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The Mammary Gland Development of the mammary gland Structure of mammary gland in mature female Inactive mammary gland Low power view of inactive mammary gland High power view of lobules in an inactive mammary gland Active mammary gland Low power view of mammary gland during pregnancy High power view of mammary gland in pregnancy Breast proliferation and lactation Involution Development of Mammary Glands The mammary glands, or breasts, are branched tubulo-alveolar glands. They are believed to be modified apocrine sweat glands. They develop as a pair of epidermal thickenings, called milk lines or mammary ridges, in the four-week old embryo of both sexes. Multiple glands develop along the ridges which extend from the axilla to the inguinal region.  In humans, only one pair usually persists, and the ridges disappear elsewhere.  In the fifth week, the primary bud of the gland grows down into the underlying dermis.  It begins to branch in the tenth week. By the 12th week, secondary buds begin to form, and will lengthen and branch throughout gestation.  In the second trimester fetus, 15-25 ingrowths of the epithelium penetrate the underlying connective tissue. They will give rise to the  lactiferous ducts, through canalization of the buds of cells. The lactiferous ducts open into a small superficial depression called the mammary pit.  Proliferation of the underlying mesoderm converts the pit into an everted nipple within a few weeks after birth. The skin around the nipple also proliferates to form the areola.   In newborns of both sexes, the ducts may be swollen with secretory material due to the influence of placental and maternal hormones. The exudate sometimes seen on the nipples of newborns is called angel milk or witch's milk.  In males, the mammary glands remain rudimentary. Experiments in mice have shown that testosterone causes an involution of the developing ducts and that its effect is mediated throught the mammary mesenchyme rather than acting directly on the ductal epithelium.  In females before puberty, the glands are composed of the lactiferous ducts which converge at  the nipple. The development of the breasts during puberty constitutes one of the female secondary sexual characteristics. Sometimes supernumerary breasts (polymastia) or nipples (polythelia)  develop along the milk lines. The latter are as common in males as in females.  The most common location is just below the normal breast. More rarely, an ectopic nipple forms off the line of the mammary ridge as a result of migration of mammary tissue.   Structure of  Mammary Gland in Mature Female Each mammary gland has 15-25 lobes of branched, tubuloalveolar glands which radiate from the nipple (mammary papilla). The lactiferous duct is the single excretory duct for each lobe. Beneath the areola, each lactiferous duct dilates into a lactiferous sinus, then narrows again before exiting at the summit of the nipple.  The lobes are separated by fibrous bands of connective tissue. Some of these bands connect with the dermis and are called the suspensory ligaments of Cooper.  The lobes are further subdivided into lobules. A lobule consists of several intralobular ducts (that is ducts within the lobules), which empty into a terminal interlobular duct (duct between lobules). The interlobular ducts empty into one of the lactiferous ducts. The extent of the development of the gland depends on whether it is in a non-lactating (inactive, resting) or lactating (active, secretory) state. The glandular elements of the adult, inactive mammary gland consist of a system of ducts from which large numbers of secretory elements develop during pregnancy.

Inactive mammary gland: In the inactive mammary gland, the glandular elements consist only of ducts. The intralobular ducts and the terminal interlobular ducts are lined with simple cuboidal, sometimes low columnar, epithelium, supported by a prominent basement membrane. A discontinuous layer of myoepithelial cells (or basket cells) lies between the intralobular duct cells and the basement membrane. These cells are epithelial in origin but show many features of smooth muscle cells. They have long, thin, cytoplasmic arms that extend around the duct cells in order to squeeze out the contents. The lactiferous ducts are lined by cuboidal or columnar epithelium for most of their length, by two layers of cuboidal cells in the lactiferous sinus, and, near their opening, by stratified squamous epithelium.  Within the lobules, the connective tissue that surrounds the intralobular ducts is loose and highly vascular. It contains a large number of cells such as fibroblasts, lymphocytes and plasma cells. The lobules have little or no fat. The lobules  are separated from one another by dense connective tissue that may contain abundant adipose tissue. In histological sections, they appear as lightly-staining islands in the surrounding dense connective tissue. The inactive mammary gland undergoes slight changes during the menstrual cycle. Early in the cycle, the ducts appear as cords with little or no lumen.  During the progestational (secretory) phase, the cells increase in height and very slight development of secretory alveoli may begin. Lumina appear in the ducts along with small amounts of secretion, and fluid accumulates in the connective tissue.

Low power view of inactive mammary gland Figure 1 shows a low power view of an inactive mammary gland. The lightly-staining lobules with loose connective tissue stand out from the dense, more darkly staining interlobular connective tissue. Within the lobules, the red-staining intralobular ducts are visible. These empty into interlobular ducts, of which two are indicated by asterisks, which in turn will empty into the much larger lactiferous ducts (not shown) which drain each lobe. Adipose tissue is frequently seen in the interlobular CT, sometimes covering a large area, as in the top right of Figure 1, and sometimes as more scattered cells, such as above the lobules shown here.

High power view of lobules in an inactive mammary gland Figure 2 shows a higher power view of some lobules, with their intralobular ducts, in an inactive mammary gland. There are much fewer collagen fibers and they are much finer than in the surrounding interlobular connective tissue. Cells cannot be distinguished at this magnification but they appear as the sprinkling of purplish dots around the intralobular ducts. An interlobular duct (asterisk) is seen leaving one of the lobules, it lies in the denser interlobular CT. Even at this magnification, it is not possible to distinguish the type of epithelium lining the ducts: it is simple cuboidal or low columnar.

Active mammary gland: Dramatic changes in the mammary gland occur during pregnancy. The ducts  in the lobules proliferate and branch and secretory alveoli sprout from them. Alveoli (or acini) are spherical collections of epithelial cells that become the active milk-secreting structures in lactation. The alveoli are made of cuboidal or low columnar epithelium with myoepithelial cells at their base. They are difficult to distinguish from the ducts (and you are not required to do so). The increase in glandular tissue is accompanied by a great decrease in the amount of interlying connective and adipose tissue. These changes progress during pregnancy. After birth, when the mammary gland is actively secreting, alveoli and their ducts completely predominate. Lobules are separated only by greatly reduced strands of dense interlobular connective tissue.  Plasma cells, lymphocytes and eosinophils infiltrate the fibrous component of the connective tissue.  The lumina of the alveoli also become much larger during pregnancy and especially after parturition, and secretory material is seen inside them. Technically, the term active mammary gland is reserved for the post-natal lactating mammary gland. During pregnancy, the gland is called proliferative. (We are only asking you to distinguish secretory versus non-secretory or resting).

Low power view of mammary gland during pregnancy Figure 3 shows a low power view of a mammary gland during late pregnancy. The lobules have increased in size and are filled with ducts and secretory alveoli. The lumina are much larger than was seen in the ducts (there were no alveoli) in the inactive state, and some secretory material is visible inside them. The amount of connective tissue separating lobules is greatly reduced, and would become even less abundant later in pregnancy and during lactation after birth.

High power view of mammary gland in pregnancy Figure 4 shows a higher power view of the mammary gland during pregnancy showing the alveoli with cuboidal epithelium. Secretory product is seen in many lumina. A blood vessel can be identified.   Breast Proliferation and Lactation Breast proliferation depends on estrogens (affect mainly  ducts) and progesterone (stimulates growth of alveoli) from the corpus luteum and placenta, and also on prolactin, human placental lactogen (or human chorionic somatomammotropin), thyroid hormone and corticosteroids.  As pregnancy progresses, the alveoli begin to secrete a protein-rich fluid called colostrum. It contains less fat, carbohydrate and potassium than milk, but more protein, vitamin A, sodium and chloride. It also contains antibodies which provide passive immunity to the baby. The antibodies are thought to be produced by the lymphocytes and plasma cells that infiltrate the stroma of the breast during its proliferation. They are secreted across the glandular cells. The number of these cells decreases after parturition. A few days after birth, colostrum is replaced by lipid-rich milk. The accumulation of secretory product dilates the alveolar and duct lumina and can be seen in histological sections. Lactation The lactating breast is composed almost entirely of alveoli distended with milk with thin septa of connective tissue between lobules. The secreting cells contain abundant granular endoplasmic reticulum, a moderate number of large mitochondria, a supranuclear Golgi complex and a number of dense lysosomes. Lipid droplets and secretory granules may be present in the apical cytoplasm.  The lipid component of the milk is released by apocrine secretion. It arises as lipid droplets free in the cytoplasm. The droplets coalesce to form large droplets that travel to the apical end of the cell. They become invested with an envelope of plasma membrane as they are released. A thin layer of cytoplasm is trapped between the plasma membrane and the lipid droplet.  The protein component of the mile is released by merocrine secretion. The protein is synthesized in the rough ER, and packaged into membrane-lined secretory granules in the Golgi apparatus. It is released by fusion of the granule's limiting membrane with the plasma membrane of the cell.  The lactating gland resembles the thyroid gland; however, all of the alveoli in a mammary gland are joined to a duct and the place where several alveoli open into a central channel can often be seen. Large ducts can also be seen in the connective tissue septa. (The thyroid, an endocrine gland, has no ducts).  Hormones of Lactation A number of hormones are involved in the control of lactation. The proliferation of the duct system in early pregnancy is stimulated by estrogens, glucocorticoids and growth hormone. Progesterone and prolactin are required for the final steps of lobular maturation, and in humans, placental lactogen (also called chorionic somatomammotrophin) may alse be required. Prolactin is involved in the production of milk sugars, fatty acid synthesis and production of milk fats, and elctrolyte metabolism (Na/K pump). Estradiol stimulates prolactin secretion and increases the number of mammary gland prolactin receptors, while progesterone decreases the number of receptors. Prolactin also upregulates its own receptors.  Placental lactogen has effects similar to those of growth hormone in promoting the growth, differentiation and protein synthesis in mammary glands. Both are involved in lipid mobilization. The glucocorticoids and insulin are required to maintain viability, growth and differentiation of mammary gland cells. The glucocorticoids are involved in water and electrolyte metabolism. Insulin promotes glucose uptake in the active mammary gland, and participates in stimulating the production of milk proteins and lipids.  The major hormones involved in lactation are summarized below: Estrogen: Stimulates development of duct system. Progesterone: Stimulates development of alveoli. Prolactin: Stimulates alveolar maturation, involved in milk sugar and protein production, and water and electrolyte metabolism.  Human placental lactogen (h. chorionic somatomammotropin): Similar to growth hormone. Stimulates growth, differentiation, and protein synthesis in mammary gland. Synergizes with growth hormone in lipid mobilization.  Corticosteroids: Maintains viability of, and involved in growth and differentiation of mammary gland cells. Involved in water and electrolyte metabolism.  Insulin: Stimulates production of milk proteins and lipids. In the active mammary gland, promotes glucose uptake.  Thyroid hormones: General regulation of metabolic processes.  Relaxin: A hormone produced by decidual cells that stimulates the softening of the cervix and pelvic ligaments in preparation for childbirth.  Oxytocin: Stimulates contraction of myoepithelial cells for milk release.  Suckling The act of suckling initiates sensory impulses in the nipple that are conveyed to the hypothalamus. The impulses inhibit prolactin-inhibiting factor, and prolactin is released from the adenohypophysis. The impusles also cause the release of oxytocin from the neurohypophysis. Oxytocin stimulates the contraction of the myoepithelial cells surrounding the base of the alveoli and ducts causing milk ejection. In the absence of suckling, the secretion of milk ceases.  When lactation ceases, the mammary gland reverts to the inactive state. The alveoli eventually undergo complete degeneration and fat and connective tissue increase.  Involution After menopause, the duct system gradually atrophies, with only a few scattered ducts remaining- a condition similar to that of the prepubertal gland. The connective tissue becomes increasingly dense and homogeneous.

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