Lactation

The mammary glands are specialized secretory structures derived from the skin. As the name implies, they are unique to mammals. The secretory portion of the mammary glands is arranged in lobules consisting of branched tubules, the lobuloalveolar ducts, from which multiple evaginations or alveoli emerge in an arrangement resembling a bunch of grapes. The alveoli consist of a single layer of secretory epithelial cells surrounded by a meshwork of contractile myoepithelial cells (Fig. 11) Many lobuloalveolar ducts converge to form a lactiferous duct, which carries the milk to the nipple. Each mammary gland consists of 10 to 15 lobules, each with its own lactiferous duct opening separately to the outside. In the

Arterial Blood

Blood Capillaries

Venous Blood

Arterial Blood

Blood Capillaries

Venous Blood

Secretory Epithelium

Lumen \

Capillary , Milk Duct

Lobularalveolar Duct

Secretory Epithelium

Myoepithelial Cells

Lumen \

Capillary , Milk Duct

Lobularalveolar Duct

Muscle Cells in Wall of Duct

FIGURE 11 Mammary alveolus consisting of milk-producing cells surrounded by a meshwork of contractile myoepithelial cells. Milk-producing cells are targets for prolactin, while myoepithelial cells are targets for oxytocin. (From Turner CW. Harvesting your milk crop, Oakbrook, IL: Babson Bros., 1969, p. 17. With permission.)

inactive, nonlactating gland, alveoli are present only in rudimentary form, with the entire glandular portion consisting almost exclusively of lobuloalveolar ducts. The mammary glands have an abundant vascular supply and are innervated with sympathetic nerve fibers and a rich supply of sensory fibers to the nipple and areola.

Milk secreted by the mammary glands provides nourishment and immunoglobulins to offspring during the immediate postnatal period and for varying times thereafter, depending on culture and custom. Milk provides all of the basic nourishment, vitamins, minerals, fats, carbohydrates, and proteins needed by the infant until the teeth erupt. In addition, milk contains maternal immunoglobulins that are absorbed intact by the immature intestine and provide passive immunity to common pathogens. The extraordinarily versatile cells of the mammary alveoli simultaneously synthesize large amounts of protein, fat, and lactose and secrete these constituents, by various mechanisms, along with a large volume of aqueous medium for which the ionic composition differs substantially from blood plasma. Human milk consists of about 1 % protein (principally in the form of casein and lactalbumin), about 4% fat, and about 7% lactose. Each liter of milk also contains about 300 mg of calcium. After lactation is established, the well-nourished woman suckling a single infant may produce about a liter of milk per day and as much as 3 liters per day if suckling twins. It should be apparent, therefore, that, in addition to hormonal regulation at the level of the mammary glands, milk production requires extramammary regulation by all those hormones responsible for compensatory adjustments in intermediary metabolism (see Chapters 41 and 42), calcium balance (see Chapter 43), and salt and water balance (see Chapter 29).

Growth and Development of the Mammary Glands

Prenatal growth and development of the mammary glands are independent of sex hormones and genetic sex. Until the onset of puberty, there are no differences in the male and female breast. With the onset of puberty, the duct system grows and branches under the influence of estrogen. Surrounding stromal and fat tissue also proliferate in response to estrogens. Progesterone, in combination with estrogen, promotes growth and branching of the lobuloalveolar tissue, but for these steroids to be effective prolactin, growth hormone, IGF-1, and cortisol must also be present. Lobuloalveolar growth and regression occur to some degree during each ovarian cycle. Growth, differentiation, and proliferation of mammary alveoli are pronounced during pregnancy, when estrogens, progesterone, prolactin, and hCS circulate in high concentrations.

Milk Production

Once the secretory apparatus has developed, production of milk depends primarily on continued episodic stimulation with high concentrations of prolactin, but adrenal glucocorticoids and insulin are also important in a permissive sense that needs to be defined more precisely. All of these hormones and hCS are present in abundance during late stages of pregnancy, yet lactation does not begin until after parturition. High concentrations of estrogen and particularly progesterone in maternal blood inhibit lactation by interfering with the action of prolactin on mammary epithelium. With parturition, the precipitous fall in estrogen and progesterone levels relieves this inhibition, and prolactin receptors in alveolar epithelium may increase as much as 20-fold. Development of full secretory capacity, however, takes some time. Initially, the mammary glands secrete only a watery fluid called colostrum, which is rich in protein but poor in lactose and fat. It takes about 2 to 5 days for the mammary glands to secrete mature milk with a full complement of nutrients. It is not clear whether this delay reflects a slow acquisition of secretory capacity or a regulated sequence of events timed to coincide with the infant's capacity to utilize nutrients.

Mechanism of Prolactin Action

Prolactin acts on alveolar epithelial cells to stimulate expression of genes for milk proteins such as casein and lactalbumin, enzymes needed for synthesis of lactose and triglycerides, and the proteins that govern the various steps in the secretory process. The prolactin receptor is a large peptide with a single membrane-spanning domain. It is closely related to the GH receptor and transmits its signal by activating tyrosine phosphorylation of intracellular proteins as described for the GH receptor (see Chapter 44). Binding of prolactin causes two receptors to dimerize and activate the cytosolic enzyme, Janus kinase 2 (JAK-2). Some of the proteins thus phosphorylated belong to the STAT family (for signal transduction and activation of transcription) and dimer-ize and migrate to the nucleus, where they activate transcription of specific genes. Prolactin may also signal through activation of a tyrosine kinase related to the src oncogene and by activating membrane ion channels. The signaling cascades set in motion the various events that accompany growth of the secretory alveoli as well as synthesis and secretion of milk.

Neuroendocrine Mechanisms

Continued lactation requires more than just the correct complement of hormones. Milk must also be removed regularly by suckling. Failure to empty the mammary alveoli causes lactation to stop within about a week and the lobuloalveolar structures to involute. Involution results not only from prolactin withdrawal, but also from the presence of inhibitory factors in milk that block secretion if allowed to remain in alveolar lumens. Suckling triggers two neuroendocrine reflexes critical for the maintenance of lactation: the so-called milk letdown reflex and surges of prolactin secretion.

Milk Letdown Reflex

Because each lactiferous duct has only a single opening to the outside and alveoli are not readily collapsible, application of negative pressure at the nipple does not cause milk to flow. The milk letdown reflex, also called the milk ejection reflex, permits the suckling infant to obtain milk. This neuroendocrine reflex involves the hormone oxytocin, which is secreted in response to suckling. Oxytocin stimulates contraction of myoepithe-lial cells that surround each alveolus, creating positive pressure of about 10 to 20 mm Hg in the alveoli and the communicating duct system. Suckling merely distorts the valve-like folds of tissue in the nipple and allows the pressurized milk to be ejected into the infant's mouth. Sensory input from nerve endings in the nipple is transmitted to the hypothalamus by way of thoracic nerves and the spinal cord and stimulates neurons in the supraoptic and paraventricular nuclei to release oxyto-cin from terminals in the posterior lobe (Fig. 12). These neurons can also be activated by higher brain centers, so that the mere sight of the baby or hearing it cry is often suckling stimulus suckling stimulus

j posterior lobe of pituitary j posterior lobe of pituitary

oxytocin

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