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Key Points The major 23 kDa prolactin isoform exerts its action via a transmembrane receptor, prolactin receptor (PRL-R), which belongs to the class of haematopoietic cytokine receptors Binding of prolactin to its predimerized receptor induces a conformational change in the receptor, which enables signal transduction Hyperprolactinaemia causes hypogonadotropic hypogonadism by inhibiting kisspeptin-1 secretion, which in turn disrupts hypothalamic gonadotropin-releasing hormone I secretion The first germline loss-of-function mutation in the gene that encodes PRL-R was reported in three sisters with familial idiopathic hyperprolactinaemia The 16 kDa isoform of prolactin has antitumoral and antiangiogenic actions and is involved in peripartum cardiomyopathy The role of prolactin in processes such as lactation and reproduction is well established. However, in the past few years, numerous novel functions for this hormone have been elucidated. In this Review, Bernard and colleagues discuss these newly described functions for prolactin, in particular, the mechanisms underlying infertility associated with hyperprolactinaemia, and the discovery of a mutation in the gene that encodes the prolactin receptor. Prolactin is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland, and is involved in many biological processes including lactation and reproduction. Animal models have provided insights into the biology of prolactin proteins and offer compelling evidence that the different prolactin isoforms each have independent biological functions. The major isoform, 23 kDa prolactin, acts via its membrane receptor, the prolactin receptor (PRL-R), which is a member of the haematopoietic cytokine superfamily and for which the mechanism of activation has been deciphered. The 16 kDa prolactin isoform is a cleavage product derived from native prolactin, which has received particular attention as a result of its newly described inhibitory effects on angiogenesis and tumorigenesis. The discovery of multiple extrapituitary sites of prolactin secretion also increases the range of known functions of this hormone. This Review summarizes current knowledge of the biology of prolactin and its receptor, as well as its physiological and pathological roles. We focus on the role of prolactin in human pathophysiology, particularly the discovery of the mechanism underlying infertility associated with hyperprolactinaemia and the identification of the first mutation in human PRLR .

The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expressed in a wide array of tissues, and a growing number of biological processes continue to be attributed to prolactin. In this Review, we focus on the newly discovered roles of prolactin in human health and disease, particularly its involvement in metabolic homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone, the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour. New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will also be presented and discussed.Prolactin is mainly known for its involvement in the regulation of lactation. In this Review, the authors describe other newly discovered roles of prolactin in human health and disease and discuss new data on the pathological states of hypoprolactinaemia and hyperprolactinaemia.

Prolactin (PRL) is a 23-kDa protein synthesized and secreted by lactotroph cells of the anterior pituitary gland but also by other peripheral tissues. PRL binds directly to a unique transmembrane receptor (PRLR), and the JAK2/signal transducer and activator of transcription 5 (Stat5) pathway is considered the major downstream pathway for PRLR signaling. To a lesser extent, PRL may be cleaved into the shorter 16-kDa PRL, also called vasoinhibin, whose signaling is not fully known. According to rodent models of PRL signaling inactivation and the identification of human genetic alterations in PRL signaling, a growing number of biological processes are partly mediated by PRL or its downstream effectors. In this review, we focused on PRL structure and signaling and its canonical function in reproduction. In addition to regulating reproductive functions, PRL also plays a role in behavior, notably in initiating nurturing and maternal behavior. We also included recent insights into PRL function in several fields, including migraines, metabolic homeostasis, inflammatory and autoimmune disease, and cancer. Despite the complexity of understanding the many functions of PRL, new research in this field offers interesting perspectives on physiological and pathophysiological processes.

As part of the maternal adaptations to pregnancy, mice show a rapid, profound reduction in voluntary running wheel activity (RWA) as soon as pregnancy is achieved. Here, we evaluate the hypothesis that prolactin, one of the first hormones to change secretion pattern following mating, is involved in driving this suppression of physical activity levels during pregnancy. We show that prolactin can acutely suppress RWA in non-pregnant female mice, and that conditional deletion of prolactin receptors (Prlr) from either most forebrain neurons or from GABA neurons prevented the early pregnancy-induced suppression of RWA. Deletion of Prlr specifically from the medial preoptic area, a brain region associated with multiple homeostatic and behavioral roles including parental behavior, completely abolished the early pregnancy-induced suppression of RWA. As pregnancy progresses, prolactin action continues to contribute to the further suppression of RWA, although it is not the only factor involved. Our data demonstrate a key role for prolactin in suppressing voluntary physical activity during early pregnancy, highlighting a novel biological basis for reduced physical activity in pregnancy.

Neuropeptide signalling systems comprising peptide ligands and cognate receptors are evolutionarily ancient regulators of physiology and behaviour. However, there are challenges associated with determination of orthology between neuropeptides in different taxa. Orthologs of vertebrate neuropeptide-Y (NPY) known as neuropeptide-F (NPF) have been identified in protostome invertebrates, whilst prolactin-releasing peptide (PrRP) and short neuropeptide-F (sNPF) have been identified as paralogs of NPY/NPF in vertebrates and protostomes, respectively. Here we investigated the occurrence of NPY/NPF/PrRP/sNPF-related signalling systems in a deuterostome invertebrate phylum – the Echinodermata. Analysis of transcriptome/genome sequence data revealed loss of NPY/NPF-type signalling, but orthologs of PrRP-type neuropeptides and sNPF/PrRP-type receptors were identified in echinoderms. Furthermore, experimental studies revealed that the PrRP-type neuropeptide pQDRSKAMQAERTGQLRRLNPRF-NH2 is a potent ligand for a sNPF/PrRP-type receptor in the starfish Asterias rubens. Our findings indicate that PrRP-type and sNPF-type signalling systems are orthologous and originated as a paralog of NPY/NPF-type signalling in Urbilateria.

Women are more resistant to hepatocellular carcinoma (HCC) than men despite equal exposure to major risk factors, such as hepatitis B or C virus infection. Female resistance is hormone-dependent, as evidenced by the sharp increase in HCC incidence in postmenopausal women who do not take hormone replacement therapy. In rodent models sex-dimorphic HCC phenotypes are pituitary-dependent, suggesting that sex hormones act via the gonadal-hypophyseal axis. We found that the estrogen-responsive pituitary hormone prolactin (PRL), signaling through hepatocyte-predominant short-form prolactin receptors (PRLR-S), constrained TNF receptor-associated factor (TRAF)-dependent innate immune responses invoked by IL-1β, TNF-α, and LPS/Toll-like receptor 4 (TLR4), but not TRIF-dependent poly(I:C)/TLR3. PRL ubiquitinated and accelerated poststimulatory decay of a “trafasome” comprised of IRAK1, TRAF6, and MAP3K proteins, abrogating downstream activation of c-Myc–interacting pathways, including PI3K/AKT, mTORC1, p38 MAPK, and NF-κB. Consistent with this finding, we documented exaggerated male liver responses to immune stimuli in mice and humans. Tumor promotion through, but regulation above, the level of c-Myc was demonstrated by sex-independent HCC eruption in Alb-Myc transgenic mice. PRL deficiency accelerated liver carcinogenesis in Prl ⁻/⁻ mice of both sexes. Conversely, pharmacologic PRL mobilization using the dopamine D2 receptor antagonist domperidone prevented HCC in tumor-prone C3H/HeN males. Viewed together, our results demonstrate that PRL constrains tumor-promoting liver inflammation by inhibiting MAP3K-dependent activation of c-Myc at the level of the trafasome. PRL-targeted therapy may hold promise for reducing the burden of liver cancer in high-risk men and women.

Abstract Background: Prolactin (PRL) plays an important role in mammary epithelial cell development and lactation. Increased levels of PRL are observed in human breast cancer, but the underlying mechanism and prognostic significance of PRL are still controversial. In this study, we sought to determine the significance of PRL in Chinese postmenopausal women with breast cancer. Methods: Plasma PRL levels in 326 healthy individuals and 333 postmenopausal breast cancer patients were analyzed. Immunohistochemical staining of cytoplasmic prolactin receptor (PRL-R) was performed. Moreover, the relationships between plasma PRL and clinicopathological parameters as well as survival in breast cancer patients were evaluated. Results: We found that high plasma levels of PRL was more common in breast cancer patients than in healthy individuals. We also observed that high level of PRL was associated with adverse prognostic factors, such as larger tumor size, more lymph node metastasis, advanced tumor stage, negative estrogen receptor (ER) expression, and negative progesterone receptor (PR) expression of breast cancer. Kaplan-Meier analysis showed that high plasma level of PRL correlated with poor disease-free and overall survival, while Cox regression models demonstrated that high plasma level of PRL was an independent prognostic marker for disease-free survival. The rate of PRL-R positivity among those with high plasma PRL was significantly higher than that of patients with low PRL (P < 0.05). Conclusion: The plasma PRL level and PRL-R expression in tumor tissue may be prognostic for Chinese postmenopausal women with breast cancer. The inhibition of PRL and PRL-R signaling is a potential therapeutic approach for endocrine therapy in breast cancer.

Prolactin is a hormone for which actions on the central nervous system such as neurogenesis and neuroprotection have been described by acting on specific receptors. The presence of prolactin receptors in the brain, including the hippocampus, is well documented; however, it is unknown whether these receptors change with age and whether they are related to sex. For this reason, a study of the expression of prolactin receptors, in the short and long isoforms, in the hippocampus of male and female rats has been carried out by qPCR and in situ hybridization, with a densitometric analysis in the following life stages: prepubertal, postpubertal, young adult, adult, and old. The results revealed the greater expression of the long isoform than of the short isoform in males, but not in females, with significant differences between males and females and in the different life stages studied. With significant differences, the highest expression of both isoforms appeared in male rats in the postpubertal stage, and the lowest expression was observed in adult and old animals. In situ hybridization showed differences in the localization of PRLR mRNA expression in CA1, CA3, and DG depending on the age and sex of the rats. The results obtained suggest that hippocampal aging is related to a decrease in prolactin receptors, which helps to better understand brain aging.