Fino Stefania
Definition
The mammary gland is an accessory of the reproductive system function, since it secreted milk for nourishment of the infant, but structurally and developmentally it is closely related to the integument.
Gross Anatomy
http://www.nature.com/nrc/journal/v2/n2/fig_tab/nrc721_F1.html
Introduction
Breast is localized in the upper ventral region of the torso, both in left and right side.
It’s not only present in human but it’s typical of every primate.
In female it contains the mammary gland that has the function to feed infants.
Also men develop breast but they do not produce female sex hormones that promote breast development and have high amount of testosterone that inhibits the growth.
It reaches its typical exquisite development in women during the early childbearing period but it is present only in a rudimentary form in infants, children and men.
Its average weight is 150-200g, increasing to 400-500 during lactation.
The left is generally slightly larger than the right one.
In the adult nullipara, each breast forms a discoidal, hemispherical or conical eminence on the anterior chest wall:
- Extending from the second to the sixth or seventh rib
- Extending from the lateral border of the sternum into the axilla and it can reach the latissimus dorsi muscle, extending from the lower back to the humerus bone
- Overlay the pectoralis major muscles
Structure
The breast is an inhomogeneous anatomic structure composed of layers of different types of tissue, among which predominate two types: adipose tissue and glandular tissue.
The tissue composition ratios of the breast vary among women; some breasts have greater proportions of glandular tissue than of adipose or connective tissues, and vice versa; therefore the fat-to-connective-tissue ratio determines the density of the breast. In the course of a woman’s life, her breasts will change size, shape, and weight because of the hormonal bodily changes.
The superficial tissue layer (superficial fascia) is separated from the skin by 0.5–2.5 cm of subcutaneous fat.
The suspensory Cooper’s ligaments are fibrous-tissue prolongations that radiate from the superficial fascia to the skin envelope and help maintain structural integrity.
The basic units of the breast are the terminal duct lobular units(TDLUs), which produce the fatty breast milk.
The adult breast contains 14–18 irregular lactiferous lobes that converge to the nipple, through ducts of 2.0–4.5 mm in diameter; the milk ducts (lactiferous ducts) are immediately surrounded with dense connective tissue that functions as a support framework.
The nipple of the breast is centred in an areola (nipple-areola complex, NAC).It has usually a different color than the skin of the breast itself, and it may vary from slightly lighter to very darker.As women sexually mature and also when they are pregnant, the areolae usually darken.
The nipple is surrounded by small bumps that are sebaceous glands called Montgomery's Glands or Areolar Glands. They secrete an oily substance that lubricates and conditions the surface of the nipple and the areola. This is helpful during breastfeeding, to prevent the cracking of the nipple.
Vascularization
The blood supply to the breast skin depends on the subdermal plexus, which is in communication with deeper underlying vessels supplying the breast parenchyma.
The blood supply is derived from the following vessels:
- The internal mammary perforators (most notably the second to fifth perforators)
- The thoracoacromial artery
- The vessels to serratus anterior
- The lateral thoracic artery
- The terminal branches of the third to eighth intercostal perforators
The superomedial perforator supply from the internal mammary vessels is particularly robust and accounts for some 60% of the total breast blood supply.
The venous drainage from the mammary gland is done by veins that generally accompany the arteries.
Medially, the veins drain to
- The thoracica interna vein (a tributary of the brachiocephalica vein)
- Laterally to the axillaris vein
- Intercostales posteriores veins.
The superficial (cutaneous) mammary veins are presented profusely anastomosed and easily visible during gestation, the Haller's vascular network.
Innervation
It is mainly derived from the anterolateral and anteromedial branches of thoracic intercostal nerves T3-T5. Supraclavicular nerves from the lower fibers of the cervical plexus also provide innervation to the upper and lateral portions of the breast.
Researchers believe that sensation to the nipple derives largely from the lateral cutaneous branch of T4.
International Journal of Morphology
Histology
Mammary gland is a specific type of apocrine gland specialized for manufacture of colostrum at the time of parturition.
Cells which are classified as apocrine bud their secretions off through the plasma membrane producing membrane-bound vesicles in the lumen. This method is also called decapitation secretion. The apical portion of the secretory cell of the gland pinches off and enters the lumen.
Secretory tissue is arranged into lobes and each lobes consists of many lobules. Each lobule has:
- a lactiferous duct that drains into openings in the nipple. (When a woman is not lactating, the lactiferous duct is frequently blocked by a keratin plug. This plug prevents bacteria from entering the duct in non-lactating women)
- clusters or groups of alveoli which are surrounded by a network of blood vessels.Each alveolus consists of:
- a single layer of epithelial cells (secretory cells) surrounding the central lumen into which the epithelial cells eject the milk they synthesize. Individual cells are joined to their neighbour cells on every sides by tight junctional complex structure located around the apical portion that forms a tight barrier, which prevents the passage of materials between cells under normal conditions. Secretory cells are probably also bound to adjacent cells through gap junction, which allow low molecular weight materials to pass from one cell to another
- myoepithelial cells, whose processes form a basket-like network around the alveoli where milk is stored, accomplish the milk removal from the breast by their contraction, in concert with sucking by the infant.
Let down reflex
When the infant is sucking, afferent impulses from sensory stimulation of nerve terminals in the areolus travel to the central nervous system where they promote the release of oxytocin from the posterior pituitary.
In the woman oxytocin release is often associated with such stimuli as the sight or sound or even the thought of the infant indicating a large cerebral component in this "neuroendocrine reflex".
The oxytocin is carried through the blood stream to the mammary gland where it interacts with specific receptors on myoepithelial cells, initiating their contraction and expelling milk from the alveoli into the ducts and sub-areolar sinuses.
The passage of milk through the ducts is facilitated by longitudinally arranged myoepithelial cell processes whose contraction shortens and widens the ducts, allowing free flow of milk to the nipple.
The process by which milk is forceably moved out of the alveoli is called milk ejection or let-down and is essential to milk removal from the lactating breast.
Outside the myoepithelial cells, the alveolus is surrounded by a connective tissue basement membrane. The capillary bed outside the alveolus is part of the stromal tissue between alveoli.
OXYTOCIN AND MILK EJECTION by Margaret C. Neville
Development of mammary gland from puberty to pregnancy
Puberty is preceded by several hormonal changes in the body. The female releases follicle-stimulating hormones (FSH) and lutenizing hormone (LH), in a cyclic pattern, from the anterior pituitary gland. These hormones stimulate the ovaries to synthesize and release female sex steroid hormones, }estrogens(estradiol) and progestins (progesterone).
The part of the ovarian cycle characterized by follicular growth is dominated by estrogen,
while the part characterized as the luteal phase of the cycle, when the corpus luteum develops, is dominated by progesterone.
Estrogen stimulates mammary gland proliferation. The growth is mainly that of the ducts lengthening and branching and is carried out in synergism with the anterior pituitary hormones, prolactin and somatotropin. Estrogen by itself does not stimulate duct growth very well. Duct elongation and branching occur at the actively growing end in a structure known as Terminal End Bud (TEB). The TEB represents the structure where elongation and branching of the duct takes place and estrogen stimulated cell division occurs.In general, estrogen causes cell multiplication at the tip of the TEB and enlargement of ducts (lengthening and branching of ducts).
Progesterone, instead, causes duct and ductule cells to multiply, leading to ductule development and duct enlargement or widening.
Receptors of estrogen and progesterone both appear in the mammary gland around the time of puberty.
Species with long cycles (cattle, sheep, goats, horses, humans) exhibit functional corpora lutea, which secrete progesterone during the luteal phase of the cycle. Progesterone synergizes with estrogen, prolactin and somatotropin. During the first several cycles of the female’s life, growth takes the form of duct lengthening, thickening, and branching and eventually a differentiation into lobules and alveoli takes place.
Pregnancy
The major portion of mammary growth occurs during pregnancy and is controlled by hormones. Growth of the mammary gland is slow at the beginning of pregnancy, but the rate of growth accelerates as the pregnancy advances. In the mammary gland of non-pregnant females, a large fatty pad exists. As pregnancy progresses, the adipose cells of the pad are gradually replaced by ducts, alveoli, blood vessels, and connective tissue.
Both estrogen and progesterone are required for optimal mammary growth. Both hormones are elevated during pregnancy. During the estrus cycle, when only one of these hormones is elevated at a time, there is no lobuloalveolar growth.
Prolactin:
- contributes to the increased growth and differentiation of the alveoli
- influences differentiation of ductal structures
- high levels during pregnancy and breastfeeding also increase insulin resistance, increase growth factor levels (IGF-1) and modify lipid metabolism in preparation for breastfeeding.
- during lactation is the main factor maintaining tight junctions of the ductal epithelium and regulating milk production through osmotic balance.
Progesterone is elevated throughout gestation (required for maintenance of pregnancy), while estrogen is particularly elevated during the second half of gestation. Consequently, most of the mammary growth during the first half of gestation is mainly ductal growth and lobular formation. In the second half of gestation, ductal growth continues, but most of the growth is lobuloalveolar.
Estrogen receptors in the mammary tissue initially appear coincidentely with onset of puberty and receptor numbers increase with increasing tissue weight.
Rising concentrations of estrogen:
- increase the synthesis of estrogen receptors
- increase the number of progesterone receptors, which likely contribute to the synergism observed between estrogens and progesterone on mammogenesis before lactation.
Estrogen and progesterone accelerate the rate of cell division in the mammary gland, especially in the TEB.
Progesterone:
- stimulates cell division along the duct wall
- can induce formation of alveoli
However, estrogen and progesterone synergize to produce lobule-alveolar development characteristic of pregnancy.
Proliferation and extension of ducts and alveoli to every areas of the pad continues for the entire gestation period. The significant increase in the mammary gland size during the last month of pregnancy is due to accumulation of secretion in the alveoli.
Lactation
Lactogenesis
Lactogenesis is a series of cellular changes whereby mammary epithelial cells are converted from a nonsecretory state to a secretory state. It is a two-stage process.
Biochemical changes occur in the mammary gland: there is a marked increase in the RNA level of the epithelial cells.
- Stage 1: this coincides with very limited milk synthesis and secretion before parturition when specific milk components make their first appearance in the mammary gland.
Enzymatic changes include increased synthesis of acetyl CoA carboxylase, fatty acid synthetase and increases in uptake of amino acids, glucose and other substrate for milk production.
Lactose synthesis does not begin until stage 2 of lactogenesis.
- Stage 2: copious milk secretion begins when the release of the inhibitory effects of progesterone on lactogenesis and the stimulation by the very high blood concentrations of prolactin and glucocorticoids associated with parturition occur.
At parturition, coincident with the onset of stage 2, not only is milk flow rapidly enhanced, but also the glands absorb increased quantities of metabolic substrates from the blood. A marked transition in secretory composition , from colostrum to milk generally occurs over a period of a few days.
Hormonal controls of lactogenesis
- Prolactin: lactation is inhibited during pregnancy, although the levels of human prolactin rise through pregnancy. The reason for this is the high levels of progesterone.
The receptor is a member of the cytokine receptor superfamily.
Ligand binding induces dimerization of one or more of the receptor chains, which brings together two Jak kinases, through their association with the membrane proximal intracellular region of the receptors. The proximity of the two receptor chains plus their associated Jaks results in tyrosine
cross-phosphorylation of both the Jaks and specific residues on the receptor. The phosphorylated tyrosine residues on the receptor then may act to recruit Stat proteins, which in
unstimulated cells would normally exist as monomers in the cytosol. A transient association of the Stat with the receptor results in tyrosine phosphorylation of the Stat protein,oligomerization with at least one other Stat protein and subsequent translocation into the nucleus, where the complex binds to specific sites, thereby activating transcription.
How the ilk got into milk,2009
With the birth of the placenta, and the sudden drop in pregnancy hormones (progesterone and estrogen), the elevated prolactin level brings at the milk supply.
Prolactin is released in pulses directly related to stimulation of the areola or breast.Frequent feeding in the early days increases the number of prolactin receptor sites.
Prolactin increases milk protein biosynthesis, particularly caseins. The initial response to the binding of prolactin to its receptors in an increase in ribosomal RNA and the accumulation of casein mRNA. Thus, prolactin controls expression of casein gene and probably other genes as well.
- Progesterone: progesterone binds to progesterone receptors in the cytoplasm of the secretory cells and also competes with glucocorticoids for binding on the glucocorticoid receptors. It also inhibits the ability of prolactin to induce synthesis of prolactin receptors and reduces the synergism between prolactin and glucocorticoids. These are antilactogenic effects.
- Estrogen: its role in lactogenesis is indirect one. Estrogen stimulate secretion of prolactin and possibly other hormones from the pituitary gland. Since estrogen and glucocorticoids increase the number of prolactin receptors on the mammary membranes.
- Glucocorticoids: cortisol induces differentiation of rough endoplasmic reticulum and the Golgi apparatus of the mammary epithelial cells. This differentiation is essential to permit prolactin to induce synthesis of milk proteins. This indicates the essential synergism between prolactin and the glucocorticoids to induce lactogenesis.
- Insulin and GH: both insulin and insulin-like growth factor (IGF) may be involved in glucose up take which is critical for lactose biosynthesis. Insulin may also be involved en expression of milk protein genes. Growth hormone may have an indirect effect of lactogenesis by increasing the secretion of IGFs.
Prolactin signal transduction mechanisms in the mammary gland: the role of the Jak/Stat pathway
Galactopoeisis
Galactopoeisis is defined as the maintenance of lactation once lactation has been established. The changes in mammary cell numbers and in milk yield per cell are regulated in part by galactopoietic hormones and in part by local mammary factors.
The role of milk removal complicates interpretation of the hormonal requirements for milk synthesis. Without frequent emptying of the mammary gland, milk synthesis will not persist in spite of adequate hormonal status. Conversely, maintenance of intense suckling or milking stimulus will not maintain lactation indefinitely. Nevertheless, suckling or actual removal of milk is required to maintain lactation.
Hormonal controls of galactopoeisis
The maintenance of lactation is at least partly controlled by a group of hormones collectively known as galactopoeitic hormonal complex. The hormonal complex includes prolactin, growth hormones, thyroid hormones, and glucocorticoids.
Role of milk removal in galactopoeisis
Nursing or milking stimulus triggers release of galactopoietic hormones (especially prolactin) which may stimulate the next round of secretory activity.
If milk removal is not maintained there is no stimulation for prolactin release.
Acute accumulation of milk in the gland causes an increase in intra-mammary pressure.
This increase in pressure activates the sympathetic nerves in the gland, which acts peripherally to decrease mammary blood flow. As mammary blood flow declines the availability of hormones (e.g. prolactin) and nutrients to the gland is reduced. If milk is not removed, the Feedback Inhibitor of Lactation (FIL: a milk whey protein synthesized by the mammary secretory cell) accumulates in the alveolar lumen, inhibiting further synthesis and secretion of milk.
Physiology of breast feeding and milk let down
Embryology
Embryologic development of the mammary gland consists of a series of highly ordered events involving interactions among a number of distinct cell types. These interactions are regulated by an array of systemic and local factors such as growth factors and hormones.
Development is initially identical among males and females of the same species.
During the fourth week of gestation, paired ectodermal thickenings termed mammary ridges or milk lines develop on the ventral surface of the embryo and extend in a curvilinear fashion convex towards the midline from the axillae to the medial thigh. This is the first morphologic evidence of mammary gland development. In normal human development, these ridges disappear except at the level of the fourth intercostal space on the anterior thorax, where the mammary gland subsequently develops.
During the fifth week of gestation, the remnant of the mammary ridge ectoderm begins to proliferate and is termed the primary mammary bud. This primary bud subsequently begins growth downward as a solid diverticulum into the underlying dermis during the seventh week. By the 10th week, the primary bud begins to branch, yielding secondary buds by the 12th week, which eventually develop into the mammary lobules of the adult breast.
This initial downgrowth and subsequent branching have been shown to occur as a result of an inductive influence of the extracellular matrix of the mesoderm on the primary mammary bud. This epithelial-mesenchymal signaling is probably through paracrine and juxtacrine mechanisms where the underlying mesoderm produces growth factors and hormones that interact with receptors on the overlying ectodermal cells of the primary mammary bud. The adipose tissue in the underlying mesoderm represents a significant store of lipids for the production of hormones and growth factors, which are then available to promote and regulate growth of the developing mammary gland.
During the remainder of gestation, these buds continue lengthening and branching. During the 20th week, small lumina develop within the buds that coalesce and elongate to form the lactiferous ducts. The canalization of the mammary buds with formation of the lactiferous ducts is induced by placental hormones entering the fetal circulation. These hormones include progesterone, growth hormone, insulinlike growth factor, estrogen, prolactin, adrenal corticoids, and triiodothyronine. At term, approximately 15-20 lobes of glandular tissue have formed, each containing a lactiferous duct.
The lactiferous ducts drain into retroareolar ampullae that converge into a depressed pit in the overlying skin. Each of the 15-20 lobes of the mammary gland has an ampulla with an orifice opening into this mammary pit. Stimulated by the inward growth of the ectoderm, the mesoderm surrounding this area proliferates, creating the nipple with circular and longitudinally oriented smooth muscle fibers. The surrounding areola is formed by the ectoderm during the fifth month of gestation.
Breast Anatomy and Development
