrowing. In this sow-breeding system, sudden stoppage of milk removal ends

lactogenesis II at 3 weeks postpartum, when it is actually reaching its peak. Withholding feed forthe first 2 or 3 days after withdrawal of the piglets reduces the milk flow, and gonadotropins

(pregnant mare serum gonadotropin and human chorionic gonadotropin) are then injected to speed

up and synchronize the onset ofestrus after early weaning. Complete involution of the gland occurs

after 8 days in sows.

Sudden weaning of animals in full lactogenesis usually results in gross distencion of the mammary

gland for 3 or 4 days. The interstitial fluid is laden with milk constituents (milk edema). During

initiated involution, milk secretion is unaffected for 16 hours in cows, and for 12 hours in ewes.

Distention is concomitant with neurtophilic infiltration, which is followed by the appearance of

macrophages (foamy cells, bodies of Donne) before lymphocytic dominance sets in, usually from

the fourth day in ewes.

Gradual involution does not proceed uniformly throughout the gland. Areas adjacent to the

abdominal walls are the last to involute. Even at the height of lactogenesis II, as much as 20 percent

of the mammary gland of the cow shows areas of alveoli without secretory activity. These areas

resemble those of a nonlaccaring gland, with prominent interalveolar and inrerlobular connective

tissue. Srilbesrrol (unauthorized drug) fed to cows, and injections of GH or of small doses

ofescradiol to nonpregnant cows, prolong galactopoiesis or decrease the gradual involution of the

mammary gland. Gestation stops galactopoiesis in goats and reduces milk production in cows. In

mares and bitches, large doses of estrogens are used to put a sudden end to lactogenesis.

In the involuting gland, lactoferrin production by mammary epithelial cells increases (as in acute

mastitis) to exert a bacterioscaric effect. Lactoferrin, the major ironbinding protein of milk, is a

natural protective factor. By binding to iron, lactoferrin withholds an essential nutrient frompathogenic bacteria.

(Ruckebusch, 1991)

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