Lactation Physiology (part 2)

Lactation Physiology (part 2)
فیزیولوژی تولید و ترشح شیر Lactation Physiology (part 2) By: A. Riasi (PhD in Animal Nutrition & Physiology)

Physiology of mammary gland during the dry period
During dry period the gland has three distinct functional states: The period of active involution The period of steady state involution The period of lactogenesis and colostrogenesis: Regeneration and differentiation of secretory epithelial cells Selective transport and accumulation of immunoglobulin The onset of copious secretion The physiology of the mammary gland during the dry period differs markedly from that during lactation. During lactation the primary function of the mammary gland is one of constant and continuous synthesis and secretion of milk. However, during the dry period the gland can be characterized as progressing through three distinct functional states, which are: 1- the period of active involution; 2- the period of steady state involution; 3- the period of lactogenesis and colostrogenesis. The period of active involution begins with the cessation of regular milking and is probably completed by 30 days into the dry period. The period of steady state involution does not have definitive points by beginning and ending but represents the period of time the gland is maintained in the fully involuted state. The length of this functional state will increase or decrease proportional to the length of the dry period and is in contrast to the other two functional periods which are controlled by hormonal or management events. The third functional state is that of lactogenesis - colostrogenesis and is characterized by regeneration and differentiation of secretory epithelial cells, selective transport and accumulation of immunoglobulin and the onset of copious secretion. The active period of lactogenesis and colostrogenesis most likely begins days prepartum.

The mammary gland undergoing transition at two stages: At the beginning of the dry period At the end of the dry period

Reducing the length of the dry period of dairy cows may affect: Postpartum health Reproduction performance Milk production A dry period of 45 to 60 days between lactations is generally recommended to prevent milk production losses in a subsequent lactation. Reducing the length of the dry period without loss of milk yield would improve efficiency of dairy production by reducing the number of unproductive days in the lifetime of a cow. Recently, renewed interest in the effects on postpartum health, reproduction, and milk production have provided conflicting evidence for the argument to shorten the dry period (Kuhn et al, 2006; de Feu et al., 20009; Watters et al., 2009). A better understanding of the mechanisms of mammary changes during the dry period may provide the evidence needed to develop a dry period strategy based on the biological needs of the cow.

Intra-alveolar pressure triggers the events of active involution: The appearance of lysosomes in the secretory epithelial cells. Macrophages enter the mammary tissue and secretion. The rate of synthesis of major milk constituents decrease: Fat Casein Lactose * Citrate * β-lactoglobulin α-lactalbumin The increase in intra-alveolar pressure as a result of milk accumulation is thought to trigger the events of active involution. An early event in involution is the appearance of lysosomes in the secretory epithelial cells. The lysosomes are thought to participate in autophagocytosis of secretory cell constituents. As the cells are degraded there is a loss of cell to cell contact as well as a loss of contact with the basement membrane. Heterophagocytosis of the degraded epithelial cells and the accumulated fat and casein is thought to be a function of the macrophages which enter the mammary tissue and secretion in large numbers during active involution. As a result of these early events in involution, the composition of the secretion changed markedly. The rate of synthesis of the major milk constituents, i.e. fat, casein, lactose, citrate, β-lactoglobulin and α-lactalbumin decreases markedly by 3 to 4 days into involution. The actual concentration of these major constituents in the secretion of the involuting gland varies. The concentration of fat, casein, β-lactoglobulin and α-lactalbumin appears not to undergo major or consistent change. In contrast, the concentration of lactose and citrate, major regulators of osmolarity of mammary secretion, decrease markedly with involution but not prior to 3 days involution.

By 7 days involution, the concentration of serum proteins in mammary secretion is significantly elevated. The permeability barriers are not totally destroyed and the mammary gland maintains a degree of control. The concentration of proteins of mammary secretions changes very little through 3 days involution, but by 7 days involution, the concentration of serum proteins in mammary secretion is significantly elevated. Thus, the marked increase in serum albumin and IgG immunoglobulin that occurs between 3 and 7 days if involution is consistent with the period of major reduction in mammary fluid volume. The increase in blood serum albumin (BSA) probably reflects an increased permeability of the secretory epithelial cell barrier to passive diffusion of serum proteins. The concentration of BSA during involution never approaches the level found in blood serum or the concentration found in mammary secretion during acute inflammation. These findings suggest that the permeability barriers are not totally destroyed and that the mammary gland maintains a degree of control even though degenerative processes are occurring within the tissue.

The concentration of the iron biding protein lactoferrin (Lf) dramatically increase. The major site of synthesis of the Lf found in bovine mammary secretions is thought to be the secretory epithelial cell. Lf is a major protein in the secretion of the non-lactating mammary gland. Lactoferrin is bacteriostatic by virtue of its ability to bind iron with great affinity. A characteristic compositional change associated with involution is the dramatic increase in concentration of the iron biding protein lactoferrin (Lf). Lactoferrin is not specific to milk as it is present in the secretions of most mucosal epithelial surfaces throughout the body. The major site of synthesis of the Lf found in bovine mammary secretions is thought to be the secretory epithelial cell. In normal bovine milk Lf is a minor whey protein and is found at mg/ml. This is in marked contrast to the concentration in human milk (3-5 mg/ml) where it would appear to be the major whey protein. The concentration of Lf increases markedly in mammary secretion during active involution of the mammary gland in both the cow and the human. We have previously postulated that the increased numbers of lysosomes observed in secretory cells undergoing active involution is the source of the Lf observed in secretions of involuting mammary glands. The concentration of Lf is in the order of 0.4 mg/ml at drying off, increases to 1.4 mg/ml at 3 days involution, 8.5 mg/ml at 7 days involution and is generally found at mg/ml by 30 days into the dry period. Lactoferrin is thought to participate in the non-specific defense of the involuting mammary gland and has been reported to be of particular importance with regard to coliform infection. Lactoferrin is bacteriostatic by virtue of its ability to bind iron with great affinity. Thus, invading bacteria are forced to compete with Lf for iron which is required for normal growth of most pathogens. The possible exception is the streptococcal species which apparently have an extremely low iron requirement. However, there are also indications that Lf or peptides derived from LF can be bactericidal. With regard to coliform infection, the bacteriostatic properties of Lf are reversed in the presence of citrate, a normal constituent of milk. Citrate, like Lf, is a chelator of iron and coliform bacteria that can utilize citrate-bound iron. The molar ratio of citrate to Lf determines the degree of coliform growth inhibition in vitro. As the molar ratio decreased, inhibition of coliform growth increased. During involution the molar ratio of citrate to Lf decreases significantly. Examples of changes in the molar ratios are 2,356, 1,197, 581 and 49 at 0, 2, 3 and 7 days involution, respectively. Thus, the molar ratio of citrate to Lf serves as a sensitive marker system for the processes of involution and lactogenesis. While there are numerous reports in the literature supporting the concept of Lf being a mediator of non-specific resistance to infection, there is a rapidly growing body of evidence suggesting that Lf may play an important role in the modulation and control of the functional processes of macrophages, lymphocytes and the PMN. Lactoferrin has been shown to interact specifically with receptors on the surface of the macrophage and the lymphocyte. As previously mentioned, Lf is a normal constituent of the PMN secondary granule. There are reports that Lf can modulate lymphocyte function, and these reports suggest that Lf suppresses the response of these cells to antigen or mitogen. That Lf receptors have been demonstrated on the surface of the macrophage and lymphocyte suggests that Lf may direct or control the influx of these cell types into mammary tissue during involution, and there is reason to speculate that once in the tissue of the involuting mammary gland, the high concentration of Lf may influence or modulate their functional activity.

Development of the Mammary Gland (Mammogenesis)
Mammary gland has allometric and isometric growth The development of mammary growth has five phases: Fetal phase Prepubertal phase Postpubertal phase Pregnancy Lactation Development of the mammary gland (Mammogenesis) Most body growth occurs relatively early in life, while the mammary gland expresses its maximal growth potential during pregnancy and early lactation. Mammary gland has allometric (growing at rates two to four times faster than the rest of the body) and isometric (growth at rates similar to the rest of the body ) growth. Mammary growth can be separated into five phases: 1) fetal, 2) prepubertal, 3) postpubertal, 4) pregnancy, and 5) lactation. Hormonal changes and nutrition levels are two of the factors which influence mammary development. Most research in this area has focused on the importance of growth in prepubertal, postpubertal, and pregnant heifers.

Timeline for the development of the mammary gland in bovines
Development of the Mammary Gland (Mammogenesis) Timeline for the development of the mammary gland in bovines Day 30, condensing ectodermal cells Day 35, mammary line Day 43, mammary bud Day 65, teat development Day 80, sprout Day 150, channel formation Embryonic development of mammary gland During embryonic development, the glandular tissue, which will form the mammary gland mesenchyme, is derived from the ectoderm. In the bovine, by day 30 of gestation, ectodermal cells condense and line up at both sides of the abdomen between the limbs and by day 35 this becomes the mammary line. Subsequently, these lines shorten and, grow more attached and deeper into the mesenchymal cells, forming a crest. At 43 days of age, this structure becomes lenticular and then spherical; by now they are called mammary buds.

The spherical bud still grows deeper into the mesenchymal cells and starts becoming different for males and females. In the female, the spherical bud evolves into a conical structure, which by day 65 starts forming the teats. By day 80, when the crown rump length is 12 cm, it becomes a sprout. The sprouts become canalized by 5 months. The primary channel forms the bases for the future teat cistern. Subsequently, secondary cords grow to make the gland cistern and major ducts; there is some stroma deposited here giving the shape of the mature udder. All canalization is presently explained by apoptosis instead of remodeling or the migration of cells. This process is similar in the ewe and nanny but, in the sow and the mare there are two primary cords associated with each bud and there are no teat cisterns. There is little development until birth.

Prepubertal mammary growth begins as isometric growth, and before puberty becomes allometric. A large portion of mammary growth before puberty is an increase in: Connective tissue Ductal growth Growth of the fat pad PREPUBERTAL MAMMARY GROWTH A large portion of mammary growth before puberty is seen as an increase in connective tissue, ductal growth, and growth of the fat pad. Prepubertal mammary growth begins as isometric growth, and before puberty mammary gland growth becomes allometric. Prepubertal nutrition can have a significant effect on future milk yield.

Feed restricted heifers can have up to 30 percent larger mammary glands at puberty. Studies have also shown that feeding high energy diets during the prepubertal period suppresses serum bovine somatotropin (bST) levels. Prepubertal nutrition can have a significant effect on future milk yield. Raising heifers on high planes of nutrition during prebubertal mammary growth has been shown to have a negative effect on milk yield. Feed restricted heifers can have up to 30 percent larger mammary glands at puberty. Furthermore, mammary tissue on heifers fed ad libitum was over 80 percent fat, while heifers fed a restricted diet have around 65 percent fat, and 13 percent more parenchymal tissue (tissue that will eventually become milk producing tissue) compared with heifers fed ad libitum. It should be noted that mammary parenchymal tissue grows into a layer of fat referred to as the fat pad. Studies have also shown that feeding high energy diets during the prepubertal period suppresses serum bovine somatotropin (bST) levels, and that serum levels of bST have a positive correlation with prepubertal mammary growth. Injections of bST during the prepubertal period can increase prepubertal mammary development compared to non-bST injected control heifers. However, by the time the heifers begin lactating there is no difference in milk yield.

Through the first several estrous cycles after puberty, rapid mammary growth continues. Most of the growth is lost through regression during the luteal phase of each estrous cycle. Nutrition plays an important, though controversial, role in postpubertal mammary development. POSTPUBERTAL MAMMARY GROWTH Rapid mammary growth continues through the first several estrous cycles after puberty has been reached. After this early postpubertal mammary development, the estrogens present during subsequent estrous cycles continues to stimulate mammary growth, although most of the growth is lost through regression during the luteal phase of each estrous cycle. Consequently, the number of estrous cycles after puberty and before pregnancy can influence total mammary growth. Nutrition plays an important, though controversial, role in postpubertal mammary development, with energy intake being particularly critical. Some studies have found that ad libitum feeding has no effect on mammary development after puberty had been reached, while others have found that feeding after puberty affects mammary development. Mammary growth is ovarian dependent, as demonstrated by comparing it to that of ovarioectomized animals, which reaches only 1/3 to 1/10 of that in an intact animal.

Mammary growth is a continuous, exponential process from conception to parturition The greatest increase occurs in mass of parenchymal tissue in late pregnancy. The increasing udder size during the fifth and sixth months of pregnancy is due to: The elongation of mammary ducts The formation of alveoli The reduction of identifiable fat cells in the fat pad MAMMARY GROWTH DURING PREGANCY The majority of mammary growth occurs during pregnancy. Mammary growth is a continuous, exponential process from conception to parturition, with the greatest increase in mass of parenchymal tissue occurring in late pregnancy. The udder increases markedly in size during the fifth and sixth months of pregnancy. This increase in udder size is due to the elongation of mammary ducts, the formation of alveoli, and the reduction of identifiable fat cells in the fat pad. Mammary epithelial cells complete differentiation during pregnancy and milk component synthesis begins. Towards mid pregnancy, a rudimentary system of the glandular lobes and lobules are well formed. In the last month of pregnancy, the alveoli show secretory activities, and the udder begins increasing in size due to the accumulation of the secretory material. By the end of pregnancy, the alveoli have become distended with milk secretion rich in fat globules and immunoglobulins. The primary cause of mammary growth during pregnancy is the simultaneously elevated blood concentrations of estrogen and progesterone, though nutrition has been shown to have a role. High levels of nutrition have been shown to be beneficial in increasing future lactation potential and in improving mammary development. In addition, studies have shown that feeding high levels of energy during pregnancy results in substantial improvements in subsequent milk yields.

Mammary growth continues in early lactation. Persistency of lactation (maintaining peak milk yield) depends on the continual survival of those milk-secreting cells. In rats, increases in total mammary DNA was seen from parturition until weaning. MAMMARY GROWTH DURING LACTATION Mammary growth continues in early lactation, but this growth may account for less than 10 percent of total mammary development in ruminants. After peak lactation (45-60 days after calving), there is a gradual decline in milk yield. Peak milk yield is dependent on the number of milk secreting cells. Persistency of lactation (maintaining peak milk yield) depends on the continual survival of those milk-secreting cells. There has been relatively little intensive research on mammary growth during lactation in dairy cattle, though there are several studies looking at this growth in rats and swine. In rats, increases in total mammary DNA was seen from parturition until weaning. The increase in DNA represents an increase in cell number and this growth is important in determining milk production. Similar results have been found in pigs where total mammary DNA increased through at least three weeks of lactation. The growth and development of the mammary gland during lactation is an area that needs further study.

Hormonal control of mammogenesis
The ovarian steroids are important for mammogenesis. Ovarioectomy affect the parenchyma tissue of mammary gland. The ovarian activity appears to mediate the actions of GH, specifically through changes in IGF-I. During pregnancy, Prl and PL provide support for mammogenesis in some species. HORMONAL CONTROL OF MAMMOGENESIS The processes of mammogenesis or mammary development are strongly controlled by the endocrine system. Role of ovarian steroids in mammogenesis Ovarian activity is important in the development of the mammary gland. Ovarioectomized heifers have smaller mammary glands in volume and in weight than intact animals. Specifically, the parenchyma tissue is affected. The ovarian activity appears to mediate the actions of GH, specifically through changes in IGF-I. Treatment of non-pregnant heifers with estrogen stimulates proliferation of mammary epithelial cells. The initiation of ovarian activity in the heifer results in the allometric growth of the mammary tissue, with respect to the body, for a few cycles and then settles into isometric growth until conception takes place. During cyclic activity, there is no significant exposure to estrogens and progesterone together; growth does not start in earnest until both hormones are present at the same time in sufficient quantities. This takes place during late pregnancy when the CL produces large amounts of progesterone and the feto-placental unit generates elevated levels of estrogens. During pregnancy, Prl and PL provide support for mammogenesis in some species, such as sheep and goats, but its importance in cattle appears to be minimal. Injections of estrogens and progesterone to non-pregnant cows, in quantities sufficient to elevate circulatory concentration to pre-partum levels for seven days, resulted in induction of lactation in 70% of the animals and these reached production levels of 70% higher than in their normal volumes. This effect appears to depend, and correlate with Prl levels available.

Mammogenesis depends not only on hormonal concentration but also on: Receptor availability within the mammary tissue The presence of transport proteins and intracellular lipids that are capable of making steroids unavailable to the tissues. Mammogenesis depends not only on hormonal concentration but also on receptor availability within the mammary tissue, as well as, the presence of transport proteins and intracellular lipids that are capable of making steroids unavailable to the tissues. These mechanisms appear to be responsible for the removal of the progesterone block and the induction of lactogenesis observed at parturition. Concentrations of progesterone receptors on mammary tissue are well correlated with lobulo-alveolar development.

Several other hormones play a permissive and supportive role in mammary growth: Placental lactogens Adrenal gland hormones Thyroid hormones Relaxin Parathyroid hormone Effect of parathyroid hormone-related protein (PTHrP) Role of other hormones in mammogenesis As mentioned before, ovarian steroids, GH and Prl certainly stimulate mammogenesis but several other hormones play a permissive and supportive role in mammary growth. Placental lactogens, which has both Prl and GH like activity, is one of them. Adrenal gland hormones and thyroid hormones also support growth through their role in normal metabolism. Mammary duct development is impaired in hypothyroidism. Relaxin and the parathyroid hormone also support mammogenesis. A protein called parathyroid hormone-related protein (PTHrP) appears to influence mammary uptake of Calcium during lactation. Other potent growth stimulators are the family of insulin-like growth factors. IGF, which are also produced locally in the mammary gland, seem to regulate cell growth, cell differentiation, cell function maintenance, and prevent apoptosis.

Other factors that may affect mammogensis: Insulin-like growth factors (IGF) Epidermal cell factors (ECF) Transforming growth factors (TGF) Fibroblast growth factors (FGFs) Other potent growth stimulators are the family of insulin-like growth factors. IGF, which are also produced locally in the mammary gland, seem to regulate cell growth, cell differentiation, cell function maintenance, and prevent apoptosis. Other compounds supporting cell development are epidermal cell factors (ECF), as well as, transforming growth factors (TGF-Î±), amphiregulin and several heregulins or substances of the family of the ECF. Their presence in mammary tissue during mammogenesis and lactogenesis has been demonstrated but their specific role is not yet understood, although it is known that they trigger DNA synthesis in mammary tissue. Fibroblast growth factors (FGFs) are about 20 small peptides with homologous aa sequences and a strong affinity for heparin and heparin-like glucosaminoglycans (HLGAGs) of the extracellular matrix (ECM). Thus, acting in a paracrine fashion to stimulate local epithelial cell proliferation and mammary gland morphogenesis.

Lactation Physiology (part 2)

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