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Зміст22.2 Development of the mammary gland
494 22 Lactation
496 22 Lactation
22.4 Maintenance of milk production
22.4 Maintenance of milk production
498 22 Lactation
While the fetus develops within its mother's uterus, it receives all the nutrients it requires via the placenta (see Chapter 20). Once it has been delivered, however, the baby needs a regular and plentiful supply of milk. Although in certain human communities, particularly in Western society, bottle-feeding with powdered 'formula milk' offers a suitable alternative, in many parts of the world the mother's breast is the only source of nourishment for the newborn infant. Here, as in all other mammalian species, lactation—the synthesis and secretion of milk following delivery—is as vital to the process of reproduction as gamete fertilization and fetal development. The formation and synthesis of milk is also called galactopoiesis.
Most placental mammals are born at a relatively advanced stage of development. This is the result of the relatively long gestation period which is made possible by the direct link between the maternal and fetal circulations established in the first weeks of pregnancy. Consequently, the infant makes considerable nutritional demands upon its mother. The human infant is no exception, and to ensure that sufficient milk of adequate calorific value is produced from the very start of lactation, preparatory changes must occur within the mammary glands during pregnancy. These changes are regulated by hormones from the placenta, pituitary, and adrenal glands and will be discussed in later sections. First, however, it will be helpful to consider the growth and development of the breasts prior to pregnancy.
The nonpregnant mammary gland is incapable of lactation
Until puberty, the immature breast consists almost entirely of ducts known as lactiferous ducts. At around puberty, gonadotropins begin to be secreted in larger amounts from the anterior pituitary and under their influence (Chapter 19) the ovaries start to increase their production of estrogenic hormones. These steroids initiate further breast development—in particular, the ducts begin to sprout and to become more highly branched. Once menstruation has commenced, progesterone, secreted during the luteal phase of each cycle, stimulates the formation of
small, spherical masses of granular cells at the end of each duct. At this stage these are known as immature alveoli and are the cells which will later develop into the milk-secreting alveoli of the lactating gland in the event of a successful pregnancy. Once menstrual cycles have been established for some time and the mammary glands have been exposed successively to estrogens and progesterone during the follicular and luteal phases of many cycles, the nonpregnant breast is said to be fully developed.
Throughout this adolescent period there is considerable deposition of fat and connective tissue which, together with the ductal growth, bring about a considerable increase in breast size and result in a gland that is highly developed even though no pregnancy has yet occurred. This is in marked contrast to most other mammals, including nonhuman primates, in which very little mammary growth is seen at all until mid or late pregnancy. Figures 22.1 and 22.2 show the basic organization of the human mammary gland. Figure 22.2 also illustrates the way in which the ducts separate the gland into lobes; there are between 15 and 20 lobes separated by fat, each lobe consists of clusters of granular cells at the ends of the lactiferous ducts. The ducts dilate near to the areola (the area of brownish pigment surrounding the nipple) to form lactiferous sinuses, each of which runs up into the nipple and opens onto its surface. Dotted around the areola are small sebaceous glands called Montgomery glands.
Although the mammary gland is fully developed by the end of puberty, small changes do take place during each menstrual cycle, as first estrogens then progesterone influence the mammary tissue. Occasionally there is some degree of secretory activity during the luteal phase of the cycle and there is often an increase in both size and weight of the gland throughout the premenstrual period due to the retention of fluid. Despite its comparatively advanced stage of development, however, the breast is not at this stage capable of large-scale lactogenesis (milk production). Before that can happen, further development, particularly of the alveoli must take place. This occurs during pregnancy, under the influence of a variety of hormones.
The development of the mammary gland during pregnancy
Most of the growth and structural changes that are essential for successful lactation take place during the first 4 months or so of
Fig. 22.1 Diagrammatic representation of the structure of the adult nonpregnant mammary gland, indicating the sites of action of progesterone and estradiol.
pregnancy. By mid-term the mammary gland is fully developed for milk secretion. The lobular ductal—alveolar system which was laid down during adolescence undergoes hypertrophy. The ducts proliferate further and the alveoli mature—the balls of granular cells become hollowed out so that alveolar cells surround a central lumen that is drained by a branch of one of the lactiferous ducts, see Fig. 22.1. The hormones thought to be responsible for these changes are the placental steroids estradiol and progesterone, and the placental peptide hormone hPL (human placental lactogen—Chapter 20). In particular, progesterone seems to be required for the alveolar changes characteristic of early pregnancy. In addition to the placental hormones, pituitary growth hormone and prolactin may also be mammotropic although their contribution at this stage is not clear. Additional adipose tissue is also deposited between the lobules of the gland during early pregnancy, adding further to the size and weight of the breast. Figure 22.2 shows the appearance of the breast tissue during pregnancy.
The alveoli are the primary sites of milk production
The mature alveoli develop under the influence of placental progesterone, prolactin and hPL. Figure 22.3 is a highly simplified diagram showing the basic organization of a mature alveolus. The alveolar wall is formed by a single layer of epithelial cells whose shape can vary from low cuboidal to tall columnar, depending on the amount of secretory material filling the central lumen. During pregnancy, but before the onset of full-scale lactation, the epithelial cells are columnar in appearance, while after delivery, once milk production is underway, the cells are usually squashed flat by material within the lumen. These epithelial cells are, of course, the cells that synthesize and secrete the constituents of milk and they show all the classical characteristics of secretory cells. They possess microvilli on their luminal surfaces and their cytoplasm is rich in mitochondria, Golgi membranes, rough endoplasmic reticulum, secretory granules,
Fig. 22.2 Sectional view of the mammary gland during pregnancy. Note the development of the alveoli.
Fig. 22.3 Cross-section of a mature (lactiferous) alveolus.
and lipid droplets. Adjacent alveolar cells are connected by junctional complexes near to the luminal surfaces, and between the basement membrane and the secretory alveolar cells are specialized cells called myoepithelial cells. These cells are, as their name suggests, contractile, and they are important for moving milk into the lactiferous ducts prior to ejection from the nipple when the baby suckles.
Lactation is triggered by the fall in steroid secretion that follows delivery
Although the breast is fully developed for milk production by around the middle of pregnancy, no significant lactogenesis takes place until after the infant has been delivered. The endocrine changes that follow delivery are necessary to activate the pre-
Fig. 22.4 Changes in the patterns of secretion of hormones before and after birth in relation to their role in the control of lactation. When milk secretion is first initiated, colostrum (C) is secreted which gradually undergoes a transition (T) until mature milk is produced (M). Milk is not secreted until the level of steroid hormones falls following delivery despite the high level of prolactin that prevails in the latter stages of pregnancy.
pared gland and trigger the synthesis and secretion of milk.
It is well established that the primary lactogenic hormone is prolactin, secreted by the anterior pituitary, and that for sustained lactation, high levels of prolactin must be maintained. It is also known that this hormone is secreted in large amounts throughout gestation, so why does lactation not occur during this time? The most widely accepted explanation is that the high circulating levels of the placental steroids, estrogens and progesterone, exert a direct inhibitory effect on the secretory activity of mammary tissue. The gland therefore remains unresponsive even to high levels of prolactin until after parturition. Figure 22.4 shows that while placental estrogen and progesterone levels drop dramatically following delivery, prolactin remains high and is then able to initiate milk production by the fully prepared breast.
The composition of human milk changes
gradually over the first weeks after
The composition of the milk produced by the mammary gland varies with the time that has elapsed since parturition. So-called 'mature milk' is not secreted until about 2 or 3 weeks postpartum. Prior to this time, fluids of varying composition are produced. For the first week or so after delivery, a fluid called colostrum is secreted, at a rate of around 40 ml a day. Colostrum is a sticky, yellowish fluid which, while relatively low in fats, lactose, and some B vitamins, is rich in protein, minerals, and vitamins A, D, E, and K. It also contains significant quantities of immunoglobulins (IgAs) which may provide the newborn infant with some resistance to infection. During the second and third weeks after birth, the composition of the fluid secreted gradually changes (see Table 22.1). Although the proportion of immunoglobulins and other proteins decreases, the milk becomes much richer in fats and sugars and its calorific value increases as a result. At this time the fluid is known as 'transitional milk', but by the time the baby is 3 weeks old the milk has attained its 'mature' composition—it is high in fats, sugars,
Table 22.1 Approximate composition of human breast milk
Note that these values are approximate as the composition changes both during a single feed and during the course of the day. In general, the fat content rises from the beginning to the end of a feed.
and essential amino acids, is iso-osmotic with plasma, and has a calorific value of about 3.1 MJ liter1 (75 kcal per 100 ml).
Breast milk contains fat, milk protein and
milk sugars; their synthesis is hormonally
Most of the fat in human milk consists of medium-chain (10-12 carbons) fatty acids. These are thought to be synthesized de novo within the alveoli of the mammary tissue under the control of the enzymes fatty acid synthetase and medium-chain acylthioester hydrolase. Prolactin and insulin are thought to regulate fatty acid synthesis by the alveoli, whose epithelial cell membranes are especially rich in prolactin receptors. Prolactin is also believed to stimulate the secretion of lipid from the cells into the central lumen of the alveolus. The mechanism by which this secretion takes place is rather interesting. The lipid is manufactured in the endoplasmic reticulum of the alveolar cell and leaves the ER in the form of lipid droplets which then migrate towards the luminal surface of the cell, increasing in size as they do so. Once it reaches the luminal surface, the droplet pushes out against the cell surface membrane, causing a bulge. The area behind the lipid droplet gradually thins and eventually the membrane 'pinches off so that the membrane-bound droplet is released into the lumen.
The major milk proteins are casein, α-lactalbumin, and lactoglobulin
The three major milk proteins have both nutritional and immunological significance, while α-lactalbumin has an additional and specific role in the synthesis of milk sugar. The basic processes of milk protein secretion and synthesis are similar to those occurring in other protein-secreting tissues such as the pancreas and liver. Amino acids, the precursors of protein synthesis, are supplied to the mammary tissue by the maternal circulation and pass from the blood into the alveolar cells via specific carrier systems. The milk proteins are synthesized in the usual way (Chapter 3) by the endoplasmic reticulum and Golgi membranes and are then packaged into vesicles which bud off from the Golgi apparatus into the cytoplasm of the alveolar cell. These vesicles, or granules, move to the luminal surface, possibly by the action of microtubules, and release their contents into the alveolar lumen by the process of exocytosis. The vesicle membrane fuses with the plasma membrane, allowing release of the vesicular contents without the cell cytoplasm coming into contact with the extracellular fluid. This release of protein vesicles, like the budding off of the lipid droplets (see above), is controlled by prolactin. It is important to realize that, while the release of fat results in a loss of cell membrane as the droplet pinches off, the exocytotic release of protein granules adds to the cell membrane by fusion of the granules with plasma membrane.
Human breast rnilk contains more than
50 different oligosaccharides, the most
abundant of which is lactose
In addition to providing the source of many of the other milk sugars, lactose also promotes the growth of intestinal flora and is therefore very important to the newborn infant. Furthermore, galactose, one of the products of lactose metabolism, is an essential component of the myelin that surrounds many nerve fibers (see Chapter 6). Lactose is synthesized within the Golgi apparatus of the alveolar epithelial cells. Its synthesis is dependent on the prior production of α-lactalbumin, which is made in the endoplasmic reticulum and passed to the Golgi. Once there, it combines with galactosyltransferase, an enzyme present within the Golgi membranes, and this enzyme system metabolizes blood glucose to form lactose which is packaged, together with the proteins, in granules that bud off from the Golgi and undergo exocytotic release into the alveolar lumen, as described earlier. The enzyme system comprising α-lactalbumin and galactosyltransferase is stimulated by prolactin but inhibited by the high levels of progesterone circulating throughout gestation.
During lactation, a mother needs to take sufficient nutrients to provide for her own bodily requirements together with those needed by the infant for its growth and development. These needs must be met by the diet. Obviously, the extra requirement will depend on the amount of milk she is producing. As a guide, an average daily feed for a baby weighing 5—6 kg is 0.8—1 liter. Since each liter of mature milk contains the energy equivalent of about 3 MJ (c. 750 kcal), this must be matched by an equivalent increase in the mother's dietary intake. A particular need is for an adequate intake of calcium and phosphate. The normal requirement for a woman of child-bearing age is about 0.8 g a day for both calcium and phosphate. An extra 0.5 g a day of both minerals is normally sufficient to match the quantities secreted in the milk.
After delivery, milk production is maintained by regular suckling
Lactation is initiated by the precipitous drop in steroid levels that occurs following removal of the placenta at the time of delivery. Why though does the breast then continue to secrete milk for as long as rhe baby requires it after this time? What is the hormonal basis underlying the maintenance of lactation? It is known that lactation will continue normally in women who have undergone removal of their ovaries but not in those who have damaged or absent pituitaries. The critical hormone for continued milk secretion appears to be prolactin. Levels of this hormone must remain high for efficient lactogenesis, and the only way this can be ensured is through regular suckling by the infant. Indeed the suckling stimulus is the single most important factor in the maintenance of established lactation—in the absence of suckling, milk production ceases after 2 or 3 weeks. Suckling, or more correctly, nipple stimulation, induces rhe release of prolacrin from the anterior pituitary gland via a neuroendocrine reflex arc in which the afferent limb is neural and the efferent limb is endocrine. Nerve impulses set up by the mechanical stimulation of the baby suckling at the breasr pass via the spinal cord and brainstem to the hypothalamus. The resulr would seem to be a fall in the output of prolactin inhibitory hormone (which is now known to be dopamine) from the hypothalamic neurons and a subsequent increase in the secretion of prolacrin—remember that prolactin release is usually suppressed by prolactin inhibitory hormone (PIH) (see Section 12.2). The prolactin then stimulates the synthesis and secretion of milk.
Prolactin output is a direct consequence of nipple stimulation
Denervation of the nipple abolishes the release of prolacrin in response ro suckling. It has also been shown rhat the amount of prolactin released depends directly on the strength and duration of the suckling stimulus. If both breasts are suckled together, for example during the feeding of twins, more prolactin is released than when a single infant is suckled. In turn, the amount of milk produced seems ro be determined directly by the levels of circulating prolactin.
To summarize: once lactation is initiated by the removal of inhibitory steroidal influences, galactopoiesis is ensured by the release of bursts of prolactin occurring each time the infant suckles—the baby makes sure of its next meal while enjoying its current one.
Milk ejection is a direct response to the suckling stimulus
The constituents of breast milk are produced by rhe alveolar epithelial cells and secreted into the alveolar lumen under the
influence of prolactin. For this to be of any value to the baby, however, the milk must be moved from the lumen to the nipple. This is the process of milk let-down and subsequent ejection, and is another example of a neuroendocrine reflex occurring as a direct response to the suckling stimulus. The hormone responsible for the let-down and ejection of milk is oxytocin, a peptide hormone synthesized within the hypothalamus and stored and secreted by the posterior pituitary gland (see Section 12.2). When the baby suckles, afferent impulses are initiated in the nipple and areola and travel to the hypothalamus—in particular the paraventricular and supraoptic nuclei. In response to this stimulation, the synthesis and secretion of oxytocin are enhanced. Oxytocin is released into the general circulation and reaches the breast where it stimulates contraction of the myoepithelial cells which, as can be seen in Fig. 22.3, lie within the alveolar basement membrane. When these cells contract, the contents of the alveolar lumen are squeezed out into the lactiferous ducts. As the ducts and sinuses fill with milk, the intra-mammary pressure rises. When it reaches a high enough level milk is actually ejected from the nipple to the suckling baby.
Fig. 22.5 Summary of the principal neuroendocrine pathways responsible for the reflex release of prolactin and oxytocin during suckling.
Figure 22.5 illustrates in a highly simplified diagram the reflex control of both prolactin and oxytocin release during suckling. The output of both hormones rises in synchrony with the episodes of suckling. While suckling seems to be the only effective stimulus for prolactin release under normal circumstances, this is not the case for oxytocin, the secretion of which may be enhanced by a number of other stimuli. Uterine contractions, for example, and mechanical stimulation of the cervix and vagina can initiate oxytocin release, e.g. during parturition (see Section 20.7). The milk-ejection reflex is readily conditioned. In cows, the rattling of the milking equipment may be sufficient to start the release of milk, while in humans the cry of a hungry baby may induce the secretion of oxytocin. By the same token, the milk-ejection reflex seems particularly susceptible to inhibition by stress, both physical and psychological, a response that may be mediated by catecholamines.
After weaning, cessation of suckling suppresses milk production
Lactation normally ceases within 2 or 3 weeks of weaning the baby onto a bottle or solid foods. This is entirely due to the loss of the suckling stimulus. In the absence of mechanical stimulation of the nipple, prolactin secretion declines and lactogenesis gradually slows down. Although milk production itself stops relatively quickly, complete involution of the mammary gland takes about 3 months. At first, milk accumulates in the alveoli and small lactiferous ducts, causing distension and mechanical atrophy of the epithelial structures. The alveolar cells are ruptured and hollow spaces form within the mammary tissue. The distension also causes compression of the capillary network supplying the alveoli and as a result of the reduced perfusion the alveolar cells become hypoxic and lack nutrients. This in turn depresses milk production. Desquamated alveolar cells and glandular debris are phagocytosed and the alveoli disappear almost completely. Consequently, the ductal system starts to dominate and the involuted alveolar epithelial cells revert to the granular, nonsecretory type characteristic of the nonpregnant state (see Fig. 22.1). All these changes occur quite naturally as a direct result of removing the suckling stimulus at the time of weaning.
It is occasionally necessary to suppress lactation artificially and rather more quickly than would occur naturally. The human mammary gland is fully prepared for lactation by the fourth month of pregnancy (Section 22.3). This means that in the event of a miscarriage or abortion after this time, milk production will commence as a result of the decline in steroid secretion following removal of the placenta. Under these circumstances it is clearly desirable to inhibit lactation as rapidly as possible. Years ago this would have been assisted by the application of ice packs and tight bandages to the breasts. Since the discovery that PIH is the neurotransmitter dopamine, pharmacological suppression of lactation has been possible through the administration of dopamine agonists such as bromocriptine.
Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, J. D. (1994). Molecular biology of the cell, (3rd edn), pp. 1160-1. Garland, New York.
Begley, D. J., Firth, J. A., and Hoult, J. R. S. (1980). Human
reproduction and developmental biology, Chapter 14. MacMillan Press, London.
Johnson, M. H. and Everitt, B. J. (1995). Essential reproduction, 4th edn), Chapter 13. Blackwell Scientific, Oxford.
Each statement is either true or false. The answers are given below.
1. a. Suckling is the single most important stimulus for milk secretion and ejection.
b. Prolactin stimulates milk ejection.
c. Oxytocin is secreted in response to suckling.
d. Prolactin stimulates the synthesis and secretion of all
the major constituents of milk.
e. Lactation can be suppressed by dopamine agonists.
2. a. Mature milk has a higher protein content than colostrum.
b. Colostrum has a higher calorific value than mature
c. During pregnancy estrogens stimulate ductal develop
ment while progesterone stimulates development of the
d. Following a miscarriage at 5 months' gestation, lacta
tion will commence.
e. Placental steroid secretion inhibits lactation during
1. Oxytocin is the hormone responsible for milk ejection.
Prolactin stimulates the synthesis of milk. Dopamine is
prolactin inhibitory hormone (PIH) therefore dopamine
agonists will suppress prolactin secretion and milk
2. Colostrum has a higher protein content than mature milk
but has a lower fat and carbohydrate content. It therefore
has a lower calorific value than mature milk. The mam
mary gland is prepared for lactation early in pregnancy
so that loss of placental steroid hormones will initiate
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