Towards targeting prolactin signaling in human diseases: Stimulate or inhibit?

Abstract

Prolactin is an anterior pituitary hormone that was originally named for its indispensable role in lactation, but increasingly it is being recognized for pleiotropic roles in metabolism, immune function, pregnancy adaptations and parental behaviour. Prolactin secretion is tightly controlled by a short-loop feedback system whereby prolactin stimulates specific neurons in the hypothalamus to release dopamine, which then inhibits prolactin secretion. During pregnancy and lactation, however, this feedback systems adapts to allow prolonged elevations in prolactin secretion, enabling a range of functions specific to these conditions. Prolactin is also released under conditions of stress in both sexes. Prolactin signals exclusively through the prolactin receptor (Prlr), but this is not a simple system. In target cells, prolactin/Prlr engages various signal transduction mechanisms including JAK2/STAT5 (canonical), PI3K/Akt, MAPK and Src family kinases. There is also evidence of local production of prolactin in non-pituitary tissues, leading to autocrine/paracrine receptor triggering independent of circulating hormone. Adding to this complexity, in many species, including humans, there are multiple ligands for the Prlr. These include placental lactogens that supplement prolactin function in pregnancy, and in primates only, pituitary growth hormone. Moreover, specific proteolytic products of these hormones exert important biological actions independent of Prlr. These functions, that are often completely distinct from those of prolactin, have led to the classification of these fragments as a new class of hormones known as vasoinhibins.