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 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.