Regulators of Mammary Function

Regulators of Mammary Function

B. Role of the Endocrine and Nervous Systems [1]

Lactogenesis - the onset of copious milk production in concert with parturition - is driven by coordinated action of prolactin, growth hormone, estrogen, glucocorticoids, and progesterone. Maintenance of elevated serum concentrations of progesterone and of progesterone receptors in the epithelial cells during gestation serve to prevent premature onset of milk component biosynthesis. As parturition approaches, serum concentrations of progesterone decrease with a consequent reduction in inhibition. During the same interval, enhanced secretion, of estrogens serves to increase prolactin receptors in the mammary gland and prolactin and glucocorticoid concentrations increase. Thus, lactogenesis relies on increasing positive stimulation and removal inhibition. In particular, prolactin has been shown to increase mRNA synthesis of milk protein genes (-lactalbumin and caseins) and promote differentiation of the epithelial cells, while glucocorticoids enhance structural differentiation of the alveolar cells and increase the half-life of mRNAs in the milk proteins. Galactopoiesis or maintenance of milk production requires delivery of vital precursors (glucose, animo acids, fatty acids, acetate) and removal of waste products. In most species studied, secretion of prolactin during lactation is critical for galactopoiesis, since experiments which reduce serum prolactin concentrations markedly reduce or even stop milk production. By contrast, in cattle, circulating concentrations of prolactin are certainly not limiting in that neither reductions in prolactin concentrations to very low levels nor administration of exogenous prolactin appreciably alters milk production. Circulating concentrations of growth hormone, however, are closely associated with maintenance or enhanced milk production. For example, genetically superior dairy cattle exhibit increased basal circulating concentrations of growth hormone and capacity to secrete growth hormone. There is also ample evidence that administration of exogenous growth hormone increases milk production. Such increases are associated with parallel increases in mammary blood flow, increased nutrient mobilization from body stores increased voluntary feed intake, and greater efficiency of nutrient absorption from the intestinal tract. The marked physiological adjustments needed to sustain high levels of milk production in superior dairy animals are dramatic and regulated by actions of the endocrine system.

C. Local Tissue Regulators

While the ovary is a primary regulator of mammary development via its production of estrogens and progesterone, increasing evidence suggests that at least some of the effects of the classic mammary mitogens (estrogens, progesterone, prolactin, and growth hormone) are mediated indirectly. Specifically, production of IGFs and their binding proteins within the mammary gland likely modulate mammary development via paracrine and/or autocrine modes of action. Production of IGFs is believed to be associated with stromal cells and the binding proteins associated with the epithelial cells. Especially in rodents, EGF and TGF- appear to be naturally important mammary mitogens. The number of EGF receptors changes in correspondence with mammary growth (i.e., highest in mid-gestation, lowest in lactation). Furthermore, apparent number of EGF receptors is increased in the distal areas of elongating mammary end-buds. TGF- mRNA has been localized in ductular and alveolar epithelial cells in mammary tissue from rats and humans.

Mammary growth ultimately depends on a balance of positive growth stimulators and growth inhibitors which act to prevent inappropriate proliferation. A number of proteins with growth inhibiting properties have been described. These include the transforming growth factor- family (TGF-), interferons, and tumor necrosis factor (TNF). A protein referred to as mammostatin, isolated from mammary cell culture media, has been shown to inhibit the proliferation of a variety of both normal and tumorgenic mammary epithelial cells but not other types of cells. Another 13-kDa inhibitory protein-mammary-derived growth inhibitor (MDGI)--has been isolated from the bovine mammary gland. The protein is structurally distinct from known growth factors and tissue concentrations of MDGI are high in tissue front lactating cows but low in tissue taken after cessation of milking. A reduction in concentration of the inhibitor would be consistent with the need for proliferation of mammary cells to begin a subsequent lactation following a nonlactating period. TGF-, which consists of five closely related polypeptides, was first described on the basis of the ability of the molecules to promote anchorage independent growth of rat kidney cells. Since that time, TGF-2 has been isolated from cows' milk and expression of mRNAs for TGF-1,2, and 3 have been studied by in situ hybridization in bovine mammary tissue. Greatest amounts of TGF-1 were in the alveolar cells, with lesser expression in subepithelial areas. Unlike TGF-1 and 3, TGF-2 was expressed only in the epithelial cells of the mammary gland. Experimentally, local implants of TGF-1 reversibly inhibit proliferation off end-buds in rodents and proliferation of mammary cells in culture.

[1] From: R. M. Akers. Lactation. Virginia Polytechnic institute and State University