Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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Vitamins

0020 All nutritionally essential vitamins are found in

human milk. Fat-soluble vitamins are present in the

core of milk fat globules (vitamin A, vitamin K) or

bound to membrane or specific binding proteins (vita-

min E, vitamin D). Water-soluble vitamins such as

folate and vitamin B

are bound to specific whey

proteins.

0021 Typical levels of vitamins in colostrum and mature

human milk are presented in Table 2. Stage of lacta-

tion and particularly maternal nutritional status are

the most important factors affecting the vitamin

content of human milk (Table 4). In general, when

maternal vitamin intakes are low, milk levels are also

low and respond to supplementation; when they are

high, milk levels approach a plateau and are less

responsive to maternal supplementation. For many

vitamins, such as folate and vitamin E, levels in milk

are largely preserved through maternal regulation

even, if maternal status is poor. For others, such as

vitamin A, vitamin D, and vitamin B

, levels in milk

may be very low with maternal deficiency, and in this

situation, inadequate for infant nutrition. Premature

delivery is another factor affecting vitamin levels in

human milk. Preterm milk has a high content of

ascorbic acid, vitamin B

, and pantothenic acid

but may not be sufficient to meet the needs of the

preterm infant for thiamin, vitamin B

, vitamin E,

and vitamin D.

0022Fat-soluble vitamins Vitamin A is present in human

milk mainly as retinyl esters (95%) and as free retinol.

Vitamin A activity is also provided as b-carotene

which accounts for up to 30% of total carotenoids

in milk. Other carotenoids present in human milk

are lycopene, lutein, and cryptoxanthin, which have

no provitamin A activity. The total level of vitamin A

shows a rapid decrease over the first month postpar-

tum. Vitamin A milk level is responsive to increased

maternal intake, particularly in mothers with poor

vitamin A status. The retinol:retinyl esters ratio in

mature milk does not change after loading with

vitamin A in well-nourished mothers but it may rise

up to 30% in vitamin A-deficient mothers. Poorly

nourished mothers have a low level of vitamin A

in their milk and are thus at risk of providing insuffi-

cient amounts to the infant. Clinical evidence of

vitamin A deficiency has been found after weaning

in infants reared on breast milk containing 30 mgdl

1

vitamin A or lower.

0023Vitamin E is present in human milk mainly as

a-tocopherol (c. 80%); the b-, d-, and g-isomers are

also present in small quantities. The level is very high

in colostrum and quite stable in mature milk; gener-

ally, it does not respond to maternal supplementation,

tbl0004Table 4 Effects of stage of lactation and maternal diet on

vitamin content of human milk

Vitamin Advancinglactation

Maternal diet

Fat-soluble vitamins

Vitamin A #þ

Vitamin D ¼þ

Vitamin E #¼

Vitamin K ¼¼

Water-soluble vitamins

Ascorbic acid "þ

Thiamin "þ

Riboflavin "þþ

Niacin "þ

Folate "þ

Vitamin B

"þþ

Vitamin B

#þ

Pantothenic acid "þ

Biotin "þ

Mature milk levels (> 1 month postpartum) compared to colostrum (1–5

days postpartum): higher ("), lower (#), or no change (¼).

þ indicates that maternal intake of the vitamin influences milk vitamin

content primarily in deficient women; þþ indicates that maternal intake

influences milk content even when vitamin status of mother is adequate; ¼

indicates no influence of maternal intake on milk content.

Adapted from: Picciano MF Human milk: nutritional aspects of a dynamic

food. Biology of the Neonate 74: 84–93. In: Jensen (1995) Handbook of Milk

Composition, San Diego: Academic Press.

tbl0003 Table 3 Fatty acid composition of human milk lipids with

different diets

Fatty acid

Western diets Nonwestern diets

wt%range wt%range

Saturated fatty acid

8:0 0.17 0.02–0.37 0.37 0.10–0.59

10:0 1.0 0.06–2.4 1.6 0.5–3.4

12:0 4.9 1.7–12.3 8.1 2.4–16.5

14:0 5.6 2.0–11.8 9.6 5.3–15.9

16:0 20.3 19.3–25.1 21.5 14.1–25.8

18:0 7.5 5.8–9.7 5.6 0.80–8.2

Monounsaturated fatty acids

14:1 n-5 0.31 0.22–0.49 0.68 0.19–5.00

16:1 n-7 3.3 1.8–5.0 0.9 0.6–2.2

18:1 n-7 3.4 3.2–3.8 2.9 2.3–3.8

18:1 n-9 (cis) 31.0 22.6–38.7 30.5 17.9–47.0

18:1 n-9 (trans) 3.6 3.1–4.7 0.9 0.5–4.9

Polyunsaturated fatty acids

18:2 n-6 12.6 9.6–16.8 13.8 8.8–23.8

18:3 n-6 0.4 0.09–1.03 0.1 0.07–0.3

20:2 n-6 0.3 0.2–0.5 0.4 0.2–0.8

20:4 n-6 0.5 0.4–0.7 0.5 0.1–0.7

18:3 n-3 0.7 0.3–1.9 0.5 0.1–1.0

20:5 n-3 0.07 0.00–0.16 0.24 0.05–1.10

22:5 n-3 0.05 0.01–0.25 0.24 0.10–0.80

22:6 n-3 0.14 0.00–0.53 0.57 0.10–1.40

Data from: Jensen (1995) Handbook of Milk Composition, San Diego:

Academic Press and Rodriguez-Palmero et al. (1999) Nutritional and

biochemical properties of human milk. Part II: Lipids, Micronutrients, and

bioactive factors. Clinics in Perinatology 26: 335–359.

LACTATION/Human Milk: Composition and Nutritional Value 3453

and is similar between populations with different

vitamin E status, suggesting that maternal vitamin E

stores are mobilized during lactation to insure

vitamin E supply to the neonate.

0024 Vitamin D-active compounds in human milk are

the 25-hydroxylated forms, cholecalciferol and ergo-

calciferol, present in the nonlipid fraction of milk at

1.5–6% of their concentration in maternal plasma.

The level of vitamin D in milk responds to maternal

intake and exposure to sunlight. The level may be

very low in women with poor vitamin D intake

(e.g., strict vegetarians) and in those who live at

northern latitudes. Exclusively breast-fed infants in

areas of poor sunlight exposure may be at risk of

vitamin D deficiency.

0025 Vitamin K in human milk occurs mainly as phyllo-

quinone. Levels in milk do not change consistently

with stage of lactation and do not relate with mater-

nal dietary intake. The level can be increased by

maternal supplementation of vitamin K at very large

doses. In general, it appears that the content of vita-

min K in human milk is low and may not be sufficient

to meet the needs of all newborns. In many countries,

it is recommended that newborns receive vitamin K

after birth.

0026 Water-soluble vitamins Except for vitamin B

, con-

centrations of water-soluble vitamins are lower in

colostrum than in mature milk. In general, levels of

water-soluble vitamins in mature human milk are

several-fold greater than those in maternal plasma.

For example, levels of ascorbic acid, thiamin, vitamin

, and folate in milk are 7–10 times the correspond-

ing plasma levels. This suggests that the mammary

gland actively transports and metabolizes these vita-

mins and regulates secretion, but mechanisms remain

largely unknown.

0027 The impact of maternal nutrition on the concen-

tration of water-soluble vitamins in milk depends on

the specific vitamin, the maternal status, and stage of

lactation. Milk levels of vitamin B

are very low

in strict vegetarian women. The level of folate in

milk is maintained with the concomitant depletion

of maternal folate. Maternal supplementation of

vitamins such as niacin, riboflavin, and vitamin B

affects levels in milk only when maternal status

is inadequate. In well-nourished mothers, maternal

supplementation at high doses has either no effect

(i.e, ascorbic acid, folate, riboflavin) or little effect

(other water-soluble vitamins) on levels in milk. The

content of vitamin B

in human milk responds to

maternal supplementation during established lacta-

tion but not during early stages. The level of vitamin

in milk is greatly reduced in women with long-

term use of oral contraceptive.

Minerals

0028Major minerals in human milk are the monovalent

ions – sodium, potassium, and chloride – and the

divalent species – calcium, magnesium, phosphate

and sulfate – followed by the trace minerals, all

distributed among the different physicochemical

compartments of milk in a highly specific manner.

Several studies have demonstrated a high bioavail-

ability of most minerals in human milk, related to

compartmentation and specific binding, as well

as their favorable interrelationship with other milk

nutrients for efficient utilization by the infant.

0029In general, mineral constituents in human milk do

not correlate with maternal diet or maternal blood

levels. Exceptions are the levels in milk of anionic

elements such as iodine, fluoride, and selenium,

which strongly reflect maternal status and intake,

and also show marked geographic differences. Stage

of lactation affects levels of all minerals in milk, with

most rapid changes occurring during the first few

days postpartum. Typical levels of minerals in

colostrum and mature human milk are presented

in Table 2.

0030Major minerals Electrolytes in milk (sodium, potas-

sium, and chloride ions) are at much lower concen-

trations than those in maternal plasma, and

collectively contribute to 10% of the total osmolarity

of human milk. Variation in levels of electrolytes from

colostrum to mature milk are inversely related to

changes in lactose concentration. Levels are not influ-

enced by nutritional factors or by maternal systemic

diseases such as diabetes, but increase two- to three

fold during mastitis.

0031Calcium is found in human milk mainly in the

aqueous phase (80%), both as a free ion and associ-

ated with low-molecular-weight species such as cit-

rate and phosphate, and bound to casein (20%). The

concentration of ionized calcium in human milk is

quite constant (3 mmol l

1

) throughout lactation.

Total calcium levels in milk increase markedly during

the first days postpartum, stabilize in mature milk,

and decline gradually in extended lactation. Magne-

sium is present mainly in the aqueous fraction of

human milk (90%) and in the lipid globule membrane

(10%). The total concentration of magnesium in

human milk falls gradually during lactation. Mater-

nal diet has no effect on calcium, magnesium, phos-

phate, and citrate levels in milk. Preterm milk may

not be sufficient to meet the infant needs for calcium

and phosphorus.

0032Trace minerals Iron in human milk is distributed in

various compartments, about one-third associated

3454 LACTATION/Human Milk: Composition and Nutritional Value

with low-molecular-weight compounds in the aque-

ous fraction, one-third with the milk fat, mainly

the outer fat globule membrane, and about 10% in

the casein fraction. At least some of the 20–30% in the

whey protein fraction is bound to lactoferrin, a glyco-

protein with two high-affinity binding sites for ferric

iron, but only 3–5% of the total iron-binding capacity

is used. Lactoferrin has been frequently proposed to

account for the high bioavailability of iron in human

milk.

0033 The total concentration of iron in human milk is

highest during the first few days after birth, with a

30% decrease during the first month of lactation

followed by more stable levels. Neither iron supple-

mentation of nursing women with adequate iron

status nor poor maternal iron status has been shown

to affect the level of iron in milk. There are reported

geographic differences in human milk iron levels not

related to maternal diet or nutritional status. The

concentration of lactoferrin is higher in colostrum

(5–6mgml

1

) than in mature milk (1.5 mg ml

1

Lactoferrin content may be elevated in milk of

women with very high iron intakes, and is reduced

in generally malnourished women.

0034 Zinc in human milk is distributed between the

aqueous (40–70%), lipid (10–30%), and casein

(10–45%) fractions. Serum albumin and citrate,

followed by glutamate and picolinate, are the major

zinc-binding ligands in the whey fraction; alkaline

phosphatase, present in the fat globule membrane,

appears as the major zinc-binding protein of human

milk fat; and phosphoserine residues are the primary

zinc-binding sites in caseins. Zinc in human milk

is utilized very efficiently by infants. Breast-fed

infants were shown to maintain high plasma zinc

values compared to formula-fed infants even if

the concentration of zinc in the formula was about

three times that in breast milk. Human milk has

therapeutic value in treating infants suffering from

acrodermatitis enteropathica, a hereditary zinc-defi-

ciency disease.

0035 The concentration of zinc is very high in human

colostrum, then declines throughout lactation. The

most marked decrease (three- to fivefold) occurs

during the first 2 weeks postpartum. Levels do not

appear to be directly related to maternal nutritional

status. Values reported from developed and develop-

ing countries are very similar. The effect of maternal

zinc supplementation on milk zinc levels may depend,

however, on maternal zinc status. For example, in

lactating women with marginal zinc intakes it was

shown that the decline in zinc concentration in milk

over 1–9 months postpartum was significantly less in

zinc-supplemented compared to nonsupplemented

women.

0036Most (75%) of the copper in human milk is in the

whey fraction, mainly associated to serum albumin

and citrate; 15–20% is in the fat phase and the

remainder (5%) is bound to casein. Citrate and free

amino acids are believed to contribute to the efficient

absorption of copper from human milk. The concen-

tration of copper is generally high in colostrum and

falls mainly during the first month but less markedly

than that of zinc. The concentration of copper in

human milk does not appear to be affected by mater-

nal dietary intake or nutritional status of copper. The

copper content of human milk may not be sufficient

to meet the needs of the preterm infant.

Bioactive Components of Human Milk

Defense agents

0037The defense agents in human milk provide protection

for the infant not only against infections, but also

against diseases such as insulin-dependent diabetes

mellitus, Crohn’s disease, and atopic and allergic

diseases. The mucosal surfaces of the intestinal and

respiratory tracts of the infant are the major targets

for their action, but some may also have a systemic

effect after being taken up into the circulation. In

general, the concentrations of the defense agents in

human milk decrease with the progression of lacta-

tion. They are thus higher in a period when the de-

fense system of the infant is immature and when there

is a low production of immune agents in mucosal

secretions. In order to play their roles in the infant’s

intestinal tract, these defense agents have to survive

digestion, at least partially. Compartmentation and

the presence of antiproteinases in milk, resistance to

digestion, and low secretion of hydrochloride and

pancreatic enzymes are mechanisms that allow sur-

vival of the defense factors in the gastrointestinal tract

of the infant.

0038Leukocytes Leukocyte levels are high in colostrum

and decrease in mature milk (less than 10% of the

colostrum value). Neutrophils and macrophages rep-

resent about 90%, and lymphocytes about 10%, of

the leukocytes in human milk. Leukocytes in human

milk may transmit immunocompetence and promote

maturation of the gastrointestinal tract of the infant

through the secretion of cytokines, immunoglobulin

A (IgA), and growth factors. They may also protect

the breast against infection.

0039Soluble antiinfectious agents Many are effective

mainly as antibacterial factors but some may be

antiviral, antifungus, and antiprotozoan factors

LACTATION/Human Milk: Composition and Nutritional Value 3455

also. They may act by direct inhibition of the growth

of pathogens, inhibition of binding of bacterial

pathogens and toxins to mucosal surfaces, and

promotion of the growth of protective microorgan-

isms. The main antiinfectious agents in human

milk are:

0040 Lactoferrin: most of it (> 90%) is present in milk

in the form of apolactoferrin, which competes

with siderophilic bacteria for ferric iron, thus

impairing the proliferation of pathogenic micro-

organisms. However, lactoferrin may have a more

complex antimicrobial effect since it can sensitize

microorganisms to antibiotics and to the attack of

lysozyme by the release of lipopolysaccharides

from bacterial cell walls.

0041 Digestive products of milk lipids: products of

human milk lipid digestion, especially medium-

chain, mono- and polyunsaturated fatty acids

and monoacylglycerols, exert antiviral, antibacter-

ial, and antifungal activity in vitro. The bile salt-

stimulated lipase of human milk appears to be

important in the production of these antimicrobial

lipids.

0042 Enzymes: peroxidase, which is produced by milk

leukocytes, catalyzes the oxidation of thiocyanate

ions to products with bacteriostactic activity.

Lysozyme cleaves peptidoglycans in the cell wall

of susceptible bacteria, causing their lysis.

0043 Secretory IgA and other immunoglobulins (IgG,

IgM, and IgD): secretory IgA (sIgA) is the principal

immunoglobulin in human milk, secreted as

dimeric IgA bound to a secetory component. Its

concentration is higher in colostrum than in

mature milk. sIgA protects the infant against

mucosal pathogens in the maternal environment,

and its antibody specifity reflects the maternal

immunological experience. It causes agglutination

of bacteria, blocks adhesion of several bacteria,

viruses, and parasites to mucosal surfaces in the

intestinal and respiratory tracts, neutralizes

toxins, and prevents translocation of gut bacteria

through the epithelial barrier.

0044 k-Casein and mucin: like other glycoproteins,

including sIgA, they interact with pathogenic bac-

teria and viruses, possibly through their carbo-

hydrate side chains, inhibiting their adhesion to

epithelial cells, thus preventing microbial colon-

ization and invasion of intestinal tissue.

0045 Oligosaccharides: human milk contains several

complex oligosaccharides, which are monomers

of glucose, galactose, N-acetylglycosamine,

fucose, and neuraminic acid. Almost all carry lac-

tose at the reducing end. Oligosaccharides act as

soluble receptor analogs of epithelial cell surface

carbohydrates and are therefore potent inhibitors

of bacterial adhesion to epithelial surfaces. Their

biological functions are closely related to their

conformation. The nitrogen-containing oligosac-

charides also favor the proliferation of intestinal

bifidobacteria and lactobacilli, resulting in an

acidic intestinal environment, which aids in sup-

pressing the growth of enteric pathogens. Glyco-

proteins, such as lactoferrin and k-casein, exert a

similar effect, ascribed to their oligosaccharide

moiety. Glycoconjugates, such as monosialo-

gangliosides, are receptor analogs for heat-labile

toxins produced by bacteria, thus inhibiting bind-

ing of toxins.

0046Anti-inflammatory factors They protect the infant’s

intestinal tract against inflammatory damage and

modulate inflammatory process. Several antiinfec-

tious agents in human milk also have antiinflamma-

tory activity. For instance, lactoferrin inhibits the

formation of oxygen radicals by scavenging free

iron, inhibits the complement system, and suppresses

cytokine release from macrophages stimulated with

bacterial products. Lysozyme interferes with the pro-

duction of superoxide anion. Enzymes such as cata-

lase and glutathione peroxidase act by degrading and

removing hydrogen peroxide. Somatostatin-like

immunoreactivity has been detected in human milk

and may act as an antiinflammatory factor due to its

immunosuppressive properties. Other antiinflamma-

tory factors present in human milk are cortisol,

epithelial growth factor, polyamines, antioxidants

(ascorbate-like compound, uric acid, b-carotene,

tocopherol), and inhibitors of nonoxidative in-

flammatory systems (prostaglandins and platelet-

activating factor).

0047Immunomodulators Human milk components,

besides providing passive protection for the neonate,

may also directly modulate the immunological devel-

opment of the infant. The immunomodulators in

human milk include bioactive substances which

have other primary biological functions, such as hor-

mones and growth factors, substances that present an

overlapping of their antiinfectious or antiinflamma-

tory properties, and those that are actual immuno-

logical factors, such as cytokines and chemokines.

Some examples of the major immunomodulators in

human milk are prolactin, which may modulate

differentiation and function of gut-associated lymph-

oid tissue (e.g., intraepithelial lymphocytes); antiidio-

typic sIgA, which can provide natural immunization to

the infant by sensitizing it against foreign antigens and

microbial agents; lactoferrin, which suppresses in vitro

antibody production and T-lymphocyte proliferative

3456 LACTATION/Human Milk: Composition and Nutritional Value

response to antigens; nucleotides, which can act locally

at the respiratory and alimentary tract, or systemically,

enhancing T-cell maturation and function, and provid-

ing partial resistance to bacterial infection; b-casomor-

phins, which are derived from casein digestion and

have opioid-like activity, and may be able to regulate

intestinal motility and immunostimulating functions.

0048 Several cytokines (interleukin (IL)-1b, IL-6, IL-10,

interferon-g, tumor necrosis factor-a), chemokines

(IL-8, growth-related peptide, monocyte chemotactic

protein) and granulocyte- and macrophage-colony-

stimulating factors are present in human milk. These

substances are protein hormones which mediate both

natural and specific immunity and direct the develop-

ment and functions of the immune system. The poten-

tial role of the immunological factors present in human

milk, which would have to retain their biological ac-

tivity in the gastrointestinal tract and to be transferred

to the circulation of the infant, could compensate for

the developmental delay of the neonate immune

system, both at the mucosal and systemic sites.

Growth factors and hormones

0049 Several nonpeptide hormones and hormonally active

peptides are present in human milk. Among the

former are the thyroid hormones, cortisol, progester-

one, and estrogens. Examples of peptide hormones

and growth factors, which promote the development

and maturation of organ systems, are insulin, epithe-

lial growth factor (EGF) and insulin-like growth

factors (IGF-1 and 2). Both EGF and IGFs stimulate

the growth of intestinal tissue. Other substances in

human milk, such as lactoferrin and nucleotides, also

have similar epithelial growth-promoting activities

of intestinal cells in vitro or in animal models. The

growth and maturation of the gut epithelial barrier

would benefit the infant by limiting the penetration

of foreign antigens in the intestinal mucosa. Gastro-

intestinal regulatory peptides (gastrin, gastric inhibi-

tory peptide, gastrin-releasing peptide, neurotensin,

somatostatin, etc.) and hypothalamic and hypo-

physeal hormones (prolactin, growth hormone,

thyrotropin-releasing hormone, thyroid-stimulating

hormone, gonadotrophin-releasing hormone, etc.)

are also present in human milk. Leptin, a peptide

hormone secreted by adipocytes and involved in the

regulation of energy metabolism and food intake, is

also present in human milk, as a result of the possible

transfer from maternal plasma and also of the secre-

tion by mammary epithelial cells.

Binding proteins for vitamins, minerals, and

hormones

0050 The binding proteins in human milk may improve

solubilization and protect the ligands throughout

their passage in the gastrointestinal tract of the infant

and may increase the bioavailability of the vitamins

and minerals attached to them. Binding proteins for

vitamin D, thyroxine, and corticosteroids are present

in human milk. Cobalamin- and folate-binding

proteins in human milk show antimicrobial effects

in vitro and enhance folate and cobalamin absorption

in the neonatal period through specific receptors

in animal and in intestinal membrane models. How-

ever, their role in cobalamin and folate absorption in

infants is still not known. The role of lactoferrin from

human milk in enhancing iron absorption by the

infant is still controversial, but it might act as a regu-

lator of iron absorption when iron stores are ad-

equate and as an enhancer of iron absorption in

deficiency states.

Enzymes

0051Several enzymes present in human milk are important

in neonatal development. Proteinases, which could aid

in hydrolysis of milk proteins, thus improving their

bioavailability, may have their action limited by the

antiproteinases also present. The antiproteinases

would nevertheless have a beneficial effect by protect-

ing bioactive milk proteins against hydrolysis in milk

and in the infant’s intestine. a-Amylase facilitates the

digestion of polysaccharides by the infant, and its

concentration in milk increases with the stage of lacta-

tion, reaching a plateau at 6 months. This is important,

since salivary and pancreatic a-amylase only reaches

adequate levels in the infant by 2 years after birth.

Lysozyme, peroxidase, and glutathione peroxidase

are all defense agents in human milk.

0052In addition to the lipoprotein lipase, human milk

contains another lipase that is bile salt-dependent. It

is called milk digestive lipase or bile salt-stimulated

lipase and it is the most extensively studied enzyme in

human milk. It facilitates the hydrolysis of milk fat

in the intestine in the neonatal period, aiding the

incipient endogenous lipid digestive function of

the newborn, especially in premature infants. It acts

on lipid substrates and also on water-soluble esters

and its concentration is lower in colostrum than in

mature milk. The milk digestive lipase completely

hydrolyzes triglycerides, since it lacks positional or

fatty acid specificity. The contribution of milk lipases

to the newborn’s endogenous lipases results in an

enhancement of antibacterial and antiviral effects

due to the production of free fatty acids and mono-

glycerides that have antiinfective properties.

See also: Ascorbic Acid: Properties and Determination;

Calcium: Properties and Determination; Copper:

Properties and Determination; Enzymes: Functions and

Characteristics; Fatty Acids: Properties; Growth and

LACTATION/Human Milk: Composition and Nutritional Value 3457

Development; Iron: Properties and Determination;

Lactation: Physiology; Lactose; Pregnancy: Maternal

Diet, Vitamins, and Neural Tube Defects; Retinol:

Properties and Determination; Tocopherols: Properties

and Determination; Vitamins: Overview; Zinc: Deficiency

Further Reading

Fomon SJ (ed.) (1993) Nutrition of Normal Infants. St.

Louis: Mosby.

Jensen RG (ed.) (1995) Handbook of Milk Composition,

San Diego: Academic Press.

Picciano MF (1998) Human milk: nutritional aspects of a

dynamic food. Biology of the Neonate 74: 84–93.

Kunz C, Rodriguez-Palmero M, Koletzko B and Jensen R

(1999) Nutritional and biochemical properties of human

milk. Part I: General aspects, proteins, and carbohy-

drates. Clinics in Perinatology 26: 307–333.

Rodriguez-Palmero M, Koletzko B, Kunz C and

Jensen R (1999) Nutritional and biochemical properties

of human milk. Part II: Lipids, micronutrients,

and bioactive factors. Clinics in Perinatology 26:

335–359.

Physiology

M Neville, UCHSC, Denver, CO, USA

Background

0001 The provision of a specialized maternal body fluid,

milk, for neonatal nutrition frees the mother from the

necessity of providing a specific environment for

rearing of the young. It allows birth to occur at an

early stage of development and provides a time of

intense maternal interaction with the newborn during

early behavioral development. In addition, the nutri-

tional reserves of the mother may be able to sustain

the suckling through a period of famine. For all these

reasons, lactation allows mammals to adapt to a wide

variety of environments. It is becoming increasingly

clear that breast milk is the most appropriate source

of nutrition for human infants at least up to the age

of 6 months. Many components of human milk, in-

cluding, but not-limited to, the protein lactoferrin,

growth factors, long-chain polyunsaturated fatty

acids (LCPUFA), bile salt stimulated lipase, and anti-

infectious oligosaccharides and glycoconjugates are

not duplicated in formula. These components may

be particularly important for the challenged infant

(e.g., the preterm infant, infants with feeding prob-

lems, and infants in homes lacking adequate sanita-

tion) but are increasingly being shown to be beneficial

to healthy infants in well-protected environments as

well.

0002After reviewing the macronutrient composition of

milk, we will summarize the anatomical structure of

the mammary gland at both the gross and micro-

scopic levels to provide a basis for discussion of the

processes of milk secretion and ejection. The stages of

mammary development will be summarized briefly.

The process of lactogenesis, the onset of copious milk

secretion around parturition, will be discussed as it

relates to milk composition, the provision of colos-

trum to the infant, and the relative roles of hormones

and milk removal in initiating milk secretion. We will

examine the regulatory mechanisms that help

adapt the milk supply both to maternal food supply

and to the requirements of the infant. The effects of

dietary composition and maternal metabolic status

on milk composition and secretion will be summar-

ized, followed by a brief discussion of the involution

of the mammary epithelium after the termination of

suckling.

Milk Composition

0003After the period of colostrum formation, the compos-

ition of human milk is relatively constant, although

some nutrients vary significantly within the feed and

with duration of lactation. Breast-feeding can provide

adequate nutrition for at least 4 months after

birth; whether human milk alone provides sufficient

nutrients after this period is currently a matter of

controversy. The major macronutrients in milk are

the sugar, lactose, (a disaccharide unique to milk),

oligosaccharides, milk fat (mainly in the form of tri-

glyceride), proteins, including casein, lactoferrin,

secretory immunoglobulin A (sIgA), a-lactalbumin

and many others present at lower concentrations,

and minerals including sodium, potassium, chloride,

calcium, and magnesium. The secretion mechanisms

for most of these milk components are not as well

understood. There are many minor components, in-

cluding enzymes, vitamins, trace elements, and

growth factors whose function and secretion are less

well understood. The concentrations of the major

components of human milk are compared with

those of bovine milk in Table 1.

0004The major differences between human and bovine

milk can be related to the specific needs of the young

of the two species. For example, the concentration of

lactose is higher and that of the mono- and divalent

ions lower in human than in cow’s milk. The high

concentration of lactose provides a large amount of

‘free water’–that is, water that does not need to be

obligatorily excreted by the kidneys with salts, pro-

viding a reserve for temperature regulation via

3458 LACTATION/Physiology

sweating in human infants. The high concentration of

casein in bovine milk provides protein and associated

calcium and phosphate to support the very rapid

growth of the young calf. In general, casein is re-

moved when bovine milk is used to produce infant

formula designed for the much more slowly growing

human infant. There are a number of agents in human

milk that protect against gastrointestinal and respira-

tory infections, including the oligosaccharides that

recently have been shown to interact specifically

with pathogen receptors, lactoferrin, and secretory

IgA. These compounds are present at very small con-

centrations in bovine milk and infant formula.

The Anatomy of the Breast

0005 The secretory apparatus of the breast consists of

15–25 ducts extending from the nipple and coursing

through the mammary fat pad to terminate in grape-

like clusters of alveoli (Figure 1). Each duct serves a

specific lobule. The lobules are separated and sup-

ported by thick connective tissue septa and, in the

nonpregnant nonlactating breast, by large amounts

of adipose tissue. Blood vessels, nerves, and lympha-

tics run in the septa, which merge imperceptibly with

the fascia at the anterior thoracic wall. The nipple,

which serves as the termination point for the lactifer-

ous ducts, is surrounded by an area of pigmented

skin, the areola, containing sebaceous glands and

sweat glands. The areola serves as the termination

point for the fourth intercostal nerve, which carries

sensory information about suckling to the spinal

cord and brain. This is extremely important in the

regulation of oxytocin secretion from the posterior

pituitary and prolactin from the anterior pituitary.

The mammary ducts expand slightly to form sinuses

beneath the areola.

0006Histologically, the secretory compartment of the

breast consists of ducts and alveoli. The larger ducts

appear to have two layers of cuboidal epithelium.

Smaller ductules and alveoli have a single luminal

epithelial layer surrounded by a discontinuous layer

of contractile cells, the myoepithelium (Figure 2).

This latter network of cells forms a basket-like frame-

work around the alveoli and runs longitudinally

along the ducts. Myoepithelial cells contract in re-

sponse to oxytocin, ejecting milk from the alveoli,

where it is stored after secretion by the luminal

tbl0001 Table 1 Comparison of the macronutrient contents of human

and bovine milk

Component Humanmilk Bovine milk

Carbohydrates (g dl

1

)

Lactose 7.3 4.0

Oligosaccharides 1.2 0.1

Proteins (g dl

1

)

Caseins 0.2 2.6

a-Lactalbumin 0.2 0.2

Lactoferrin 0.2 Trace

Secretory IgA 0.2 Trace

b-Lactoglobulin 0 0.5

Milk lipids (%)

Triglycerides 4.0 4.0

Phospholipids 0.04 0.04

Minerals and other ionic constituents (mM)

Sodium 5.0 15

Potassium 15.0 43

Chloride 15.0 24

Calcium 7.5 30

Magnesium 1.4 5

Phosphate 1.8 11

Bicarbonate 6.0 5

fig0001Figure 1 Camera lucida drawing of a sagital section through

the breast of a 19-year-old nulligravida. From Dabelow A (1941)

Die postnatale Entwicklund der menschlischen Milchdruse

und ihr Korrelationen. Morphology Journal 85: 361–416, with

permission.

LACTATION/Physiology 3459

epithelial cells. Adipocytes are intimately associated

with the glandular elements, as is a prominent blood

supply.

0007 Although the location and external form of the

mammary glands differ from one species to another,

the mechanisms of milk production are remarkably

similar. Milk is produced and stored in alveolar units

like that shown in Figure 2. Removal of the milk is

accomplished by a process called milk ejection,

during which, milk is forced from the alveoli by con-

traction of surrounding myoepithelial cells. Milk

ejection is often called the ‘let-down reflex,’ and the

milk exits through ductules into ducts draining sev-

eral clusters of alveoli. In the human, the small ducts

coalesce into 15–25 main ducts that drain sectors of

the gland. The main ducts dilate into small sinuses as

they near the areola, where they open directly on

the nipple. For milk removal, the entire areola

with the underlying milk sinuses is drawn into the

infant’s mouth, and the milk is withdrawn by

the stripping action of the tongue.

0008 In comparison with related dermal glands such as

the salivary and sweat glands, the rate of milk secre-

tion is slow, about 1.5 ml of milk per gram of tissue

per day, and the secretory product is stored in the

alveolar spaces until it is forced out by myoepithelial

cell contraction. The larger ducts play a passive role

in milk secretion, merely transferring the milk from

the alveolar stores to the subareolar sinuses, where it

is available to the suckling infant. Because the com-

position of the aqueous phase of milk changes very

little during a feed or milking, it is unlikely that

reabsorptive processes, like those important in the

formation of saliva or sweat, play a significant role

in determining milk composition.

0009Although the mammary epithelial cells are ultim-

ately responsible for converting most precursors into

milk constituents and transporting them to the mam-

mary lumen, other cell types are also intimately in-

volved in milk production, as illustrated in Figure 2.

We have already mentioned the myoepithelial cells

responsible for milk ejection from the breast. The

mammary ducts and alveoli are embedded in a stroma

that contains fibroblasts, adipocytes, plasma cells,

and blood vessels. Blood flow is greatly expanded

during lactation to make available the large amounts

of substrate required for milk synthesis. During lacta-

tion, B lymphocytes ‘home’ in to the mammary gland,

where they become plasma cells and settle in the

interstitial space producing the immunoglobulins

that ultimately find their way into milk. Stromal

cells synthesize the growth factor IGF-1, which may

promote survival of mammary epithelial cells. The

mammary epithelium should, therefore, be viewed

as an integrator of the activities of many cells and

organs that contribute in a coordinated fashion to the

synthesis and secretion of milk and its ejection from

the gland.

Mechanisms of Milk Secretion

0010Figure 3 shows a single mammary epithelial cell in a

lactating mammary gland. It is positioned on a base-

ment membrane, and processes of myoepithelial cells

course along its basal surface. Tight junctions join

this cell to its neighbors, and in lactation, they

prevent the direct transfer of interstitial fluid

III

MFG

FDA

Capillary

Golgi

RER

fig0003Figure 3 Mammary epithelial cell showing the pathways for the

secretion of milk components. See text for further information.

SV, secretory vesicles; RER, rough endoplasmic reticulum;

ME, myoepithelial cell process; TJ, tight junction; GJ, gap junction;

D, desmosome; BM, basement membrane; FDA, fat-depleted

adipocyte; PC, plasma cell.

The mammary alveolus and its neighbors

Blood supply

Adipocytes

Myoepithelial

cell

Basal lamina

Alveolusa

d Ductule

Milk

fig0002 Figure 2 Cartoon showing the relation of the mammary epithe-

lial compartment composed of mammary ducts and alveoli to the

other anatomical compartments of the gland: the myoepithelial

cells, the stroma composed of adipocytes and fibroblasts, and the

extensive blood supply. Milk secretion by the epithelial cells into

the alveolar lumen is indicated by arrows.

3460 LACTATION/Physiology

components to the alveolar lumen. Four major trans-

cellular pathways are responsible for the secretion of

milk components during lactation. The paracellular

pathway is open during pregnancy and, under certain

other conditions, allowing movement of interstitial

fluid components into the milk space and the flux of

milk components in the other direction.

Pathway I: Exocytosis

0011 The exocytotic pathway secretes milk components

by a mechanism similar to exocytotic secretion in

all endocrine and exocrine glands. Casein and

a-lactalbumin are synthesized and secreted via this

largely constitutive secretory pathway, which is also

responsible for the secretion of lactose, calcium,

phosphate, citrate, and most other components of

the aqueous phase of milk. Lactose is synthesized in

the terminal portion of the Golgi vesicles from glu-

cose and UDP (uridine diphosphate)-galactose by the

enzyme galactosyl transferase using a-lactalbumin as

an essential coenzyme. Lactose contributes two-

thirds of the osmolarity of human milk. Various gly-

cosyl transferases responsible for the formation of the

wide variety of complex oligosaccharides present in

human milk are also found in the terminal Golgi.

Pathway II: Lipid Secretion

0012 The mechanism for the secretion of lipid is unique to

the mammary epithelium. Triacyglycerols are synthe-

sized in the mammary alveolar cell from glycerol and

free fatty acids. The free fatty acids are derived from

the plasma lipid using the enzyme lipoprotein lipase,

from plasma free fatty acids carried there on albumin

or by synthesis within the alveolar cell from glucose.

Free fatty acids synthesized in the mammary alveolar

cell are medium-chain fatty acids with 12 or 14

carbons rather than the long-chain fatty acids derived

from the plasma. Once synthesized, the triacylglycer-

ols form droplets, merge, and gradually move to the

apical membrane. When they reach the apical surface

of the cell, they press on the membrane, gradually

becoming enveloped, and eventually pinch off as

membrane-bound milk fat globules. The membrane

of the milk fat globule prevents coalescence of the fat

droplets and serves to deliver both triglycerides and

phospholipids to the infant.

0013 The composition of milk triglycerides depends on

the diet. On the usual high-fat diet consumed by the

American woman, the fatty acid composition reflects

dietary lipid with long-chain fatty acids predominat-

ing and a fair proportion of unsaturated fatty acids

reflecting the consumption of vegetable oils (Table 2).

In this condition, only about 10% of the milk fatty

acids are synthesized in the mammary gland itself

as medium-chain fatty acids (C8–C14). On high-

carbohydrate, low-fat diets, the proportion of fatty

acid synthesized in the mammary gland from

carbohydrate increases, leading to an increase in

medium-chain fatty acids, as can be seen from the

data from the milks of Nigerian women in Table 2.

The milks of the Nigerian women also contained a

higher proportion of n-3 LCPUFA. On reduced- or

low-calorie diets, much of the milk fat is derived from

adipose tissue; in this case, the composition of the

triglycerides resembles depot fat.

Pathway III: Transmembrane Transport

0014There are transport mechanisms for only a few milk

components in the apical membrane of the mammary

alveolar cell. This membrane is known to be

permeable to monovalent ions such as sodium, potas-

sium, and chloride, as well as to glucose. It is imper-

meable to divalent cations and disaccharides such as

lactose. The mechanisms that control the substantial

concentration gradients of monovalent cations across

this membrane are not understood.

Pathway IV: The Transcytotic Pathway

0015Proteinaceous substances from the interstitial space

find their way into milk via transcytotic pathways.

tbl0002Table 2 Major fatty acids of human milks (wt%)

Fattyacid Human

milk

Human

milk

Saturated fatty acids

Intermediate- and medium-chain (formed in mammary gland)

8:0 Octanoic acid 0.46

10:0 Decanoic acid 1.03 0.54

12:0 Lauric acid 4.40 8.34

14:0 Myristic acid 6.27 9.57

Long chain

16:0 Palmitic acid 22.00 23.35

18:0 Stearic acid 8.06 10.15

Monounsaturated fatty acids

16:1 n-7 (cis) Palmitoleic acid 3.29 0.91

18:1 n-9 (cis) Oleic acid 31.30 18.52

18:1 n-9 (trans) 2.67 0.86

Polyunsaturated fatty acids (PUFA) (essential fatty acids)

18:2 n-6 Linoleic acid 10.76 11.06

18:3 n-3 Linolenic acid 0.81 1.41

Long-chain PUFA (n-6)

18:3 n-6 g-Linolenic acid 0.16 0.12

20:2 n-6 0.34 0.26

20:3 n-6 Dihomo-g-linolenic acid 0.26 0.49

20:4 n-6 Arachidonic acid 0.36 0.82

Long-chain PUFA (n-3)

20:5 n-3 Eicosapentaenoic acid 0.04 0.48

22:5 n-3 0.17 0.39

22:6 n-3 Docosahexaenoic acid 0.22 0.93

Data from Jensen RG (1995) Handbook of Milk Composition, San Diego, CA:

Academic Press.

Data from Nigerian women who also had a diet high in fish, as reflected in

the n-3 LCPUFA.

LACTATION/Physiology 3461

One of these pathways, that for the secretion of IgA,

is well understood. An IgA receptor on the basolateral

membrane of the cell interacts with dimeric IgA made

by plasma cells residing in the interstitial spaces of the

mammary gland. The IgA is endocytosed and trans-

ported in a vesicle to the apical membrane, where it is

secreted with a piece of its transporter (called

‘secretory component’) into the milk. The secretory

component renders the protein resistant to protease,

and the IgA thus has a reasonable survival time in the

infant’s intestine, where it may contribute to protec-

tion from infectious agents. Many other proteins that

are not synthesized in the mammary alveolar cell

enter milk via transcytosis, e.g., hormones such as

insulin and prolactin, growth factors such as IGF-

1 and even serum albumin.

Pathway V: Paracellular Transport

0016 During lactation, tight junctions (Figure 3) form a

seal between alveolar cells, closing the paracellular

pathway and completely isolating the alveolar lumina

from the interstitial spaces. In pregnancy, after invo-

lution and during mastitis, these junctions open by

mechanisms that are not well understood. At these

times, even large proteins can be transferred between

the milk space and interstitial space. Under these

conditions, plasma components like sodium, chlor-

ide, and albumin enter the milk space directly from

the interstitial space, milk components like lactose

enter the blood stream, and the concentrations of

sodium and chloride in milk are high.

0017 Cells from the immune system pass into milk via

the paracellular pathway. They appear to be able to

squeeze even through the tight junctions of the lactat-

ing gland.

Mammary Development

0018 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 of these stages has different control

mechanisms, only some of which are understood des-

pite decades of study. The developmental cycle of the

mammary gland is usually divided into four stages: (I)

mammogenesis, or development, (II) sensory differ-

entiation (III) secretory initiation, and (IV) lactation

and (V) involution. Mammogenesis takes place in the

embryo, and at puberty. Sensory differentiation may

begin at late puberty and is completed during preg-

nancy. Secretory initiation begins at parturition and is

completed during the first 3–5 days after birth in the

human. Lactation lasts as long as milk continues to be

removed from the breast after birth of the infant.

Involution is the regression of the gland after suckling

has been discontinued. Each phase has its own unique

control mechanisms.

Embryogenesis

0019The mammary gland begins to develop in the fourth

week of fetal life as a thickening of the epidermis that

gradually begins to invade the underlying paren-

chyma forming an epithelial bud. This bud branches

and canalizes forming about 15–20 rudimentary

ducts consisting of a lumen surrounded by a layer of

ductal epithelium with an underlying layer of myo-

epithelial cells. The entire process requires about 28

weeks, during which time, a fully committed epithe-

lial rudiment and an underlying fat pad are formed, as

well as the nipple. It is becoming clear that inter-

actions between the epithelium and the underlying

stroma are critical in determining the morphology

of the structures formed. Towards the end of preg-

nancy, the mammary epithelium of the infant may

become secretory under the influence of the maternal

steroid hormones, and at birth, many infants secrete a

small amount of milky fluid called ‘witches’ milk.

Postnatal Development

0020During childhood, the mammary gland does little

more than keep pace with the general growth of the

body.

Pubertal Development

0021One of the earliest signs of puberty in girls is enlarge-

ment of the breast. This enlargement involves both

the epithelium and the adipose stroma, an obligatory

substratum for epithelial growth. Transplant experi-

ments in rodents have shown that the mammary epi-

thelium grows only in white adipose tissue fat pads

and best in the mammary fat pad. Under the influence

of estrogen from the developing ovary, the ducts

begin to elongate. The most direct evidence that es-

trogen is essential for ductal development comes from

experiments in which time-release pellets were used

to deliver drugs directly into the developing gland.

Implantation of estrogen pellets enhances ductile de-

velopment, whereas implantation of pellets that re-

lease antiestrogens into the local tissue environment

inhibits ductal growth. Estrogen receptors are found

in the stroma as well as in scattered epithelial cells.

Pregnancy

0022During pregnancy, the increasing concentrations of

sex steroids along with prolactin and placental lacto-

gen bring about maximal development of the breast.

Lobular development intensifies until the fat pad is

completely filled with epithelial structures. By mid-

pregnancy, the alveolar cells have differentiated

3462 LACTATION/Physiology