Hormonal control of the mammary blood-milk barrier and its role in establishing and maintaining milk production.

The blood-milk barrier (BMB) forms at parturition when the gland switches form a non-lactating state to one of copious milk production and becomes leaky again when milk removal ceases and mammary involution is initiated. In this review the importance of the BMB in milk production and, in particular, its hormonal regulation is explored. Tight junctions (TJ) between adjacent mammary epithelial cells form a barrier to the two-directional paracellular movement of small molecules between the blood and milk and are responsible for establishing and maintaining the BMB. They form part of the cell's junctional complex and consist of transmembrane proteins that are linked to the mammary cell's cytoskeleton. This means that when, during lactation, TJ become "leaky" the resulting perturbation of the cytoskeleton interferes with the cell's secretory function. As such, TJ are involved in regulating and maintaining milk production. Mammary TJ are under hormonal control, with progesterone, glucocorticoids, prolactin, parathyroid hormone-related peptide (PTHrP) and serotonin (5-HT) being the key hormones. Progesterone prevents closure of TJ and the immediate prepartum drop in its concentration is a prerequisite for TJ closure. A simultaneous increase in the levels of glucocorticoids and prolactin is necessary for full TJ closure and initiation and maintenance of lactation. Both PTHrP and 5-HT are important hormones in maintaining extracellular calcium concentrations, a requirement for maintaining TJ integrity. Whereas PTHrP reduces TJ permeability, necessary for establishing and maintaining milk production, 5-HT has an opening effect on TJ. The latter may help speed up mammary involution and facilitate the movement of immune factors into the gland, preventing intramammary infections. In summary, mammary TJ make up the BMB and play a role in establishing and maintaining milk production and are under hormonal control, with progesterone, glucocorticoids, PTHrP and 5-HT being key regulatory hormones and prolactin likely playing a supporting role.