Lactation
Milk, which sustains mammalian infants through
the first few months of life, is
produced by the mammary glands (Fig. 53) under the influence of the pituitary
protein hormone prolactin (Chapter 44). The glands comprise several
lobules that are composed of acini (also called alveoli), similar
in structure to the salivary glands and the exocrine pancreas (Chapters 37 and
40). The lobules empty into lactiferous ducts. As the ducts approach the
areola (nipple), they open out to form lactiferous sinuses before
narrowing again to emerge at the ampulla on the nipple. The ducts and
sinuses are organized so that milk collects within them rather than flowing
freely to the ampulla. They are lined by myoepithelial cells that
contract to expel milk from the breast. Progesterone, oestrogen, prolactin,
cortisol and growth hormone are all required to complete development of the
mammary glands, which occurs during the late stages of pregnancy; for the rest
of adult life the glandular tissue is rather small. Milk is formed by intense
activity of the epithelial cells lining the acinus. The acinar secrete fats
(triglycerides), proteins (principally casein, α-lactalbumin and
lactoglobulin B) and sugars (mostly lactose) to produce an isotonic
liquid that is roughly 4% fat, 1% protein and 7% sugar, with almost 100
additional trace nutrients, including many ions (including Ca2+),
some immunoglobulins (antibodies) in the form of IgA (Chapter 10) and growth
factors, such as insulin-like growth factor-1 (IGF-1) and epidermal growth
factor (EGF) (Chapter 46). Colostrum, the first secretion of the mammary
glands after birth, is particularly rich in protein, but has a lower sugar
concentration than mature milk. It also contains high levels of antibodies (Chapter
10) that provide the infant with basic immunological protection in the first
days of life. At least four secretory processes are synchronized in the
epithelial cells, exocytosis, lipid synthesis and secretion, transmembrane
secretion of ions and water, and transcytosis of extra-alveolar
proteins such as hormones, albumin and immunoglobulins from the interstitial
spaces.
Hormonal control
Plasma prolactin levels rise
steadily during pregnancy, but the lactogenic effects of the hormone are
inhibited by the presence of progesterone and oestrogen, so that its main role
during gestation is to promote mammary growth. Note however that progesterone
and oestrogen are also essential during late
pregnancy to stimulate
duct and alveoli growth respectively, and without this pre-exposure the
mammary glands will not respond to prolactin after birth. The loss of these
placental steroids at term (Chapter 52) allows prolactin to exert its full
effects on milk production, provided that cortisol and insulin are also
present. Placental lactogens, which are similar to prolactin and are
thought to bind to the same receptor, may contribute to mammary gland
development during pregnancy, though their function in humans is not fully
understood. Prolactin acts through a receptor linked to a Janus kinase–signal
transduction and activation of transcription (JAK–STAT) system (Chapter 47)
that activates the genes producing
milk proteins and the synthetic enzymes for lactose and triglycerides. The
production of nutrients is termed galactopoiesis. Prolactin also
increases blood flow to the gland, and stimulates the delivery of nutrients
into milk by exocytosis (proteins) or specific membrane transport systems
(sugars, fats, antibodies); these actions are referred to as lactogenesis.
Prolactin is an unusual anterior
pituitary hormone in that it is released constitutively (i.e. without a
stimulus) from pituitary lactotrophs, and the primary control from the
hypothalamus is inhibitory via dopamine, although other hypophysiotropic
hormones may also be involved (Chapter 44; Fig. 53). After birth, the main
stimulus that maintains prolactin release is suckling. Milk production
thus continues for as long as the infant continues to feed from the mother.
Prolactin inhibits luteinizing hormone (LH) release from the pituitary and
maintains the mother in a
low state of
fertility until the
infant is weaned. This is a useful mechanism for spacing births, but is
not 100% effective in humans. Prolactin-secreting tumours of the pituitary
render the patient infertile, but this can be overcome by the administration of
the dopamine agonist bromocriptine, which inhibits prolactin release long
enough for ovulation to occur. Prolactin is released in several conditions
other than around birth: sleep, stress, eating and exercise are all associated
with elevated plasma prolactin, although the exact function of this release is
not yet known.
Milk let down reflex
Prolactin stimulates milk
production, but another hormone is required to eject milk from the acini onto
the surface of the nipple. Stimulation of areolar mechanoreceptors by suckling
infants activates a neural pathway that ascends to the paraventricular and
supraoptic nuclei of the hypothalamus via the lateral cervical nucleus
of the brain stem. This pathway excites magnocellular neurones (Chapter 44) to
secrete pulses of oxytocin into the blood at 2–10-min intervals. It is not
certain how the suckling stimulus, which is continuous, is translated into
episodic activity in oxytocin-releasing cells. The oxytocin pulses seem to
arise from the simultaneous activation of all oxytocin neurones in both nuclei.
The hormone is a potent stimulant of myoepithelial cells, which pump milk from
the lactiferous sinuses out through the nipple and into the mouth of the
infant. Milk let down encourages further suckling by the recipient, which leads
to more oxytocin release, and so makes up another positive feedback system that
operates until the infant is sated. This milk ejection reflex (Fig. 53)
is also stimulated in response to the crying of infants as a result of
psychological conditioning. However, the reflex is strongly inhibited by
maternal stress, which is one of the most common causes of failure of lactation
in new mothers. In animals, the release of oxytocin in the brain has been shown
to facilitate maternal behaviour, but works only after preexposure to
progesterone and oestrogens.
