Is prolactin receptor signaling a target in dopamine-resistant prolactinomas?

The hypothalamic neuroendocrine catecholamine dopamine regulates the lactotroph function, including prolactin (PRL) secretion, proliferation, and apoptosis. The treatment of PRL-secreting tumors, formerly known as prolactinomas, has relied mainly on this physiological characteristic, making dopamine agonists the first therapeutic alternative. Nevertheless, the group of patients that do not respond to this treatment has few therapeutical options. Prolactin is another physiological regulator of lactotroph function, acting as an autocrine/paracrine factor that controls PRL secretion and cellular turnover, inducing apoptosis and decreasing proliferation. Furthermore, the signaling pathways related to these effects, mainly JAK/STAT and PI3K/Akt, and MAPK, have been extensively studied in prolactinomas and other tumors as therapeutic targets. In the present work, the relationship between PRL pathophysiology and prolactinoma development is explored, aiming to comprehend the value of PRL and PRLR-associated pathways as exploratory fields alternative to dopamine-related approaches, which are worth physiological characteristics that might be impaired and can be potentially restored or upregulated to provide more options to the patients.

Effects of prolactin on movement disorders and APOE, GFAP, and PRL receptor gene expression following intracerebral hemorrhage in rats.

Objectives: Intracerebral hemorrhage (ICH) occurs mostly in the striatum. In ICH, blood prolactin level increases 3-fold. The effects of intracerebroventricular injection (ICV) of prolactin on motor disorders will be investigated. Materials and Methods: This study was performed on 32 male Wistar rats in 4 groups: sham, ICH, and prolactin with 1 µg/2 µl (P1) and 2 µg/2 µl (P2) doses. Results: The weight of animals on days 1 (P˂0.01), 3, and 7 (P˂0.05) in the sham and P2 groups increased compared with the ICH group. Neurological Deficit Score (NDS) in ICH and P1 groups decreased, and increased compared with sham and ICH groups (P˂0.001), respectively. NDS in the P1 group increased compared with the P2 group on days 1 (P˂0.0 5), 3, and 7 (P˂0.001). The duration time of rotarod in ICH and P1 groups decreased and increased compared with sham and ICH groups (P˂0.001), respectively. The duration time of rotarod in the P1 group on days 3 and 7 increased compared with the P2 group (P˂0.001). Travel distance in days 1(P˂0.01), 3(P˂0.001), and 7(P˂0.01) decreased in the ICH group. Prolactin receptor (PRL receptor) expression in ICH, P1, and P2 groups increased compared with sham and ICH groups (P˂0.001). Glial fibrillary acidic protein (GFAP) expression (P˂0.001) and apolipoprotein E (APOE) (P˂0.01) expression in the ICH group increased compared with the sham group. GFAP and APOE expression in the P1 group increased compared with the ICH group (P˂0.001). APOE expression in the P1 group increased compared with the P2 group (P˂0.001). Conclusion: According to the results, prolactin reduces movement disorders.

Remarkable genetic diversity detected at river buffalo prolactin receptor (PRLR) gene and association studies with milk fatty acid composition.

Prolactin is an anterior pituitary peptide hormone involved in many different endocrine activities and is essential for reproductive performance. This action is mediated by its receptor, the prolactin receptor, encoded by the PRLR gene. In this study, we sequenced and characterized the Mediterranean river buffalo PRLR gene (from exon 3 to 10), and we found remarkable genetic diversity. In particular, we found 24 intronic polymorphisms and 13 exonic SNPs, seven of which were non-synonymous. Furthermore, the polymorphisms identified in the 3'-UTR were investigated to establish their possible influence on microRNA binding sites. Considering all the amino acid changes and the observed allelic combinations, it is possible to deduce at least six different translations of the buffalo prolactin receptor and, consequently, the presence at the PRLR gene of at least six alleles. Furthermore, we identified a deletion of a CACTACC heptamer between nucleotides 1102 and 1103 of exon 10 (3'-UTR), and we developed an allele-specific PCR to identify the carriers of this genetic marker. Finally, the SNP g.11188A>G, detected in exon 10 and responsible for the amino acid replacement p.His328Arg, was genotyped in 308 Italian Mediterranean river buffaloes, and an association study with milk fat traits was carried out. The statistical analysis showed a tendency that approached significance for the AA genotype with higher contents of odd branched-chain fatty acids. Thus, our results suggest that the PRLR gene is a good candidate for gene association studies with qualitative traits related to buffalo milk production.

Neuroendocrine Control of Broodiness.

In the majority of vertebrates, survival of offspring to sexual maturation is important for increasing population size, and parental investment in the young is important for reproductive success. Consequently, parental care is critical for the survival of offspring in many species, and many vertebrates have adapted this behavior to their social and ecological environments. Parental care is defined as any behavior that is performed in association with one's offspring (Rosenblatt, Mayer, Siegel. Maternal behavior among nonprimate mammals. In: Adler, Pfaff, Goy, editors. Handbook of behavioral neurobiology. New York: Plenum; 1985. p. 229-98) and is well characterized in mammals and birds. In birds (class Aves), this is due to the high level of diversity across species. Parental behavior in birds protects the young from intruders, and generally involves nest building, incubation, and broody behavior which protect their young from an intruder, and the offspring are reared to independence. Broodiness is complexly regulated by the central nervous system and is associated with multiple hormones and neurotransmitters produced by the hypothalamus and pituitary gland. The mechanism of this behavior has been extensively characterized in domestic chicken (Gallus domesticus), turkey (Meleagris gallopavo), and pigeons and doves (family Columbidae). This chapter summarizes broodiness in birds from a physiology, genetics, and molecular biology perspective.

Prolactin affects bovine oocytes through direct and cumulus-mediated pathways.

The available evidence points to participation of PRL in regulation of mammalian oocyte maturation. The aim of the present study was to characterize pathways of PRL action on bovine oocytes. We analyzed (1) the presence of the PRL receptor and its mRNA isoforms in oocytes and cumulus cells; (2) the effect of PRL on meiosis resumption and the role of cumulus cells, the NO/NO synthase system, protein kinase C, and tyrosine kinases in this effect; and (3) PRL effects in the presence of gonadotropins on the developmental capacity of cumulus-free and cumulus-enclosed oocytes. The transcript and protein expression of the PRL receptor in the cells were detected by reverse transcription polymerase chain reaction and immunocytochemistry, respectively. The nuclear status of oocytes was assessed after culture of cumulus-oocyte complexes (COCs) and denuded oocytes (DOs) with or without PRL (5-500 ng/mL) for 7, 14, or 24 hours. Besides, DOs were incubated for 7 hours in the absence or the presence of PRL (50 ng/mL) and/or L-NAME (an inhibitor of NO synthase), genistein (an inhibitor of tyrosine kinases), or calpostin C (a protein kinase C inhibitor). After IVM in 2 different systems containing PRL (50 ng/mL) and/or gonadotropic hormones, a part of oocytes underwent IVF and IVC and the embryo development was tracked until the blastocyst stage. Messenger RNA of long and short isoforms of the PRL receptor was revealed in both oocytes and cumulus cells. Immunocytochemistry confirmed the presence of the PRL receptor in oocytes and the cumulus investment. In the absence of gonadotropins (system 1), PRL retarded meiosis resumption in DOs but not in cumulus-enclosed oocytes, with this effect being short term, dose dependent, suppressed by L-NAME and genistein, and unaffected by calpostin. In systems containing gonadotropins, PRL did not affect nuclear maturation and the cleavage rate of cumulus-free and cumulus-enclosed oocytes. However, in the case of COCs, it raised the blastocyst yield both in system 2 (from 20.5%-40.9%, P < 0.01) and in system 3 (from 21.7%-33.9%, P < 0.05). The findings show for the first time the functioning of the direct pathway of PRL signaling into bovine oocytes, as confirmed by the expression of receptors of PRL and its direct meiosis-retarding effect involving activation of tyrosine kinases and NO synthase. Furthermore, this is the first demonstration that the beneficial effect of PRL on the oocyte developmental capacity is achieved via cumulus cells containing PRL receptors.

Sex-dependent roles of prolactin and prolactin receptor in postoperative pain and hyperalgesia in mice.

Although surgical trauma activates the anterior pituitary gland and elicits an increase in prolactin (PRL) serum levels that can modulate nociceptive responses, the role of PRL and the PRL-receptor (PRL-R) in thermal and mechanical hyperalgesia in postoperative pain is unknown. Acute postoperative pain condition was generated with the use of the hindpaw plantar incision model. Results showed endogenous PRL levels were significantly increased in serum, operated hindpaw and spinal cords of male and female rats 24h after incision. These alterations were especially pronounced in females. We then examined the role of the PRL system in thermal and mechanical hyperalgesia in male and female mice 3-168 h after plantar incision with the use of knock-out (KO) mice with PRL or PRL-R gene ablations and in wild-type (WT) mice. WT mice showed postoperative cold hyperalgesia in a sex-dependent manner (only in females), but with no effect on heat hyperalgesia or mechanical allodynia in either sex. Studies in KO mice showed no effect of PRL and PRL-R gene ablation on heat and cold hyperalgesia in male mice, while heat hyperlgesia were reduced 3-72 h post-surgery in female PRL and PRL-R KO mice. In contrast, PRL and PRL-R ablations significantly attenuated mechanical allodynia 3-72 h post-surgery in both male and female mice. Overall, we found elevated PRL levels in serum, hindpaws and spinal cords after incision, and identify a contributory role for the PRL system in postoperative pain responses to thermal stimuli in females and to mechanical stimuli in both males and females.