The Breast And Lactation
The human mammary gland is
derived from ectoderm. It is first visible in the 4-week embryo as a bud or
nodule of epithelial tissue appearing along a line known as the milk crest. In
the more developed embryo, this crest extends from the midaxilla to the
inguinal region and may be the site of supernumerary breasts or nipples in the
adult. The rudimentary epithelial nodule first becomes buried in embryonic mesenchyme,
where it undergoes further differentiation, apparently under the influence of
paracrine signals from the mesenchyme. Secondary epithelial buds form cellular
cords that elongate, bifurcate and cavitate. These cords become the excretory
and lactiferous ducts of the mammary gland.
The human mammary gland is a
compound tuboalveolar structure composed of 15–25 irregular lobes radiating out
from the nipple (Fig. 23.1). Individual lobes are embedded in adipose tissue
and separated by dense layers of connective tissue. Each lobe is further
subdivided into lobules, connected to the nipple by lactiferous ducts. The
lactiferous ducts are lined by a stratified squamous epithelium. Loose connective
tissue (stroma) surrounds the lactiferous ducts and permits their ready
distension during lactation.
At birth, the breast is
rudimentary and consists almost entirely of primitive lactiferous ducts.
Although it may secrete a few drops of milk, called “witch’s milk,” this
secretory function is short-lived and the breast quickly becomes quiescent
until puberty. At puberty, ovarian estrogens stimulate the lactiferous duct
system to grow. After menarche, exposure
to cyclic progesterone induces further ductal growth and development of
rudimentary lobules at the ends of the ducts. The breasts continue to grow for
several years after menarche as the lactiferous ducts progressively subdivide,
elongate and hollow out, and adipose tissue accumulates. However, complete
lobular development and maturation will not occur in the absence of pregnancy.
At the beginning of pregnancy
there is rapid growth and branching of the terminal portions of the rudimentary
lobules under the influence of chorionic gondotropin. Vascularity increases
dramatically. The pregnant woman often perceives these two changes as a
“tingling” or ”tension” in her breasts. This sensation begins shortly after
conception and may last throughout the first trimester. At about 8 menstrual
weeks of pregnancy, sustained progesterone exposures initiates complete
alveolar differentiation. True glandular acini appear as hollow alveoli lined
with a single layer of myoepithelial cells. The highly branched myoepithelial
cells form a loose network surrounding the alveoli. The alveoli connect to the
larger lactiferous ducts through intralobular ducts. Alveolar secretion begins
in the second trimester of pregnancy. By the third trimester, an immunoglobulin-rich
secretion is seen distending the alveoli.
While the role of ovarian
steroids in breast development is clearly clinically established (prepubertal
gonadal failure is associated with absence of breast development), animal
models suggest that other hormones may also be involved in human breast
development. Insulin exposure causes multiplication of epithelial cells and
formation of lobuloalveolar architecture. Complete
cytologic and functional differentiation of the epithelial cells lining the
alveoli requires exposure to cortisol, insulin and prolactin. Receptors for
growth factors such as insulin-like growth factor 1 (IGF-1) and epidermal
growth factor (EGF) have been demonstrated on human mammary cells, suggesting
an important role for their ligands in breast development and function.
Milk formation
Milk has more than 100
constituents. It is basically an emulsion of fat in a liquid phase that is
isotonic with plasma. Mature human milk contains 3–5% fat, 1% protein, 7%
lactose and 0.2% minerals, and delivers 60–75 kcal/dL. The principal class of
human milk lipids is triglycerides. The main proteins in human milk are casein,
α-lactalbumin, lactoferrin, immunoglobulin A, lysozyme and albumin. Casein and
α-lactalbumin are specific milk proteins; α-lactalbumin is part of the enzyme
complex lactose synthetase. Lactose is the primary sugar in human milk. Free
amino acids, urea, creatinine and creatine are also present. Minerals include
sodium, potassium, calcium, mag- nesium, phosphorus and chloride. As the
composition of human breast milk continues to be studied, several peptide
hormones, including EGF, transforming growth factor α (TGF-α), somatostatin and
IGF-1 and IGF-2 have also been identified. The first milk secreted after
delivery is called colostrum. It contains a higher protein content (largely
immunoglobulins) and lower sugar content than subsequent secretions.
The alveolar epithelial cells
that make milk are polarized, highly differentiated cells whose function is to
accumulate, synthesize, package and export the components of milk. At least
four transcellular pathways are required for appropriate milk formation within
the alveolus of the breast. The first involves secretion of monovalent
cations and water. Water is drawn across the alveolar cell by a con-
centration gradient generated by specific milk sugars; ions follow an
electrochemical gradient. The second involves
receptor-mediated transport of immunoglobulins. Immunoglobulin A (IgA)
enters the epithelial cell after binding to its receptor, becomes internalized
and is transported either to the Golgi apparatus or the apical membrane of the
cell for secretion. The third pathway involves the synthesis and transport
of milk lipids, which are synthesized in the cytoplasm and smooth
endoplasmic reticulum. They then aggregate into droplets that coalesce to form
larger fat globules. These are discharged from the apical part of the cell into
the alveolar lumen. The final pathway involves exocytosis of secretory
vesicles containing specific milk proteins, calcium, phosphate, citrate and
lactose. These vesicles form in the Golgi apparatus. Here, casein, the
specific milk protein, forms micelles with calcium and phosphate. The Golgi is
impermeable to lactose. Because lactose is an osmotically active sugar, water
is drawn into the Golgi and lactose content thereby determines the milk’s
liquid volume. A fifth pathway is required for milk formation: it is not
transcellular, but paracellular. Immunoglobulins, such as IgA, plasma proteins
and leukocytes can move between alveolar cells that have lost their tight
junctions.
Regulation of milk production
Regulation of the quantity and
content of breast milk is largely under hormonal control, with prolactin being
the most important regulatory hormone in humans, although its actions require
synergism with several others. Prolactin concentrations in the plasma rise
steadily throughout pregnancy, from less than 20 ng/mL to over 200 ng/mL at term (Chapter 18). In breastfeeding women,
basal serum prolactin levels remain elevated for about 4–6 weeks postpartum,
then fall to nonpregnant levels despite continued lactation. For about the next
2 months, suckling causes spikes of prolactin release. Even with production of
a litre or more of breast milk per day, this reflex is also gradually lost.
The pivotal role of prolactin in
the initiation of breastfeeding was established by blocking secretion of the
hormone from the pituitary using the dopamine agonist, bromocriptine. When
bromocriptine is given to women shortly after delivery, prolactin levels drop
precipitously to nonpregnant levels. Breast engorgement and lactation never
occur. Estrogens can also be used to suppress lactation immediately postpartum,
but they work through a different mechanism. After estrogen administration,
prolactin levels remain quite elevated, but no milk is formed. Thus, estrogens
inhibit the action of prolactin on the breast, which is probably why lactation
does not occur before delivery. With delivery of the placenta, the source of
the large amount of circulating estrogen is removed. Circulating estrogens drop
precipitously and breast milk begins to form within 24–48 h. Bromocriptine
adminis- tered later in the postpartum period also inhibits lactation, but only
until the process no longer depends on prolactin.
Prolactin has several actions at
the cellular level. It stimulates the synthesis of α-lactoglobulin and casein
in breast tissue primed by insulin and cortisol. It stabilizes casein mRNA,
prolonging its half-life eightfold. Prolactin stimulates milk fat synthesis and
may be involved in sodium transport in mammary tissue. Interestingly, and
unlike other polypeptide hormones, prolactin binding to its receptor does not
stimulate adenylate cyclase activity.
The lactation reflex
Although prolactin is responsible
for initiating milk production, milk delivery to the infant and lactation
maintenance depend on mechanical stimulation of the nipple. The suckling
stimulus is known as milk ejection or letdown. Although suckling
is the major stimulus for milk letdown, the reflex can be conditioned. The cry
or sight of an infant and preparation of the breast for nursing may cause
letdown, while pain, embarrassment and alcohol can inhibit it.
The suckling reflex is initiated
when sensory impulses originating in the nipple enter the spinal cord through
its dorsal roots. A multisynaptic neural pathway ascends to the magnocellular
supraoptic and paraventricular nuclei of the hypothalamus via activincontaining
neurons in the nucleus solitarius tract. Impulse recognition results in
episodic oxytocin release from the posterior pituitary. Oxytocin then
stimulates the myoepithelial cells lining the milk ducts to contract, thereby
causing milk “ejection.”
A large surge in prolactin
release is temporally associated with the episodic oxytocin release induced by
nursing, but this surge will occur independently of the oxytocin changes. This
transient pulse of prolactin induces milk formation for the next feeding.
Smoking can inhibit this prolactin surge and cause a decrease in milk
production.
The suckling reflex also affects
the activity of the gonadotropin- releasing hormone (GnRH) pulse generator.
Suckling inhibits gonadotropin release and ovulation does not typically occur.
The effectiveness of lactation in suppressing gonadal function is directly
related to the frequency and duration of nursing. Among the !Kung
hunter-gatherers in Africa, the average interval between births is 44 months in
spite of early postpartum resumption of coitus and lack of contraception.
Mothers nurse about every 15 minutes and children are in immediate proximity to their mothers all day and night
for 2 years or more.
