.
Hormones The master regulators of breast development are the
steroid hormones,
estrogen, and
progesterone, growth hormone (GH), mostly via its secretory product,
insulin-like growth factor 1 (IGF-1), and
prolactin. These regulators induce the expression of
growth factors, such as
amphiregulin,
epidermal growth factor (EGF), IGF-1, and
fibroblast growth factor (FGF), which in turn have specific roles in breast growth and maturation. GnRH induces the secretion of the
gonadotropins,
follicle-stimulating hormone (FSH) and
luteinizing hormone (LH), from the
pituitary gland. During
prenatal development, infancy, and childhood, GH and IGF-1 levels are low, but progressively increase and reach a peak at puberty, with a 1.5- to 3-fold increase in pulsatile GH secretion and a 3-fold or greater increase in serum IGF-1 levels being capable of occurring at this time. In late adolescence and early adulthood, GH and IGF-1 levels significantly decrease, and continue to decrease throughout the rest of life. as well as locally in the breasts. Although IGF-1 is responsible for most of the role of GH in mediating breast development, GH itself has been found to play a direct, augmenting role as well, as it increases
estrogen receptor (ER) expression in breast
stromal (connective) tissue, while IGF-1, in contrast, has been found to not do this. In addition to estrogen and GH/IGF-1 both being essential for pubertal breast development, they are
synergistic in bringing it about. Despite the apparent necessity of GH/IGF-1 signaling in pubertal breast development however, women with
Laron syndrome, in whom the
growth hormone receptor (GHR) is defective and insensitive to GH and serum IGF-1 levels are very low, puberty, including breast development, is delayed, although full sexual maturity is always eventually reached. Moreover, breast development and size are normal (albeit delayed) in spite of GH/IGF-1 axis insufficiency, and in some the breasts may actually be large in relation to body size. The relatively large breasts in women with Laron syndrome have been suggested to be due to increased secretion of
prolactin (which is known to produce breast enlargement) caused by a drift phenomenon from
somatomammotrophic cells in the
pituitary gland with a high GH secretion. However, by 15 weeks, ductal development has caught up with that of normal mice and the ducts have fully distributed throughout the mammary fat pad, although the ducts remain narrower than those of wild-type mice. During
embryonic development, the breast buds, in which networks of
tubules are formed, are generated from the
ectoderm. These
rudimentary tubules will eventually become the matured
lactiferous (milk) ducts, which connect the
lobules (milk "containers") of the breast, grape-like clusters of
alveoli, to the nipples. Until puberty, the tubule networks of the breast buds remain rudimentary and quiescent, causes growth of and transformation of the tubules into the matured ductal system of the breasts. Under the influence of estrogen, the ducts sprout and elongate, and terminal end buds (TEBs), bulbous structures at the tips of the ducts, penetrate into the fat pad and branch as the ducts elongate. Progesterone, in conjunction with GH/IGF-1 similarly to estrogen, affects the development of the breasts during puberty and thereafter as well. In addition, progesterone produces modest lobuloalveolar development (alveolar bud formation or ductal sidebranching) starting at puberty, with growth and regression of the alveoli occurring to some degree with each menstrual cycle. Estrogen and progesterone levels increase dramatically, Estrogen and progesterone cause the secretion of high levels of prolactin from the
anterior pituitary, which reach levels as high as 20 times greater than normal menstrual cycle levels. Further ductal development, by estrogen, again in conjunction with GH/IGF-1, occurs during pregnancy. acting together, mediate the completion of lobuloalveolar development of the breasts during pregnancy. Both PR and
prolactin receptor (PRLR) knockout mice fail to show lobuloalveolar development, and progesterone and prolactin have been found to be synergistic in mediating growth of alveoli, demonstrating the essential role of both of these hormones in this aspect of breast development.
Growth hormone receptor (GHR) knockout mice also show greatly impaired lobuloalveolar development. In addition to their role in lobuloalveolar growth, prolactin and hPL act to increase the size of the nipple-areolar complex during pregnancy. By the end of the fourth month of pregnancy, at which time lobuloalveolar maturation is complete, the breasts are fully prepared for lactation and breastfeeding.
Leptin has also been found to be an important factor in mammary gland development, and has been found to promote mammary epithelial cell proliferation. In contrast to the female-associated sex hormones, estrogen and progesterone, the male-associated sex hormones, the
androgens, such as
testosterone and
dihydrotestosterone (DHT), powerfully suppress the action of estrogen in the breasts. At least one way that they do this is by reducing the expression of the estrogen receptor in breast tissue. In the absence of androgenic activity, such as in women with
complete androgen insensitivity syndrome (CAIS), modest levels of estrogen (50 pg/mL) are capable of mediating significant breast development, with CAIS women showing breast volumes that are even above-average. due to the ovaries in females producing high amounts of estrogens but low amounts of androgens and the
testes in males producing high amounts of androgens but low amounts of estrogens, are why males generally do not grow prominent or well-developed breasts relative to females.
Calcitriol, the hormonally active form of
vitamin D, acting through the
vitamin D receptor (VDR), has, like the androgens, been reported to be a negative regulator of mammary gland development in mice, for instance, during puberty. as well as precocious mammary gland development. In addition, VDR knockout has also been shown to result in increased responsiveness of mouse mammary gland tissue to estrogen and progesterone, which was represented by increased cell growth in response to these hormones. and this finding has been interpreted as indicating that vitamin D may be essential for lobuloalveolar development. A possible mechanism of the negative regulatory effects of the VDR on breast development may be indicated by a study of
vitamin D3 supplementation in women which found that vitamin D3 suppresses
cyclooxygenase-2 (COX-2) expression in the breast, and by doing so, reduces and increases, respectively, the levels of
prostaglandin E2 (PGE2) and
transforming growth factor β2 (TGF-β2), a known inhibitory factor in breast development. Moreover, suppression of PGE2 in breast tissue is relevant because, via activation of
prostaglandin EP receptors, PGE2 potently induces amphiregulin expression in breast tissue, and activation of the EGFR by amphiregulin increases COX-2 expression in breast tissue, in turn resulting in more PGE2, and thus, a self-perpetuating, synergistic cycle of growth amplification due to COX-2 appears to potentially be present in normal breast tissue. Accordingly, overexpression of COX-2 in mammary gland tissue produces mammary gland hyperplasia as well as precocious mammary gland development in female mice, mirroring the phenotype of VDR knockout mice, and demonstrating a strong stimulatory effect of COX-2, which is downregulated by VDR activation, on the growth of the mammary glands.
Growth factors Estrogen, progesterone, and prolactin, as well as GH/IGF-1, produce their effects on breast development by modulating the local expression in breast tissue of an assortment of
autocrine and
paracrine growth factors, including IGF-1, IGF-2, amphiregulin, EGF, FGF,
hepatocyte growth factor (HGF),
tumor necrosis factor α (TNF-α),
tumor necrosis factor β (TNF-β),
transforming growth factor α (TGF-α),
transforming growth factor β (TGF-β),
heregulin,
Wnt, Based on research with
epidermal growth factor receptor (EGFR)
knockout mice, the EGFR, which is the molecular target of EGF, TGF-α, amphiregulin, and heregulin, has, similarly to the
insulin-like growth factor-1 receptor (IGF-1R), Estrogen and progesterone mediate ductal development mainly through induction of amphiregulin expression, and thus downstream EGFR activation. Accordingly, ERα,
amphiregulin, and EGFR knockout mice copy each other phenotypically in regards to their effects on ductal development. As both the IGF-1R and the EGFR are independently essential for mammary gland development, and as combined application of IGF-1 and EGF, through their respective receptors, has been found to synergistically stimulate the growth of human breast epithelial cells, these growth factor systems appear to work together in mediating breast development. Elevated levels of HGF and, to a lesser extent, IGF-1 (by 5.4-fold and 1.8-fold, respectively), in breast stromal tissue, have been found in
macromastia, a very rare condition of extremely and excessively large breast size. Exposure of macromastic breast stromal tissue to non-macromastic breast epithelial tissue was found to cause increased alveolar morphogenesis and epithelial proliferation in the latter. ==Lactation==