<P> At puberty, gonadotropin - releasing hormone (GnRH) begins to be secreted, in a pulsatile manner, from the hypothalamus . GnRH, in turn, induces the secretion of the gonadotropins, follicle - stimulating hormone (FSH) and luteinizing hormone (LH), from the pituitary gland . These hormones travel to the ovaries through the bloodstream and cause estrogen and progesterone to be produced by them and released into the body in fluctuating amounts with each menstrual cycle . Growth hormone (GH), which is secreted from the pituitary gland, and insulin - like growth factor 1 (IGF - 1), which is produced in the body in response to GH, are growth - mediating hormones . 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 . It has been found that both estrogen and GH are essential for breast development at puberty--in the absence of either, no development will take place . Moreover, most of the role of GH in breast development has been found to be mediated by its induction of IGF - 1 production and secretion, as IGF - 1 administration rescues breast development in the absence of GH . GH induction of IGF - 1 production and secretion occurs in almost all types of tissue in the body, but especially in the liver, which is the source of approximately 80% of circulating IGF - 1, 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 . </P> <P> Development of the breasts during the prenatal stage of life is independent of biological sex and sex hormones . 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, and the male and female breast do not show any differences . During puberty in females, estrogen, in conjunction with GH / IGF - 1, through activation of ERα specifically (and notably not ERβ or GPER), 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 . This continues until a tree - like network of branched ducts that is embedded into and fills the entire fat pad of the breast is formed . In addition to its role in mediating ductal development, estrogen causes stromal tissue to grow and adipose (fat) tissue to accumulate, as well as the nipple - areolar complex to increase in size . </P> <P> Progesterone, in conjunction with GH / IGF - 1 similarly to estrogen, affects the development of the breasts during puberty and thereafter as well . To a lesser extent than estrogen, progesterone contributes to ductal development at this time, as evidenced by the findings that progesterone receptor (PR) knockout mice or mice treated with the PR antagonist mifepristone show delayed (albeit eventually normal, due to estrogen acting on its own) ductal growth during puberty and by the fact that progesterone has been found to induce ductal growth on its own in the mouse mammary gland mainly via the induction of the expression of amphiregulin, the same growth factor that estrogen primarily induces to mediate its actions on ductal development . In addition, progesterone produces modest lobuloalveolar development (alveolar bud formation or ductal sidebranching) starting at puberty, specifically through activation of PRB (and notably not PRA), with growth and regression of the alveoli occurring to some degree with each menstrual cycle . However, only rudimentary alveoli develop in response to pre-pregnancy levels of progesterone and estrogen, and lobuloalveolar development will remain at this stage until pregnancy occurs, if it does . In addition to GH / IGF - 1, estrogen is required for progesterone to affect the breasts, as estrogen primes the breasts by inducing the expression of the progesterone receptor (PR) in breast epithelial tissue . In contrast to the case of the PR, ER expression in the breast is stable and differs relatively little in the contexts of reproductive status, stage of the menstrual cycle, or exogenous hormonal therapy . </P> <P> During pregnancy, pronounced breast growth and maturation occurs in preparation of lactation and breastfeeding . Estrogen and progesterone levels increase dramatically, reaching levels by late pregnancy that are several hundred-fold higher than usual menstrual cycle levels . 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 . IGF - 1 and IGF - 2 levels also increase dramatically during pregnancy, due to secretion of placental growth hormone (PGH). Further ductal development, by estrogen, again in conjunction with GH / IGF - 1, occurs during pregnancy . In addition, the concert of estrogen, progesterone (again specifically through PRB), prolactin, and other lactogens such as human placental lactogen (hPL) and PGH, in conjunction with GH / IGF - 1, as well as insulin - like growth factor 2 (IGF - 2), 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 . </P>

Lobulo-alveolar structure in the breast is caused by