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Lactation


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.

Lactation

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.