lactogeneisis

Biology of Lactation 342-460B

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Lactogenesis

Definition of Lactogenesis (initiation of lactation)is a series of cellular changes whereby mammary epithelial cells are converted from anonsecretory state to a secretory state. This process is normally associated with the end ofpregnancy 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 activestage. There is a marked increase in the RNA level of the epithelial cells. This causes theRNA:DNA ratio, which is less than 1 during late pregnancy, to over 2:1 duringsecretion(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 attime of parturition.

Stages of Lactogenesis

1. Stage I (Cytologic and enzymatic differentiation of alveolar epithelial cells). Thiscoincides with very limited milk synthesis and secretion before parturition when specificmilk components (e.g. fat droplets and proteins) make their first appearance in themammary gland. Stage I of lactogenesis coincides with the formation of colostrum andimmunoglobulin uptake. Lactose synthesis does not begin until stage II of lactogenesis.Enzymatic changes include increased synthesis of acetyl CoA carboxylase, fatty acidsynthetase and increases in uptake of amino acids, glucose and other substrate for milkproduction. Length of stage I of lactogenesis varies considerable among mammalianspecies. 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 0-4days before parturition and extends through a few days postpartum. Stage 2 oflactogenesis is usually shorter than stage I. Copious milk secretion begins when therelease of the inhibitory effects of progesterone on lactogenesis and the stimulation by thevery high blood concentrations of prolactin and glucocorticoids associated withparturition occur. During late pregnancy the mammary gland develops the capacity tomake 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 rapidlyenhanced, but also the glands absorb increased quantities of metabolic substrates from theblood. A marked transition in secretory composition , from colostrum to milk generallyoccurs over a period of a few days. Stage I of lactogenesis may thus be characterized asdue 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 untilparturition. 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 toand at the time of parturition. It is difficult to get any mammary secretion out of a sowuntil parturition, whereas in the cow, substantial mammary secretion volume can becollected up to several days prepartum.

Hormonal changes during lactogenesis

A number of hormonal changes are occurring in the mother's blood around the time ofparturition. Since the nutritional needs of the neonate is become even greater, at a timewhen its umbilical link is cut, it would be anticipated that the endocrine control ofparturition and lactogenesis would be closely integrated. Two types of hormonal changescan be identified;1- Release from inhibition by factors which decline in activity at parturition2- Stimulation by factors, the activity of which is enhanced at parturition

Some of these hormonal changes are specifically involved in lactogenesis. Progesteronedecreases starting a few days prepartum. Estrogen starts to peak prepartum, which in turnstimulates the periparturitent prolactin secretion. The periparturitent prolactin peak isvery important to the entire process of lactogenesis, especially in initiating copious milksecretion (stage II of lactogenesis). Glucocorticoids also peak at parturition and, there is agrowth 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 adirect effect on the mammary gland through the prolactin receptors, which are located onthe plasma membrane of the secretory cell. Numbers of prolactin receptors initiallyincrease in mammary tissue coincident with initiation of the first phase of lactogenesis.Numbers of receptors remain constant until the second phase of lactogenesis in theimmediate periparturient period, when they increase again. Such changes in receptornumbers are very likely involved in the mechanism of lactogenesis. It has been suggestedthat both the availability of prolactin and the responsiveness of the mammary epithelialcells (receptors for prolactin) are important for the “switch over” from the first to thesecond stage of lactogenesis. Prolactin is important for lactogenesis in a permissive sensesince inhibiting its release prevents lactogenesis, but elevation of its blood levels does notseem to elicit milk secretion.

Prolactin increases milk protein biosynthesis, particularly caseins. The initial response tothe binding of prolactin to its receptors in an increase in ribosomal RNA and theaccumulation of casein mRNA. Thus, prolactin controls expression of casein gene andprobably other genes as well.

Role of Progesterone

Secretion of the corpus luteum inhibits lactogenesis. Progesterone, which is veryimportant in stimulating lobuloalveolar development in pregnancy, seems also to be theprincipal factors holding both parturition and lactogenesis in abeyance. Removal ofcorpus luteum or other means of reducing progesterone leads to initiation of lactation andabortion. However, reducing progesterone in adrenalectomized or hypophysectomizedanimals does not result in lactogenesis. Thus the major concept is that positive, as well asnegative factors work in concert to control initiation of lactation.

The primary role of progesterone in lactogenesis is the inhibition of the process. Injectionof progesterone during pregnancy prevents lactose, α-lactalbumin and casein synthesis.Progesterone also blocks prolactin-induced increase in these milk constituents. It also actsdirectly on the mammary tissue to decrease the ability of prolactin to induce secretion ofα-lactalbumin.

Progesterone binds to progesterone receptors in the cytoplasm of the secretory cells andalso competes with glucocorticoids for binding on the glucocorticoid receptors. It alsoinhibits the ability of prolactin to induce synthesis of prolactin receptors and reduces thesynergism 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 ofprolactin and possibly other hormones from the pituitary gland. Since estrogen andglucocorticoids increase the number of prolactin receptors on the mammary membranes.This explains the synergetic effects among prolactin, glucocorticoids, and estrogen onlactogenesis at the mammary cell level. It has also been suggested that estrogen stimulatesynthesis of casein and α-lactalbumin in bovine and mouse.

Role of Adrenal Steroids (Glucocorticoids)

Adrenal gland secretions play a major role in lactogenesis. Although administration ofglucocorticoids will initiate lactogenesis in pregnant cows, in most species a combinationof glucocorticoids and prolactin is more effective. Cortisol induces differentiation ofrough 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 toinduce lactogenesis.

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

Role of Local Factors in Lactogenesis

Stage II of lactogenesis depends on factors arising in the mammary gland as well as onsystemic factors. Prostaglandin (PGF2α) is synthesized in the uterus and the mammarygland. PGF2α inhibits milk secretion, therefore at parturition, it must be removed orinactivated. In the mammary gland, PGF2α is inactivated few days prepartum. Milkremoval by the suckling young, immediately following parturition, also helps inremoving PGF2α from the mammary gland. If the number of suckling young is less thanthe number of glands, the unsuckled glands will clearly regress rapidly as unremovedPGF2α continues to exert its inhibitory effect. Suckling also elicit secretion of lactogenichormones.


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Role of Lactose in Lactogenesis

Decreasing progesterone and increasing glucocorticoids and prolactin secretions initiatethe synthesis α-lactalbumin. The α-lactalbumin protein interacts withgalactosyltransferase in the Golgi apparatus in synthesis of lactose. Synthesis of lactoseosmotically draws water into the Golgi and secretory vesicles. This process allows forsecretion of large amounts of milk and is the most obvious manifestation of stage 2 oflactogenesis. At the same time, synthesis of other milk components is increased. Thecontent of α-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 beenestablished. The changes in mammary cell numbers (by growth or by cell death) and inmilk yield per cell are regulated in part by galactopoietic hormones and in part by localmammary factors. The role of milk removal complicates interpretation of the hormonalrequirements for milk synthesis. Without frequent emptying of the mammary gland, milksynthesis will not persist in spite of adequate hormonal status. Conversely, maintenanceof intense suckling or milking stimulus will not maintain lactation indefinitely.Nevertheless, suckling or actual removal of milk is required to maintain lactation.

Role of HormonesThe maintenance of lactation is at least partly controlled by a group of hormonescollectively known as galactopoeitic hormonal complex. The hormonal complex includesprolactin, growth hormones, Thyroid hormones, and glucocorticoids.

Role of Prolactin

Prolactin is generally a galactopoeitic hormone. However, considerable variations existamong species regarding the role of prolactin on galactopoeisis. The importance ofprolactin (alone) in maintaining lactation has been established in some nonruminantssuch as rabbits. However, in most nonruminants and ruminants, prolactin is only onecomponent of a hormonal complex that regulates galactopoeisis. The role prolactin incows is ambiguous. Inhibition of prolactin in cows and goats had little effects on milkyield especially when compared with about 50% reduction in rodents and a near completefailure of lactation in rabbits.

There is a milking-induced or nursing-induced release of prolactin. However, this surgeof prolactin is small compared with the peripartum prolactin surge associated withlactogenesis. The milking-induced prolactin surge is a direct link between the act ofnursing (or milk removal) and the galactopoeitic hormones involved in maintaininglactation.

Role of Growth Hormones

Growth hormone is essential for maintaining lactation (galactopoeitic). Growth hormonecoordinates changes in body tissues and physiological processes that support increase insynthesis of lactose, protein, and fat in the mammary gland. Bovine somatotropin (BSTor bovine growth hormone) is now commercially produced and has been used in manydairy herds in the USA. An increase in milk yield of between 10 and 40% has beenreported. 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 notpermitted in Canada due to concerns with cow’s health.

Role of Adrenal Corticoids

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

Role of Thyroid Hormones

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

Role of Ovarian HormonesEstrogen administered in very low doses in galactopoietic. However, higher doses haveinhibitory effects. A combination of estrogen and progesterone is more inhibitory thanestrogen alone. Progesterone alone has no effect on galactopoeisis because there are noprogesterone 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 milkremoval is also important. Nursing or milking stimulus triggers release of galactopoietichormones (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, whichacts peripherally to decrease mammary blood flow. As mammary blood flow declines theavailability of hormones (e.g. prolactin) and nutrients to the gland is reduced. If milk isnot removed, the Feedback Inhibitor of Lactation (FIL) accumulates in the alveolarlumen, 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 intensityalso probably means the vigor with which the young nurse, perhaps involving the degreeof gland emptying which occurs at each nursing or the intensity of stimulation of thenipple.

Autocrine Control of Galactopoeisis

Autocrine control refers to the local factors within the mammary gland that affects milkproduction. Rate of milk secretion increases as milking frequency (removal) increases.Cows milked three times a day produced more milk than cows milked twice daily. Theresponse to milk removal is not likely the result of decreased intra-mammary pressure. Ithas been suggested that a milk constituent acts as an inhibitor of milk secretion and thatremoval 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). Theinhibitor is thought to be synthesized by the mammary secretory cell and in turn inhibitsfurther 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 andmaximal secretion rate is achieved. This gradually slows, as the role of the local factorsbecomes dominant. If milk is not removed, then the secretion rate will eventually drop tozero. However, under normal nursing or milking intervals the secretion rate does not goto 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 alveolarlumen. 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 pressureincreases enough (~70 mm Hg in the cow), then the secretion stops and milk starts to bereabsorbed. In the dairy cow secretion rate reaches zero at about 35 hours after the lastmilking. The inhibition of milk secretion that accompanies increasing intra-mammarypressure is probably caused by a chemical inhibitor rather than the increased pressure ofthe fluid itself.

Milking Frequency

In dairy cows, milking 3 times a day increases milk yield compared with milking twicedaily, although the increase is variable. The increase in milk yield can be up to 25%. Itshould be pointed out that only about 1/3 of that increase can be attributed to a decreasedintramammary pressure, the rest is likely due to better feeding and management. Inswitching from 2X to 3X/day milking, the cow’s response in thought to occur in stageswith 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) Thereis a short term (days to weeks) increase in milk secretion due to stimulation of celldifferentiation. 3) there is a long term (weeks to months) increase in milk secretion due tostimulation of cell proliferation.

lactogeneisis

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