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Comparative Lactation - Humans


Human Milk
& Lactation

Cows walking to the barn.

This section on human milk and lactation has been adapted from a lecture by Mary Francis Picciano. Dr. Picciano is Professor of Nutrition, at the Pennsylvania State University.


Introduction

The provision of a specialized maternal body fluid for neonatal nutrition allows birth to occur at an early stage of development and provides a time of intense maternal-infant interaction during early behavioral development. In addition the nutritional reserves of the mother can sustain the infant through a period of famine. In recent times humans, uniquely among mammals, have devised relatively safe and effective alternatives to breast-feeding, a phenomenon which has led to a decline in this practice in most parts of the world. These alternatives have several drawbacks: no formula has the same composition as breast milk, bottle-fed infants may be deprived of a nurturing contact with their mothers, and, particularly in less developed countries, formula-feeding may be associated with increased exposure to infection and inadequate provision of nutrients. For all these reasons, pediatricians world-wide have recommended that breast-feeding be practiced whenever possible.

The sections below discuss removal of milk, macronutrient composition of human milk, cellular mechanisms of milk secretion, and regulation of mammary development and function that are espescially relevant to humanlactation.


Removal of Milk

Suckling initiates a neuroendocrine reflex similar to that in other species: afferent impulses travel via sensory neurons from the areola to the hypothalamus. Here they stimulate special (magnocellular) neurons to fire, sending an impulse down their axons into the posterior pituitary where the hormone, oxytocin, is released. The oxytocin flows to the breast via the blood and causes contraction of the myoepithelial cells. The activity of the magnocellular neurons can be profoundly influenced by higher brain centers. For this reason emotional distress can inhibit milk-ejection. Conversely milk-ejection is subject to conditioning so that women often release oxytocin at the sound of their (or someone else's) infant's cry or in response to a picture of their infant.


Macronutrient Composition of Human Milk

Human vs. Bovine Milk Composition

Component

Human Milk

Bovine Milk

Carbohydrates

Lactose

7.3 g/dl

4.0 g/dl

Oligosaccharides

1.2 g/dl

0.1 g/dl

Proteins

Caseins

0.2 g/dl

2.7 g/dl

a-Lactalbumin

0.2 g/dl

0.1 g/dl

Lactoferrin

0.2 g/dl

Trace

Secretory IgA

0.2 g/dl

0.003 g/dl

ß-Lactoglobulin

None

0.36 g/dl

Milk Lipids

Triglycerides

4.0 %

4.0 %

Phospholipids

0.04 %

0.04 %

Minerals

Sodium

5.0 mM

15 mM

Potassium

15.0 mM

45 mM

Chloride

15.0 mM

35 mM

Calcium

8.0 mM

30 mM

Magnesium

1.4 mM

4.0 mM

Carbohydrates. Human milk has a very high lactose content, 7 grams per deciliter or about 200 mM and lactose provides about 40% of the calories available to the infant. The adaptive significance of this high lactose content (the highest of any species currently known) is probably two-fold: (1) The infant brain is large and requires glucose as a metabolic substrate; lactose is broken down into glucose and galactose prior to intestinal absorption. (2) From an osmotic standpoint, the secretion of lactose obligates the concomitant secretion of a large amount of water. This water is sufficient to meet the infant's needs for sweating and transpirational water loss, high in a warm climate, as well as for urine formation. Because lactose can be synthesized only from glucose, maternal glucose utilization is increased by about 30% in the fully lactating woman.

More than 50 oligosaccharides of different structure also have been identified in human milk, these compounds comprise up to 1.2% of mature human milk (compared to about 0.1% of bovine milk). The components of these complex sugars include glucose, galactose, fucose, N-acetylglucosamine, and sialic acid and represent a significant proportion of the nonprotein nitrogen found in human milk. Some of these may act as growth factors for lactobacillus which populates the gastrointestinal tract of the breast-fed infant, or as protective factors against certain bacterial toxins. However, their real function is not understood.

Human milk proteins. Human milk has a relatively low casein content compared with other mammals, approximately 0.2 g/dl in mature milk, probably reflecting the relatively slow growth rate of the human infant. Most of the casein in human milk is bound in micellar form. The casein micelle also contains most of the calcium and phosphate. The other major milk proteins that are synthesized in the mammary gland are a-lactalbumin and lactoferrin, both are present at a concentration of about 0.2 g/dl in mature human milk. a-Lactalbumin functions in the synthesis of lactose, the major carbohydrate in milk. Lactoferrin is an iron-binding protein found in high concentration in human colostrum and milk. It is considered to be a protective factor in milk because of its anti-bacterial properties. Only about 5-10% of its iron-binding capacity is occupied so that one mechanism of bacteriostasis is thought to be binding of iron needed by bacteria to multiply. Lactoferrin concentration in the mammary secretion is increased in colostrum, during mastitis, and following involution. The fourth major milk protein is secretory immunoglobulin A (sIgA), also present in mature milk at a concentration of about 0.2 g/dl. This protein is synthesized by cells of the immune system and transported into milk by a specific mechanism described below. It is also thought to act as a protective factor; its concentration is much higher in colostrum (up to 10 g/dl) and in post-involutional secretion than in mature milk. Other proteins in human milk include lysozyme (which has a particularly high activity in human milk), lipases, growth factors and many others.

Milk lipids. Although the fat content is highly variable, on the average milk lipids comprise about 4% of human milk. The majority of these lipids are triglycerides. About 20% of the triglycerides are synthesized from medium chain fatty acids made in the mammary gland itself, the remaining 80% are derived from plasma. The medium chain fatty acids are unique to mammary secretions. Milk also contains phospholipids and cholesterol in much smaller, but apparently regulated quantities.

Mineral content of human milk. Compared to the mineral content of most milks, human milk contains very small amounts of macrominerals such as sodium (8 mM), potassium (15 mM), chloride (14 mM), calcium (7 mM) and magnesium (about 1 mM). The low concentrations of these substances reflect both the high concentration of lactose (leaving little residual osmotic activity for monovalent ions) and the low concentration of casein providing little binding activity for calcium.

Breast milk vs. formulas. Infant formulas initially were based on cow milk composition, but have evolved somewhat to reflect human milk composition. This is still an area of concern. Infant formulas generally are made from cow milk or soybean ingredients. The casein : whey protein ratio for cow milk is ~80 : 20 compared to human milk with a 40 :60 ratio. Human milk does not establish as hard a curd in the stomach of the infant as cow milk casein will. The presence of ß-lactoglobulin (not present in human milk) or soy proteins in formulas can lead to a dietary protein allergy.

Several amino acid differences exist between human and cow milk that can present problems in feeding cow milk-based formulas to certain infants. Human milk has a high cysteine : methionine ratio and some taurine. Cow milk has a lower cys : met ratio and essentially no taurine. The human infant's liver and brain have only low levels of cystathionase, the enzyme that converts methionine to cysteine (the fetus and pre-term infant are completely lacking this enzyme). Cysteine is important for central nervous system development. Taurine is made from cysteine (the enzyme is cysteinesulfonic acid decarboxylase), and taurine is needed in the infant for brain development and function, retinal development and function, and conjugation of bile salts. Cow milk-based formulas may not contain optimal levels of cysteine or taurine. Another amino acid problem in human milk vs. cow milk-based formulas is the concentration of phenylalanine and tyrosine. Human milk is low in Phe and Tyr (particularly milk from mothers of pre-term infants). Infants have limited ability to metabolize these amino acids, which can build up and cause Phenylalanine Ketone Urea (PKU babies).

Cow milk has lower lactose than human milk. Lactose may be particularly important as a glucose (energy) source for the rapidly developing brain of the human infant. Generally, cholesterol is very low in formulas (1-3 mg/dl) compared to human milk (7-47 mg/dl) or cow milk (10-35 mg/dl). Cholesterol is needed by the infant in challenging the development of cholesterol metabolizing enzymes and it contributes to synthesis of nerve tissue and bile salts.

The Ca : P ratio is 2.29 for human milk vs. 1.26 for cow milk. Formulas low in cow milk can cause hypocalcemia and tetany. High P in formulas may lead to hyperphosphatemia and low serum Ca. Iron is low in human and cow milk, and most formulas are fortified with iron. Both iron and zinc are more efficiently absorbed from human milk than from cow milk.

Contaminants in human milk. Most lipophilic and many hydrophilic compounds will pass into the milk of the mother. Many antibiotics, anticoagulants, antithyroid drugs, alcohol, nicotine, and caffeine will be transferred to the milk. Many lipohilic environmental contaminants which are stored in the body adipose tissue of the mother are mobilized during lactation and end up in the milk (such as pesticides, industrial contaminants like PCBs, and many known carcinogens).


Cellular Mechanisms of Milk Secretion

Milk protein and lactose. The mechanisms of synthesis and secretion of milk proteins and lactose in the human are similar to those in other species.

Synthesis of milk lipid. The mechanisms of milk fat synthesis and secretion are similar to other monogastric species. The major lipid of milk, triglyceride, is synthesized in the mammary alveolar cell from free fatty acids and glycerol. Both of these constituents can be derived from the blood stream or manufactured in the mammary alveolar cell itself. The proportion of fatty acids synthesized in the mammary gland is strongly influenced by diet: on a normal western diet (~40% fat) only about 20% of fatty acids are synthesized in the mammary gland, the remainder are obtained from the chylomicra of the blood stream using the enzyme lipoprotein lipase. Their composition represents the composition of dietary or adipose depot fatty acids. The lipids synthesized in the mammary gland are medium chain (12:0, 14:0, and 16:0) fatty acids rather than the long chain (16:0, 18:1) fatty acids synthesized in the adipose tissues. On high carbohydrate, low fat diets as much as 40% of the fatty acids may be synthesized in the mammary gland. Although the enzyme, thioesterase II, responsible for the early termination of fatty acid synthesis in the mammary gland, has been purified and characterized, the advantage to mother or infant of these medium chain fatty acids is not yet clear.

The fat concentration in milk is probably the most variable of all milk constituents. The most consistent change is an increase from the beginning to the end of the feeding or nursing. Thus, foremilk can have a fat concentration as low as 1%, whereas hindmilk can have a fat concentration approaching 12%. Overall the mean concentration appears to be about 4%; however, this value is subject to large sampling errors unless special care is taken in the collection of milk samples. There is an apparent diurnal variation in milk fat content as well; however, this likely results from varying degrees of emptying of the breast rather than an inherent variation in the rate of lipid synthesis.

Secretion of immunoglobulins into milk. Extensive work on both liver and mammary gland has revealed the presence of a receptor on the basolateral surface of the cell that binds and internalizes dimeric immunoglobulins such as IgA from the interstitial spaces. The IgA is transported across the mammary epithelial cell in vesicles and remains bound to its receptor. Just prior to secretion into the milk space the receptor is cleaved and the IgA is secreted with a portion of receptor, now called secretory component, still attached. Secretory component is thought to partially protect the IgA from digestion in the infant's G.I. tract.

Secretion of salts and water into milk. Although it is known that monovalent ions, such as sodium, potassium and chloride, cross both the Golgi and the apical plasma membranes of the mammary alveolar cell, the mechanisms by which the concentrations of these milk constituents are regulated are poorly understood. Within any species their concentrations are very constant. However, there is tremendous species variation indicating that specific mechanisms must come into play.

Milk composition during pregnancy, mastitis, and after involution. Under these conditions the junctional complexes between mammary alveolar cells become leaky and sodium, chloride, and other plasma constituents appear at higher concentrations in milk, giving the milk a slightly salty taste.


Regulation of Mammary Development and Function

The mammary gland is one of the few organs that undergoes almost the entire cycle of development, differentiation, function, and involution in the adult animal. Each stage has a different control mechanism.

Stages of mammary development. At birth the rudiments of the functional mammary gland are in place: the nipple and areola are formed along with a rudimentary system of mammary ducts extending into a small fat pad on the thoracic wall. The cells of this ductal system are committed mammary alveolar cells and often secrete milk products (witches milk) for a few days after birth of the infant of either sex. It is thought that maternal hormones are responsible for differentiation of these cells to the secretory phase: withdrawal of these hormones brings on temporary secretory activity just as in the mother (see below). Within two weeks the mammary gland has regressed to a rudimentary system of small ducts; it remains at this stage until puberty when the advent of estrogen secretion by the ovaries brings about the first stage of mammogenesis, or mammary development. Mammogenesis is completed during pregnancy, with the gland becoming competent to secrete milk sometime after midpregnancy. The onset of copious milk secretion or lactogenesis is held in check until after parturition. In humans lactogenesis (referred to as the time when the milk "comes in") starts about 40 hours after birth of the infant and is largely complete within five days. Milk secreted during the period between colostrum secretion and mature milk is called transition milk. Full lactation, or the secretion of mature milk, continues as long as the infant receives substantial quantities of milk from his mother, up to three to four years in some cultures. When nursing has ceased the gland undergoes partial involution, a process which is only completed after menopause. Each of the four stages of mammary development, mammogenesis, lactogenesis, lactation and involution is specified by both systemic and local hormonal control mechanisms.

Regulation of mammogenesis. Mammogenesis commences at puberty with the onset of estrogen secretion by the ovaries, usually between the ages of 10 and 12 in the girl. Estrogen causes enlargement of the mammary fat pad, one of the most estrogen-sensitive tissues in the human body, as well as lengthening and branching of the mammary ducts. About 40% of male children also initiate mammary development during puberty due to the tendency of the testis to secrete significant quantities of estrogens in early phases of its development. As testosterone secretion increases this function is lost. Estrogen stimulates mammary growth and acts through both local effects on mammary tissue and through stimulation of pituitary growth factors. An intact pituitary gland is necessary for estrogen stimulation of mammary growth in animals. With the onset of the menstrual cycle the presence of progesterone stimulates the partial development of mammary alveoli, so that by the age of 20 the mammary gland in the woman who has not been pregnant consists of a fat pad through which course 10 to 15 long branching ducts, terminating in grape-like bunches of mammary alveoli. In the absence of pregnancy the gland maintains this structure until menopause.

During pregnancy full lobuloalveolar development takes place under the continued stimulation of estrogen, progesterone and the rising levels of prolactin from the pituitary and placental lactogen (also called human chorionic somatomammotropin) from the placenta. The cells of the mammary fat pad diminish in size and their place is taken by the developing ducts and alveoli. About midpregnancy the gland begins to produce small amounts of a protein- and fat-rich mammary secretion sometimes referred to as precolostrum. It seems likely that mammary development continues through the duration of pregnancy since milk secretion by mothers of premature infants often appears to be diminished. Although the mammary cells are fully competent to secrete milk after about mid pregnancy, the process is held in check by the high levels of circulating progesterone.

Lactogenesis. In most species lactogenesis, or the onset of copious milk secretion, occurs just prior to parturition. However, in humans (and guinea pigs) the process is delayed for about 40-48 hours due to a delay in the fall of progesterone to levels that no longer inhibit lactation. Three factors are necessary for successful lactogenesis: a developed mammary epithelium, continued high plasma prolactin levels, and a fall in progesterone and estrogen. The process can be inhibited by drugs like bromocryptine that inhibit pituitary prolactin secretion. It has been shown to be delayed in certain women in the presence of retained placental fragments which presumably secrete progesterone. It can be partially inhibited by high doses of estrogen, a treatment that is no longer used because of the risk of uterine cancer. It is important to note that the milk "comes in" at the same rate whether the infant suckles during the first 48 hours or not. Thus the onset of milk secretion depends, not on milk removal from the breast, but on the changes in hormonal status associated with parturition. As we will see below, continued milk secretion does depend on milk removal from the breast. The involutional process sets in after 3 to 4 days if breast-feeding is not initiated.

Lactogenesis is associated with an abrupt increase in milk volume secretion, which goes from a mean of about 50 ml per day on day two of lactation to about 500 ml per day on day 4. After this time there is a gradual volume increase to about 850 ml/day by three months postpartum. There are also profound changes in milk composition during the early postpartum period as the junctional complexes between the cells close and the production of milk products comes into high gear. The most notable changes are a decrease in sodium and chloride concentrations, an increase in lactose and citrate concentrations and an increase in fat concentration. These changes are not synchronous. Rather sodium and chloride fall and fat rises during the first 24 hours after parturition while lactose and citrate rise somewhat more slowly indicating that the processes of tight junction closure and the onset of intense secretory activity are asynchronous. In addition the protein concentration of the protective proteins IgA and lactoferrin increase. By 10 days postpartum the milk has assumed the composition characteristic of mature milk. There are minor composition changes that continue throughout lactation.

Lactation. Milk production appears to continue in women so long as the infant is suckled more than one time per day. Two hormones are necessary for this continued production: oxytocin and prolactin. As discussed above oxytocin is necessary for the milk ejection reflex that extrudes milk from the alveolar lumen. Prolactin is necessary for continued milk production by the mammary alveoli. The secretion of both hormones is promoted by the afferent nerve impulses sent to the hypothalamus by the process of suckling. However, whereas the secretion of oxytocin is highly influenced by the activity of higher brain centers, prolactin secretion appears to be determined primarily by the strength and duration of the suckling stimulus. Although prolactin levels fall with prolonged lactation, at least some basal level appears to be necessary for continued milk production.

Role of local factors in regulation of milk production. There is growing evidence that the volume of milk produced by women is primarily a function of infant demand and is unaffected by maternal factors such as nutrition, age, parity (except at very high parities). From a physiological standpoint the important question is "how does the amount of milk withdrawn from the breast alter the rate of milk synthesis?" There appears to be no direct relation between prolactin levels and milk production and therefore it is thought that the rate of milk production depends on control mechanisms localized within the mammary gland. The milk itself contains an inhibitor of milk production (Feedback Inhibitor of Lactation; FIL) that builds up if the milk remains in the gland over a prolonged period of time. Adequate milk removal from the breast is absolutely necessary for continued milk production.

Infant demand in the regulation of milk production. It is becoming increasingly clear that maternal nutrition and other maternal factors play a surprisingly small role in the regulation of human milk production. Furthermore, there appears to be a quantitative link between infant demand and the amount of milk produced. During weaning, the rate of milk production decreases in proportion to the amount of supplementary food taken in by the infant. These findings are important, because they suggest that infant factors should be considered first when problems of inadequate milk production are encountered.

Involution. Although there is a reduction in milk production during gradual weaning, the term involution is restricted to the changes in the mammary gland that occur after complete cessation of lactation. These changes have been incompletely documented histologically in women, but appear to involve a gradual replacement of ducts and alveoli with stromal and fat tissue and the reversion of the mammary alveolar cells to a less differentiated state. There is substantial loss of epithelial cells, probably through apoptosis (programmed cell death). Suckling alone may promote reinduction of lactation in this state, although the evidence here is mainly anecdotal based on suckling of infants by aunts and grandmothers in some tribal societies. In any case complete regression of the gland to the virgin state appears only to occur after menopause with the loss of all female sex steroid hormones.

Pre-term infants.

- enzymes for carbohydrate metabolism are not fully developed
- protein, Ca and Na in human milk are too low for growth equal to that in utero
- if they receive human milk between 28 and 32 weeks of gestational age, there is;
inadequate weight gain
inadequate increase in body length
inadequate skeletal mineralization
- some per-term infants are too weak or developmentally unable to suckle

 
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