prolactin

C Subfamily
CC Subfamily
CXC Subfamily
CX3C Subfamily

Chemokines

gp130 (IL6ST) shared
IL13RA1 shared
IL3RB (CSF2RB) shared
ILRG shared

interleukin 18
interleukin 18 proprotein
interleukin 1 alpha
interleukin 1, alpha proprotein
interleukin 1 beta
interleukin 1, beta proprotein

interleukin 17
interleukin 17b
interleukin 17E
interleukin 17E isoform 1

IL-1 Family /IL-17 Family

interleukin 10
interleukin 19
interleukin 19 isoform 2
interleukin 20
interleukin 22
interleukin 24
interleukin 24 isoform 1
interleukin 28A
interleukin 28B
interleukin 29

IL-10 Family

interferon alpha family, gene 1
interferon, alpha 1
interferon beta
interferon, beta 1
interferon epsilon 1
interferon, epsilon 1
interferon gamma
interferon, gamma
interferon kappa
interferon, kappa
interferon, omega 1

Interferon Family

CSF1 Egf Flt3l
FLT3LG HGF Kitl
KITLG Pdgfa PDGFB
PDGFC Pdgfd PLEKHQ1
VEGF Vegfa VEGFB
VEGFC

PDGF Family

AMH Bmp2 Bmp7
GDF5 Inhba INHBB
INHBC INHBE Tgfb1
TGFB2 TGFB3

TGF-β Family

CD40LG Eda Fasl
FASLG Lta LTB
TNF Tnfsf10 Tnfsf11
TNFSF12 Tnfsf13 TNFSF13B
Tnfsf14 TNFSF18 TNFSF4
TNFSF7 TNFSF8 TNFSF9

TNF Family

PROLACTIN

LATEST LITERATURE

1: Diabetes, 2010 Sep 7,
HIGH LEVELS OF SERUM PROLACTIN PROTECT AGAINST DIABETIC RETINOPATHY BY INCREASING OCULAR VASOINHIBINS.

[Abstract]AbstractObjective- Increased retinal vasopermeability (RVP) occurs early in diabetes and is crucial for the development of sight-threatening proliferative diabetic retinopathy (DR). The hormone prolactin (PRL) is proteolytically processed to vasoinhibins, a family of peptides that inhibit the excessive RVP related to DR. Here, we investigate the circulating levels of PRL in association with DR in men, and test whether increased circulating PRL, by serving as a source of ocular vasoinhibins, can reduce the pathological retinal vasopermeability in diabetes. Research Design and Methods- Serum PRL was evaluated in 40 non-diabetic and 181 diabetic men at various stages of DR. Retinal vasoinhibins were measured in rats rendered hyperprolactinemic by placing two anterior pituitary grafts under the kidney capsule and in PRL receptor null mice. RVP was determined in hyperprolactinemic rats subjected to the intraocular injection of vascular endothelial growth factor (VEGF) or made diabetic with streptozotocin. Results- The circulating levels of PRL increased in diabetes and were higher in diabetic patients without retinopathy than in those with proliferative DR. In rodents, hyperprolactinemia led to vasoinhibin accumulation within the retina; genetic deletion of the PRL receptor prevented this effect, indicating receptor-mediated incorporation of systemic PRL into the eye. Hyperprolactinemia reduced both VEGF-induced and diabetes-induced increase of RVP. This reduction was blocked by bromocriptine, an inhibitor of pituitary PRL secretion that lowers the levels of circulating PRL and retinal vasoinhibins. Conclusions- Circulating PRL influences the progression of DR after its intraocular conversion to vasoinhibins. Inducing hyperprolactinemia may represent a novel therapy against DR.

2: Molecular cancer, 2010 Sep 2, 9(1)
Sprouty1, a new target of the angiostatic agent 16K prolactin, negatively regulates angiogenesis.

[Abstract]ABSTRACT: BACKGROUND: Disorganized angiogenesis is associated with several pathologies, including cancer. The identification of new genes that control tumor neovascularization can provide novel insights for future anti-cancer therapies. Sprouty1 (SPRY1), an inhibitor of the MAPK pathway, might be one of these new genes. We identified SPRY1 by comparing the transcriptomes of untreated endothelial cells with those of endothelial cells treated by the angiostatic agent 16K prolactin (16K hPRL). In the present study, we aimed to explore the potential function of SPRY1 in angiogenesis. RESULTS: We confirmed 16K hPRL induced up-regulation of SPRY1 in primary endothelial cells. In addition, we demonstrated the positive SPRY1 regulation in a chimeric mouse model of human colon carcinoma in which 16K hPRL treatment was shown to delay tumor growth. Expression profiling by qRT-PCR with species-specific primers revealed that induction of SPRY1 expression by 16K hPRL occurs only in the (murine) endothelial compartment and not in the (human) tumor compartment. The regulation of SPRY1 expression was NF-kappaB dependent. Partial SPRY1 knockdown by RNA interference protected endothelial cells from apoptosis as well as increased endothelial cell proliferation, migration, capillary network formation, and adhesion to extracellular matrix proteins. SPRY1 knockdown was also shown to affect the expression of cyclinD1 and p21 both involved in cell-cycle regulation. These findings are discussed in relation to the role of SPRY1 as an inhibitor of ERK/MAPK signaling and to a possible explanation of its effect on cell proliferation. CONCLUSIONS: Taken together, these results suggest that SPRY1 is an endogenous angiogenesis inhibitor.

3: Endocrinology, 2010 Sep 1, 121(3-4)
A Novel Antagonistic Effect of the Bone Morphogenetic Protein System on Prolactin Actions in Regulating Steroidogenesis by Granulosa Cells.

[Abstract]To investigate the mechanism by which prolactin (PRL) regulates follicular steroidogenesis in the ovary, we examined the functional roles of PRL in steroidogenesis using rat oocyte/granulosa cell coculture and focusing on the bone morphogenetic protein (BMP) system. The expression of long and short forms of PRL receptor (PRLR) were detected in both oocytes and granulosa cells, and PRL effectively up-regulated PRLR expression in granulosa cells in the presence of FSH. PRL suppressed FSH-induced estradiol production and increased FSH-induced progesterone production in granulosa cells. The PRL effects on FSH-induced progesterone were blocked by coculture with oocytes, implying roles of oocyte-derived factors in suppression of progesterone production in PRL-exposed granulosa cells. In accordance with the data for steroids, FSH-induced aromatase expression was suppressed by PRL, whereas FSH-induced steroidogenic acute regulatory protein, P450scc (P450 side-chain cleavage enzyme), and 3beta-hydroxysteroid dehydrogenase type 2 levels were amplified by PRL. However, forskolin- and N(6),O(2)-dibutyryl cAMP-induced steroid levels and FSH- and forskolin-induced cAMP were not affected by PRL, suggesting that PRL action on FSH-induced steroidogenesis was not due to cAMP-protein kinase A regulation. Treatment with a BMP-binding protein, noggin, facilitated PRL-induced estradiol reduction, and noggin increased PRL-induced progesterone production in FSH-treated granulosa cells cocultured with oocytes, suggesting that endogenous BMPs reduce progesterone but increase estradiol when exposed to high concentrations of PRL. PRL increased the expression of BMP ligands in oocyte/granulosa cell coculture and augmented BMP-induced phosphorylated mothers against decapentaplegic 1/5/8 signaling by reducing inhibitory phosphorylated mothers against decapentaplegic 6 expression through the Janus kinase/signal transducer and activator of transcription (STAT) pathway. In addition to STAT activation, PRL enhanced FSH-induced MAPK phosphorylation in granulosa cells, in which ERK activation was preferentially involved in suppression of FSH-induced estradiol. Furthermore, noggin treatment enhanced PRLR signaling including MAPK and STAT. Considering that BMPs suppressed PRLR in granulosa cells, it is likely that the BMP system in growing follicles plays a key role in antagonizing PRLR signaling actions in the ovary exposed to high concentrations of PRL.

4: Journal of proteome research, 2010 Aug 31, 14(3)
Stathmin, a new target of PRL-3 identified by proteomic methods, plays a key role in progression and metastasis of colorectal cancer.

[Abstract]To better understand the role of PRL-3 in progression and metastasis of colorectal cancer (CRC), we searched for PRL-3 associated proteins using proteomic methods. We identified 39 proteins regulated by PRL-3 based on proteomic strategy. Stathmin, a key oncoprotein, was proved to be a new PRL-3 associated protein. Notably, co-immunoprecipitation assays in both endogenous CRC cell lines and CRC tissues indicated that PRL-3 could interact with stathmin. And, both stathmin and PRL-3 contributed to microtubule (MT) destabilization of CRC cells. Moreover, Gain-of-function and loss-of-function analyses revealed that stathmin promoted proliferation, motility and migration of human CRC cells. Immunohistochemical analysis of 149 colorectal tumor samples showed that overexpression of stathmin was strongly correlated with tumor differentiation (P=0.035), tumor invasion (P=0.024), lymph node status (P<0.001), Dukes classification (P<0.001) and TNM staging (P<0.001) of CRC patients. Univariate and multivariate survival analyses further supported that over-expression of stathmin protein was a potential independent poor prognostic factor for CRC. Our results reveal many PRL-3 associated proteins for the first time. The oncoprotein stathmin playes a key role in CRC as a new target of PRL-3. Interaction between PRL-3 and stathmin leads to MT destabilization of CRC cells, which contributes to progression and metastasis of CRC.

5: Journal of nutrigenetics and nutrigenomics, 2010 Aug 26, 3(1)
Effect of Sauropus androgynus Leaf Extracts on the Expression of Prolactin and Oxytocin Genes in Lactating BALB/C Mice.

[Abstract]Sauropus androgynus is traditionally consumed by Indonesians and is believed to increase breast milk production during lactation. Lactation, a process of milk synthesis and secretion, occurs with the help of 2 hormones, prolactin and oxytocin. The expressions of genes encoding prolactin and oxytocin were analyzed in lactating BALB/C mice brains using qRT-PCR. A total of 24 lactating BALB/C mice were fed with experimental diets for 12 days. Two groups of lactating mice were fed with diets containing either young or mature S. androgynus leaf extracts. For the control, one group of lactating mice was fed a diet without S. androgynus leaf extracts. Supplementation of young S. androgynus leaf extracts increased the expression of prolactin and oxytocin genes in lactating mice 9.04- and 2.25-fold, respectively. Meanwhile, supplementation of mature S. androgynus leaf extracts increased the expressions of both genes 15.75- and 25.77-fold, respectively, compared to the control group. The result suggested that mature S. androgynus leaf extracts significantly increased the expressions of both genes in lactating BALB/C mice and was predicted to correlate with papaverine content, which is only detected in mature S. androgynus leaves at a concentration of 0.38 +/- 0.04 mug.ml(-1).

6: British journal of cancer, 2010 Aug 24, 3(1)
Prolactin serum levels and breast cancer: relationships with risk factors and tumour characteristics among pre- and postmenopausal women in a population-based case-control study from Poland.

[Abstract]Background:Previous prospective studies have found an association between prolactin (PRL) levels and increased risk of breast cancer. Using data from a population-based breast cancer case-control study conducted in two cities in Poland (2000-2003), we examined the association of PRL levels with breast cancer risk factors among controls and with tumour characteristics among the cases.Methods:We analysed PRL serum levels among 773 controls without breast cancer matched on age and residence to 776 invasive breast cancer cases with available pretreatment serum. Tumours were centrally reviewed and prepared as tissue microarrays for immunohistochemical analysis. Breast cancer risk factors, assessed by interview, were related to serum PRL levels among controls using analysis of variance. Mean serum PRL levels by tumour characteristics are reported. These associations also were evaluated using polytomous logistic regression.Results:Prolactin levels were associated with nulliparity in premenopausal (P=0.05) but not in postmenopausal women. Associations in postmenopausal women included an inverse association with increasing body mass index (P=0.0008) and direct association with use of recent/current hormone therapy (P=0.0006). In case-only analyses, higher PRL levels were more strongly associated with lobular compared with ductal carcinoma among postmenopausal women (P=0.02). Levels were not different by tumour size, grade, node involvement or oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status.Conclusions:Our analysis demonstrates that PRL levels are higher among premenopausal nulliparous as compared with parous women. Among postmenopausal women, levels were higher among hormone users and lower among obese women. These results may have value in understanding the mechanisms underlying several breast cancer risk factor associations.British Journal of Cancer advance online publication, 24 August 2010; doi:10.1038/sj.bjc.6605844 www.bjcancer.com.

7: General and comparative endocrinology, 2010 Aug 21, 107(34)
Assessment of luteinizing hormone and prolactin immunoactivity in Asian and African elephant urine using assays validated for serum.

[Abstract]Analysis of serum hormones is useful for timing artificial insemination (LH) and diagnosing pregnancy (prolactin) in elephants. However, these tests require blood collection, which is not tolerated by all animals, and is impractical for field studies. Thus, developing a means to obtain these measures noninvasively could improve species management. Matched urine and serum was collected from Asian and African elephants daily throughout the follicular phase and after administration of a GnRH analogue for LH determination, and in pregnant and nonpregnant females for prolactin analyses using immunoassays validated for elephant serum. Despite identifying robust increases in circulating hormone concentrations, no concomitant changes in urinary LH or prolactin immunoactivity was detected. Concentration of samples by centrifugal filtration or ethanol precipitation did not increase the ability to measure biologically relevant changes in endogenous urinary LH or prolactin immunoactivity. Sample matrix interference was ruled out following sufficient recovery of exogenous LH or prolactin added to samples, except for samples concentrated >35-fold where some interference was suspected. These results suggest that elephants either do not excrete native LH or prolactin in urine, or concentrations are too low to be measured accurately by standard immunoassay techniques that are valid for serum analyses. Thus, it does not appear feasible or economically viable to use these non-invasive tests for ovulation detection or for pregnancy diagnosis in elephants.

8: Reproduction (Cambridge, England), 2010 Aug 23, 325(1-2)
Prolactin secretion patterns: basic mechanisms and clinical implications for reproduction.

[Abstract]Prolactin (PRL) is one of the most versatile hormones in the mammalian body affecting reproductive, sexual, metabolic, immune, and other functions. It is therefore not surprising that the neural control of PRL secretion is complex, involving the coordinated actions of several hypo-thalamic nuclei. A plethora of experimental data exists on the hypothalamic control of hormone secretion under various physiological stimuli. There have even been mathematical models and computer studies published which help to understand the complex hypothalamic-pituitary network. Nevertheless, the putative role of PRL for human reproduction still has to be clarified. Here we review data on the underlying mechanisms controlling PRL secretion using both experimental and mathematical approaches. These investigations primarily focus on rhythmic secretion in rats during early pregnancy or pseudopregnancy and they point to the important role of oxytocin as a crucial PRL-releasing factor. Recent data on human studies and their theoretical and clinical implications are reviewed as well. In particular, studies demonstrating a sustained PRL surge after sexual climax in males and females are presented, indicating possible implications for both sexual satiation and reproductive functions. Taking this data together, there is evidence for the hypothesis that the PRL surge induced by sexual activity, together with the altered PRL rhythmic pattern, is important for successful initialization of pregnancy not only in rodents but possibly also in humans. However, further investigations are needed to clarify such a role in humans.

9: Journal of neuroendocrinology, 2010 Aug 13, 182(4)
Activity of hypothalamic dopaminergic neurones during the day of oestrus: involvement in prolactin secretion.

[Abstract]Abstract A secretory surge of prolactin occurs on the afternoon of oestrus in cycling rats. Pituitary prolactin is inhibited by dopamine. We evaluated the activity of the neuroendocrine dopaminergic neurones during oestrus and dioestrus, as determined by dopaminergic activity in the median eminence (ME) and neurointermediate lobe of the pituitary (NIL) and Fos-related antigen (FRA) expression in tyrosine hydroxylase (TH)-immunoreactive (ir) neurones of ARC and Pe. During oestrus, 4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio in the ME decreased at 16:00 h coinciding with the increase in plasma prolactin levels. Likewise, the expression of FRA in TH-ir neurones of Pe and rostral-, dorsomedial- and caudal-ARC also decreased at 16:00 h. On dioestrus, DOPAC/dopamine ratio in the ME and FRA expression in TH-ir neurones of Pe and rostral-ARC decreased at 18:00 h, whereas prolactin levels were unaltered. No variation in dopaminergic activity was found in the NIL on either oestrus or dioestrus. The number of TH-ir neurones in the ARC and parameters of dopaminergic activity were found to be generally lower on oestrus as compared to dioestrus. The transitory decrease in the activity of neuroendocrine dopaminergic neurones temporally associated with the prolactin surge on the afternoon of oestrus suggests a role for dopamine in the generation of oestrous prolactin surge.

10: Biology of reproduction, 2010 Aug 18, 325(1-2)
Characterization of the Effects of Prolactin in Gonadotroph Target Cells.

[Abstract]Hyperprolactinemia is a major cause of infertility, brought about by inhibition of gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus and impairment of luteinizing hormone (LH) output from the pituitary gland. However, whereas prolactin (PRL) actions within the brain have been investigated extensively, its specific effects at the level of pituitary gonadotroph target cells remain unclear. Here, we provide evidence that the actions of PRL within the gonadotroph are more complex than originally envisaged. Using a gonadotroph cell monoculture, the first series of studies showed that PRL is paradoxically a potent stimulator of LH release, with a three- to four-fold increase in LH values at hyperprolactinemic concentrations of PRL. Conversely, PRL dose-dependently modulated the LH secretory response to GnRH in a biphasic manner, with classical suppression of LH output only detected under a narrow dose range. In contrast, at all doses tested, PRL blocked the LHB mRNA response to the secretagogue. Subsequent work revealed that the stimulatory effects of PRL on LH release are not mediated by the conventional cytokine receptor pathways, but by a novel JAK2-PIK3-PKC-dependent signaling cascade. Moreover, the studies showed that these actions of PRL within gonadotroph cells are controlled by dopamine, the main hypothalamic inhibitory regulator of prolactin release in vivo. Our findings have unraveled specific actions of PRL within the gonadotroph and the cell-signaling interactions that ultimately underlie hyperprolactinemia-induced infertility.

11: Clinical endocrinology, 2010 Aug 13, 182(4)
Recombinant Human Prolactin for the Treatment of Lactation Insufficiency.

[Abstract]ABSTRACT Context: Lactation insufficiency has many etiologies including complete or relative prolactin deficiency. Exogenous prolactin may increase breast milk volume in this subset. We hypothesized that recombinant human prolactin (r-hPRL) would increase milk volume in mothers with prolactin deficiency and mothers of preterm infants with lactation insufficiency. Design: Study 1: R-hPRL was administered in an open label trial to mothers with prolactin deficiency. Study 2: R-hPRL was administered in a randomized, double-blind, placebo-controlled trial to mothers with lactation insufficiency that developed while pumping breast milk for their preterm infants. Patients: Study 1: Mothers with prolactin deficiency (n=5). Study 2: Mothers of premature infants exclusively pumping breast milk (n=11). Design: Study 1: R-hPRL (60 mug/kg) was administered subcutaneously every 12 hours for 28 days. Study 2: Mothers of preterm infants were randomized to receive r-hPRL (60 mug/kg), placebo or r-hPRL alternating with placebo every 12 hours for 7 days. Measurements: Change in milk volume. Results: Study 1: Peak prolactin (27.9+/-17.3 to 194.6+/-19.5 mug/L; p<0.003) and milk volume (3.4+/-1.6 to 66.1+/-8.3 mL/day; p<0.001) increased with r-hPRL administration. Study 2: Peak prolactin increased in mothers treated with r-hPRL every 12 hours (n=3; 79.3+/-55.4 to 271.3+/-36.7 mug/L; p<0.05) and daily (101.4+/-61.5 vs. 178.9+/-45.9 mug/L; p<0.04), but milk volume increased only in the group treated with r-hPRL every 12 hours (53.5+/-48.5 to 235.0+/-135.7 mL/day; p<0.02). Conclusion: Twice daily r-hPRL increases milk volume in mothers with prolactin deficiency and in preterm mothers with lactation insufficiency.

12: Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion, 2010 Aug 10, 34(6)
[Diabetic ketoacidosis as the first manifestation of a mixed growth hormone and prolactin-secreting tumor.]

[Abstract]BACKGROUND: Perospirone was developed in Japan and is used for the treatment of schizophrenia and related illnesses. The authors investigated the relationship between the dosage of perospirone and the plasma levels of perospirone and its active metabolite, ID15036, and also evaluated the impact of the plasma concentrations of perospirone and ID15036 on the plasma prolactin level to examine whether perospirone or ID15036 affected the dopamine D(2) blockade, in psychiatric patients treated with perospirone. METHODS: The subjects consisted of 21 adults treated with perospirone (4-60 mg/day). The plasma perospirone and ID15036 levels were measured in 21 patients and serum prolactin levels were investigated in 10 male patients with schizophrenia. RESULTS: The plasma ID15036 level was higher than the plasma perospirone, and a positive correlation was observed between the dosage of perospirone and the ID15036 levels (p=0.032). The 10 male patients showed a positive correlation between the plasma perospirone levels and plasma prolactin levels (r=0.688, p=0.028) and between the plasma ID15036 levels and prolactin levels (r=0.775, p=0.009). CONCLUSION: The plasma levels of ID15036 may have a greater impact on the dopamine D(2) blockade than perospirone in patients treated with perospirone.

13: Journal of psychopharmacology (Oxford, England), 2010 Aug 10, 34(6)
Prolactin and smoking status in antipsychotic-treated patients.

[Abstract]Studies investigating the relationship between cigarette smoking and prolactin secretion in the general population have yielded inconsistent results. Many antipsychotic drugs increase prolactin secretion, but there are no published studies that have investigated the relationship between smoking and prolactinaemia in antipsychotic-treated patients. We obtained prolactin levels from 228 antipsychotic-treated patients in secondary care mental health services and investigated the relationship between prolactinaemia and cigarette smoking. Twenty-three percent (n = 52) of patients had hyperprolactinaemia. Patients prescribed typical or a combination of typical and atypical antipsychotics had a significantly higher prevalence of hyperprolactinaemia and higher mean prolactin concentration. Both current and ex-cigarette smokers had significantly lower mean prolactin levels and a lower prevalence of hyperprolactinaemia, but after controlling for potentially confounding variables, only current smoking status was a significant predictor of lower prolactin levels (OR 2.3, 95% CI 1.2 to 4.7, p = 0.002). In this preliminary, cross-sectional study, there was a robust statistical relationship between cigarette smoking and prolactinaemia. The mechanism(s) underpinning this association needs further investigation.

14: Proceedings of the National Academy of Sciences of the United States of America, 2010 Aug 9, 34(6)
Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors.

[Abstract]Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor growth is thus needed. Stat5 has been recently shown to promote human prostate cancer cell survival/proliferation and to be associated with early prostate cancer recurrence. Stat5 is the main signaling pathway triggered by prolactin (PRL), a growth factor whose local production is also increased in high-grade prostate cancers. The first aim of this study was to use prostate-specific PRL transgenic mice to address the mechanisms by which local PRL induces prostate tumorogenesis. We report that (i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, (ii) this model recapitulates prostate tumorogenesis from precancer lesions to invasive carcinoma, and (iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63-positive basal cells, and of stem cell antigen-1-positive cells identified as a stem/progenitor-like subpopulation. Because basal epithelial stem cells are proposed to serve as tumor-initiating cells, we challenged the relevance of local PRL as a previously unexplored therapeutic target. Using a double-transgenic approach, we show that Delta1-9-G129R-hPRL, a competitive PRL-receptor antagonist, prevented early stages of prostate tumorogenesis by reducing or inhibiting Stat5 activation, cell proliferation, abnormal basal-cell pattern, and frequency or grade of intraepithelial neoplasia. This study identifies PRL receptor/Stat5 as a unique pathway, initiating prostate tumorogenesis by altering basal-/stem-like cell subpopulations, and strongly supports the importance of further developing strategies to target locally overexpressed PRL in human prostate cancer.

15: The Journal of reproduction and development, 2010 Jul 20, 323(2)
Analysis of Prolactin Gene Expression and Cleaved Prolactin Variants in the Mouse Testis and Spermatozoa.

[Abstract]Prolactin (PRL) has long been known to be a hormone responsible for mammary gland development and lactation in females, whereas its role in males is still unclear. Thus, we investigated male mouse (m) PRL protein and mRNA expression in spermatozoa at various differentiation stages in the testes. Quantitative RT-PCR and in situ hybridization detected the expression of PRL not only in Leydig cells but also in germ cells, in particular in spermatogonia. The nucleotide sequence of testis PRL mRNA was the same as that in the pituitary. The mPRL was detected in Leydig cells and in round and elongated spermatids of the testes by immunohistochemistry. Immunoblotting detected 2 forms of mPRL in the testes, one form was 23-kDa PRL, and the other form was smaller than full-length PRL. Based on these results, we focused on N-terminal cleaved PRL to determine its involvement in spermatogenesis. Immunohistochemistry using two sets of antibodies, one that recognized full-length PRL and N-terminal cleaved PRL and another that recognized full-length PRL and C-terminal cleaved PRL, suggested that intact PRL was localized in the nucleus of round spermatids, while N-terminal cleaved PRL variants were localized in the Golgi apparatus of the sperrmatid nuclei of round spermatids, cytoplasms of elongated spermatids and in the spermatozoa tails. These findings suggest that PRL is ectopically expressed in the spermiogenesis and spermatogenesis and that cleaved PRL variants were localized in the Golgi apparatus of spermatids and in spermatozoa tails.

16: Heart (British Cardiac Society), 2010 Jul 23, 323(2)
Prolactin: a new therapeutic target in peripartum cardiomyopathy.

[Abstract]Peripartum/postpartum cardiomyopathy (PPCM) is a potentially life-threatening disease of uncertain aetiology in previously healthy women. Clinical and experimental data suggested inflammation, autoimmune processes, apoptosis and endothelial dysfunction as typical pathophysiological features of PPCM. Recent data discovered that unbalanced peri/postpartum oxidative stress linked to proteolytic cleavage of the nursing hormone prolactin into a potent anti-angiogenic, pro-apoptotic and pro-inflammatory 16-kDa subform as a potential pathomechanism for the development of PPCM. Consistent with these idea, blockade of prolactin by bromocriptine, a dopamine D2 receptor agonist, prevented the onset of disease in an experimental model of PPCM and appeared successful in small pilot trials with respect to prevention or treatment of PPCM in patients. Here we highlight the current state of knowledge on diagnosis of PPCM, provide novel insights into the pathophysiology behind the disease and outline potential consequences for the clinical management and treatment options for patients at risk for or with PPCM.

17: Fertility and sterility, 2010 Jul 22, 323(2)
Sequence variation analysis of the prolactin receptor C-terminal region in women with premature ovarian failure.

[Abstract]Using a mouse model expressing only the PRL receptor short isoform mimicking premature ovarian failure, signaling pathways induced by PRL were analyzed in mouse ovaries. Sequencing of the coding portion of exons 10 and 11, specific to the long and short receptor isoform, respectively, did not revealed any mutation in 101 women with premature ovarian failure.

18: Oncogene, 2010 Jul 19, 323(2)
Janus kinase 2 is required for the initiation but not maintenance of prolactin-induced mammary cancer.

[Abstract]The prolactin receptor (PRLR), its associated Janus kinase 2 (Jak2) and the signal transducer and activator of transcription 5 (Stat5) are essential for normal mammary gland development. Owing to the upregulation of the PRLR and the local synthesis of its ligand in neoplastic cells, it has been proposed that PRL can act as a local growth factor in human breast cancers. This notion is supported by experimental evidence in transgenic mice, which showed that the mammary-specific expression of PRL contributes to carcinogenesis in vivo. To assess the importance of Jak2/Stat5 signaling during mammary cancer initiation and progression, we generated a PRL-induced mammary cancer model that allows the functional ablation of the Jak2 gene in the mammary epithelium before and after neoplastic transformation. Collectively, the results of this study show that the functional ablation of Jak2 protects against the onset of PRL-induced mammary tumorigenesis, suggesting that targeting this kinase is a relevant strategy for mammary cancer prevention. Surprisingly, Jak2 deficiency did not affect the growth and survival of PRL-induced mammary cancer cells in culture and in vivo. Consequently, Jak2 cannot be a sole therapeutic target to treat the established disease. PRL-induced mammary cancers exhibited an upregulation of ErbB2 and other ErbB receptor tyrosine kinases that may supersede the functionality of PRLR signaling through Jak2.Oncogene advance online publication, 19 July 2010; doi:10.1038/onc.2010.274.

19: Clinical and experimental dermatology, 2010 Jul 2, 18(1)
Serum prolactin levels in psoriasis and correlation with cutaneous disease activity.

[Abstract]Summary Background. Prolactin (PRL), a neuropeptide secreted by the anterior pituitary gland, possesses a variety of physiological actions. It has been implicated as an important immunomodulator and exerts a proliferative effect in cultured human keratinocytes via specific receptors. Some studies have indicated an increase in serum PRL levels in psoriasis and exacerbation of psoriasis when a prolactinoma is present. Aim. To evaluate the correlation between serum PRL levels and Psoriasis Area and Severity Index (PASI). Methods. Serum PRL levels were measured in 20 patients (10 mean, 10 women, age range 18-88 years) with plaque-type psoriasis before and after a 6-week period of topical treatment with tacalcitol ointment. Results were compared with a group of 20 healthy volunteers. Results. Serum PRL levels were significantly increased in the psoriatic group compared with the control group (P < 0.001) and were significantly reduced after treatment (P = 0.001). There was a correlation between pretreatment serum PRL levels and PASI (r = 0.33; P = 0.02). Conclusions. These results indicate that serum PRL levels may serve as a biological marker of psoriatic disease activity.

20: Clinical and experimental dermatology, 2010 Jul 2, 18(1)
Serum prolactin levels osteoradionecrosis: complications of radiotherapy.

[Abstract]Summary Background. Prolactin (PRL), a neuropeptide secreted by the anterior pituitary gland, possesses a variety of physiological actions. It has been implicated as an important immunomodulator and exerts a proliferative effect in cultured human keratinocytes via specific receptors. Some studies have indicated an increase in serum PRL levels in psoriasis and exacerbation of psoriasis when a prolactinoma is present. Aim. To evaluate the correlation between serum PRL levels and Psoriasis Area and Severity Index (PASI). Methods. Serum PRL levels were measured in 20 patients (10 mean, 10 women, age range 18-88 years) with plaque-type psoriasis before and after a 6-week period of topical treatment with tacalcitol ointment. Results were compared with a group of 20 healthy volunteers. Results. Serum PRL levels were significantly increased in the psoriatic group compared with the control group (P < 0.001) and were significantly reduced after treatment (P = 0.001). There was a correlation between pretreatment serum PRL levels and PASI (r = 0.33; P = 0.02). Conclusions. These results indicate that serum PRL levels may serve as a biological marker of psoriatic disease activity.

21: Endocrine-related cancer, 2010 Jul 2, 323(2)
Prolactin and estrogen synergistically regulate gene expression and proliferation of breast cancer cells.

[Abstract]The pituitary hormone prolactin (PRL) plays an important role in mammary gland development. It was also suggested to contribute to breast cancer progression. In vivo data strongly supported a crucial role of PRL in promoting tumour growth; however, PRL demonstrated only a weak if any pro-proliferative effect on cancer cells in vitro. Several recent studies indicated that PRL action in vivo may be influenced by the hormonal milieu, e.g. other growth factors such as estradiol (E2). Here, we explored the potential interplay between PRL and E2 in regulation of gene expression and cell growth. PRL alone induced either a weak or no proliferative response of T47D and BT-483 cells, respectively, while it drastically enhanced cell proliferation in E2-stimulated cultures. Affymetrix microarray analysis revealed 12 genes to be regulated by E2, while 57 genes were regulated by PRL in T47D cells. Most of the PRL-regulated genes (42/57) were not previously described as PRL target genes, e.g. WT1 and IER3. 105 genes were found to be regulated upon PRL and E2 co-treatment: Highest up-regulation was found for EGR3, RUNX2, EGR1, MAFF, GLIPR1, IER3, SOCS3, WT1 and AREG. PRL and E2 synergized to regulate EGR3, while multiple genes were regulated additively. These data show a novel interplay between PRL and E2 to modulate gene regulation in breast cancer cells.

22: Trends in endocrinology and metabolism: TEM, 2010 Jul 2, 323(2)
Prolactin: an emerging force along the cutaneous-endocrine axis.

[Abstract]Prolactin (PRL), one of the most diverse regulators in mammalian biology, is produced in both human skin and hair follicles. Important advances in our understanding of the intracutaneous regulation and functions of PRL have recently been made using the serum-free skin and hair follicle organ culture technique. Given that human skin is the largest peripheral endocrine organ and a key interface between the endocrine, nervous and immune systems, a detailed understanding of PRL in the cutaneous context promises to have far-reaching implications beyond the skin. The current review presents a timely cutaneous perspective on the production, regulation and functions of PRL and summarizes the key questions facing extrapituitary PRL research in general and cutaneous PRL research in particular.

23: Annals of clinical biochemistry, 2010 Jul, 47(Pt 4)
Hyperprolactinaemia caused by antipsychotic drugs: a new application for prolactin assays.

[Abstract]Prolactin is a natriuretic hormone and acts by inhibiting the activity of renal tubular Na(+)-K(+)-ATPase activity. These effects require an intact renal dopamine system. Here, we have studied by which mechanism prolactin and dopamine interact in Sprague-Dawley rat renal tissue. Na(+)-K(+)-ATPase activity was measured as ouabain-sensitive ATP hydrolysis in microdissected renal proximal tubular segments. Intracellular signaling pathways were studied by a variety of different techniques, including Western blotting using phosphospecific antibodies, immunoprecipitation, and biotinylation assays. We found that dopamine and prolactin regulated Na(+)-K(+)-ATPase activity via similar signaling pathways, including protein kinase A, protein kinase C, and phosphoinositide 3-kinase activation. The cross talk between prolactin and dopamine 1-like receptors was explained by a heterologous recruitment of dopamine 1-like receptors to the plasma membrane in renal proximal tubular cells. Prolactin had no effect on Na(+)-K(+)-ATPase activity in spontaneously hypertensive rats, a rat strain with a blunted response to dopamine. These results further emphasize the central role of the renal dopamine system in the interactive regulation of renal tubular salt balance.

24: Experimental biology and medicine (Maywood, N.J.), 2010 Jun 24, 24(7)
Differential involvement of insulin-like growth factor-I and estrogen on prolactin cells in the mouse anterior pituitary.

[Abstract]Estrogen and insulin-like growth factor-I (IGF-I) stimulate prolactin (PRL) production, release and proliferation of PRL-producing cells (PRL cells) in the anterior pituitary. PRL cells in adult estrogen receptor alpha (ERalpha) knockout (alphaERKO) mice and IGF-I knockout (IGF-IKO) mice are decreased considerably in number. To investigate a correlation between 17beta-estradiol (E2) and IGF-I on PRL production, IGF-I wild-type (WT) or IGF-IKO mice were ovariectomized at day 8 and the number of PRL cells was examined at days 20 and 60. Although PRL cell number at day 20 and WT or IGF-IKO mice ovariectomized at day 8 was similar to that in intact WT or IGF-IKO mice, PRL cells in adult WT or IGF-IKO mice ovariectomized at day 8 were significantly decreased as compared with those in intact WT or IGF-IKO mice. Therefore, estrogen is essential for PRL cell differentiation between days 20 and 60, regardless of IGF-I. While PRL cells in WT ovariectomized mice increased from days 20 to 60, those in IGF-IKO ovariectomized mice did not increase, suggesting that IGF-I modified PRL cell differentiation after day 20. ICI 182,780 (anti-estrogen) treatment canceled an increase of PRL cells in 30-day-old ovariectomized WT mice, indicating that the presence of ERalpha is important. The number of PRL cells in alphaERKO mice was similar to that in WT mice at day 20; however, PRL cells in alphaERKO mice at day 60 were not increased in number from day 20, supporting the idea that estrogen is essential for PRL cell differentiation after day 20. Finally, the percentage of PRL cells in IGF-IKO mice was decreased as compared with that in WT mice at day 20; therefore, IGF-I affects PRL cells before day 20. In conclusion, PRL cell differentiation is differently regulated by E2 and IGF-I depending on the age.

25: Neuroscience, 2010 Sep 1, 169(3)
Prolactin reduces the damaging effects of excitotoxicity in the dorsal hippocampus of the female rat independently of ovarian hormones.

[Abstract]We reported previously that lactation prevents the cell damage induced by kainic acid (KA) excitotoxicity in the CA1, CA3, and CA4 areas of the dorsal hippocampus compared to rats in diestrus phase, and hypothesize that pronounced fluctuations of hormones, such as ovarian steroids and prolactin (PRL), have a role in the neuroprotection of the dorsal hippocampus during lactation. PRL is thought to be involved in modulating neural excitability and seizure activity. To investigate actions of prolactin that minimize KA-induced cell damage in the hippocampus, female intact and ovariectomized (OVX) rats were treated for 4 days with a daily dose of 100 mug of prolactin or vehicle. On the third day of prolactin treatment, rats received a systemic dose of 7.5 mg/kg of KA and were sacrificed 48 h later. Immunostaining for Neu-N revealed a significant decrease in cell number in the CA1, CA3 and CA4 areas of intact or OVX, vehicle-treated rats after KA, whereas prolactin treatment prevented cell loss in the CA3 area of intact, and in the CA1, CA3, and CA4 of OVX rats. Fluoro-Jade C staining confirmed these observations. Kainate-induced seizure behavior progressed further in OVX rats, but was attenuated in prolactin-treated rats, both intact and OVX, compared to vehicle-treated rats. These data indicate that prolactin diminishes the damaging actions of excitotoxicity in the kainate model of epilepsy.

26: General and comparative endocrinology, 2010 Sep 1, 168(2)
D2 Dopamine receptor subtype mediates the inhibitory effect of dopamine on TRH-induced prolactin release from the bullfrog pituitary.

[Abstract]Dopamine receptors in mammals are known to consist of two D1-like receptors (D1 and D5) and three D2-like receptors (D2, D3 and D4). The aim of this study was to determine the dopamine receptor subtype that mediates the inhibitory action of dopamine on the release of prolactin (PRL) from the amphibian pituitary. Distal lobes of the bullfrog (Rana catesbeiana) were perifused and the amount of PRL released in the effluent medium was measured by means of a homologous enzyme-immunoassay. TRH stimulated the release of PRL from perifused pituitaries. Dopamine suppressed TRH-induced elevation of PRL release. Quinpirole (a D2 receptor agonist) also suppressed the stimulatory effect of TRH on the release of PRL, whereas SKF-38393 (a D1 receptor agonist) exhibited no such an effect. The inhibitory action of dopamine on TRH-induced PRL release from the pituitary was nullified by the addition of L-741,626 (a selective D2 receptor antagonist) to the medium, but not by the addition of SCH-23390 (a selective D1 receptor antagonist). These data indicate that the inhibitory effect of dopamine on TRH-evoked PRL release from the bullfrog pituitary gland is mediated through D2 dopamine receptors.

27: American journal of physiology. Endocrinology and metabolism, 2010 Jun 15, 24(7)
Bone modeling in bromocriptine-treated pregnant and lactating rats: possible osteoregulatory role of prolactin in lactation.

[Abstract]Lactogenic hormone prolactin (PRL) directly regulates osteoblast functions in vitro and modulates bone remodeling in nulliparous rats, but its osteoregulatory roles in pregnant and lactating rats with physiological hyperprolactinemia remained unclear. Herein, bone changes were investigated in rats treated with bromocriptine (Bromo), an inhibitor of pituitary PRL release, or Bromo+PRL at different reproductive phases, from mid-pregnancy to late lactation. PRL receptors were strongly expressed in osteoblasts lining bone trabeculae, indicating bone as a target of PRL actions. By using dual energy X-ray absorptiometry, we found a significant increase in bone mineral density in the femora and vertebrae of pregnant rats. Such pregnancy-induced bone gain was, however, PRL-independent, and may have resulted from the increased cortical thickness. Bone trabeculae were modestly changed during pregnancy as evaluated by bone histomorphometry. On the other hand, lactating rats especially in late lactation showed massive bone loss in bone trabeculae, but not in cortical shells. Further study in Bromo- and Bromo+PRL-treated rats suggested that PRL contributed to the decreases in trabecular bone volume and number, and the increases in trabecular separation and eroded surface, as well as a paradoxical increase in bone formation rate in late lactation. Uncoupling of trabecular bone formation and resorption was evident in lactating rats, with the latter being predominant. In conclusion, pregnancy mainly induced cortical bone gain, whereas lactation led to trabecular bone loss in both long bones and vertebrae. Although PRL was not responsible for the pregnancy-induced bone gain, it was an important regulator of bone modeling during lactation.

28: Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion, 2010 Jun 7, 89(11)
[Use of a new protocol for prolactin extraction and reduction of false hyperprolactinemia.]

[Abstract]INTRODUCTION: Numerous authors have reported that prolactin measurement is influenced by several factors and consequently the values obtained may not faithfully reflect the physiological reality of the individual studied. Unless a series of measures is adopted, especially in the pre-analytic stage, values may be falsely elevated. The objective of the present study was to evaluate the extent to which optimization or non-optimization of the extraction procedure translates into higher results and how reports expressed in terms of monomeric (biologically active) prolactin could be crucial to adopt a diagnosis and therapeutic approach. MATERIAL AND METHODS: We performed two extractions in each woman (following the protocol universally used for this kind of analysis): one through direct puncture and another 60min later without a new puncture (a catheter was inserted in the site of the first puncture and kept permeable by salinization). The monomeric fraction was then studied, if required. RESULTS: A statistically significant difference was observed between the 2 extractions. The monomeric fraction was three times lower in the second extraction than in the first. DISCUSSION: The results of this study justify systematic use of extraction techniques that avoid the stress of venous puncture, as well as the use of the term biologically active prolactin [monomeric (little) prolactin fraction] in reports.

29: Endocrinology, 2010 Jun 9, 89(11)
Prolactin Family of the Guinea Pig, Cavia porcellus.

[Abstract]Prolactin (PRL) is a multifunctional hormone with prominent roles in regulating growth and reproduction. The guinea pig (Cavia porcellus) has been extensively used in endocrine and reproduction research. Thus far, the PRL cDNA and protein have not been isolated from the guinea pig. In the present study, we used information derived from the public guinea pig genome database as a tool for identifying guinea pig PRL and PRL-related proteins. Guinea pig PRL exhibits prominent nucleotide and amino acid sequence differences when compared with PRLs of other eutherian mammals. In contrast, guinea pig GH is highly conserved. Expression of PRL and GH in the guinea pig is prominent in the anterior pituitary, similar to known expression patterns of PRL and GH for other species. Two additional guinea pig cDNAs were identified and termed PRL-related proteins (PRLRP1, PRLRP2). They exhibited a more distant relationship to PRL and their expression was restricted to the placenta. Recombinant guinea pig PRL protein was generated and shown to be biologically active in the PRL-responsive Nb2 lymphoma cell bioassay. In contrast, recombinant guinea pig PRLRP1 protein did not exhibit PRL-like bioactivity. In summary, we have developed a new set of research tools for investigating the biology of the PRL family in an important animal model, the guinea pig.

30: Journal of the American Academy of Dermatology, 2010 Jun, 62(6)
Elevation of serum prolactin levels in patients with pemphigus vulgaris: a novel finding with practical implications.

[Abstract]Prolactin (PRL) is one of the most versatile hormones found in the pituitary of vertebrates and exerts its actions through binding to a specific PRL receptor (PRLR). Here we describe the cloning and characterization of a second prolactin receptor (ntPRLR2), isolated from the ovary of Nile tilapia (Oreochromis niloticus). The newly identified PRLR cDNA was 2011 bp in length and encoded 529 amino acids. It shared 31.6% identity in nucleotide sequence and 29.2% in deduced amino acid sequence with the first PRLR identified in Nile tilapia (ntPRLR1). Both of these ntPRLRs resemble the long form mammalian PRLRs. The nominated ntPRLR2 was further confirmed as a real prolactin receptor based on its competence to transactivate the beta-casein and c-fos promoters in the transiently ntPRLR2-transfected HEK293 cells. The ntPRLR2 gene also found to encode a 864-bp short form transcript in the ovary, which was confirmed by Northern blot analysis. A tissue distribution study by real-time PCR revealed that the mRNA of both receptors (ntPRLR1 and ntPRLR2) was widely expressed in different tissues, with an extremely high abundance in the osmoregulatory organs, including the gills, intestine and kidney. ntPRLR1 mRNA was more abundant than ntPRLR2 in the testis, while the reverse expression pattern was found in the ovary. In the ovary, ntPRLR2 mRNA demonstrated a distinct gonadal development-dependent expression profile, with significantly higher levels at a sexual mature stage than at sexual recrudescent and sexual regressed stages. When challenged with estradiol, ntPRLR2 mRNA expression was up-regulated by E2, whereas E2 had no significant effect on ntPRLR1.

31: Endocrinology, 2010 May 12, 167(1)
Evidence for a Role of Prolactin in Calcium Homeostasis: Regulation of Intestinal Transient Receptor Potential Vanilloid Type 6, Intestinal Calcium Absorption, and the 25-Hydroxyvitamin D3 1{alpha} Hydroxylase Gene by Prolactin.

[Abstract]Increased calcium transport has been observed in vitamin D-deficient pregnant and lactating rats, indicating that another factor besides 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is involved in intestinal calcium transport. To investigate prolactin as a hormone involved in calcium homeostasis, vitamin D-deficient male mice were injected with 1,25(OH)2D3, prolactin, or prolactin + 1,25(OH)2D3. Prolactin alone (1 mug/g body weight 48, 24, and 4 h before termination) significantly induced duodenal transient receptor potential vanilloid type 6 (TRPV6) mRNA (4-fold) but caused no change in calbindin-D9k. Combined treatment with 1,25(OH)2D3 and prolactin resulted in an enhancement of the 1,25(OH)2D3 induction of duodenal TRPV6 mRNA, calbindin-D9k mRNA, and an induction of duodenal calcium transport [P < 0.05 compared with 1,25(OH)2D3 alone]. Because lactation is associated with an increase in circulating 1,25(OH)2D3, experiments were done to determine whether prolactin also has a direct effect on induction of 25-hydroxyvitamin D3 1alpha hydroxylase [1alpha(OH)ase]. Using AOK B-50 cells cotransfected with the prolactin receptor and the mouse 1alpha(OH)ase promoter -1651/+22 cooperative effects between prolactin and signal transducer and activator of transcription 5 were observed in the regulation of 1alpha(OH)ase. In addition, in prolactin receptor transfected AOK B-50 cells, prolactin treatment (400 ng/ml) and signal transducer and activator of transcription 5 significantly induced 1alpha(OH)ase protein as determined by Western blot analysis. Thus, prolactin, by multiple mechanisms, including regulation of vitamin D metabolism, induction of TRPV6 mRNA, and cooperation with 1,25(OH)2D3 in induction of intestinal calcium transport genes and intestinal calcium transport, can act as an important modulator of vitamin D-regulated calcium homeostasis.

32: American journal of physiology. Renal physiology, 2010 May 12, 167(1)
Prolactin and Dopamine 1 like Receptor Interaction in Renal Proximal Tubular Cells.

[Abstract]ABSTRACT Prolactin is a natriuretic hormone and acts by inhibiting the activity of renal tubular Na(+), K(+)-ATPase activity. These effects require an intact renal dopamine system. Here we have studied by which mechanism prolactin and dopamine interact in Sprauge Dawley rat renal tissue. Na(+), K(+)-ATPase activity was measured as ouabain sensitive ATP hydrolysis in micro dissected renal proximal tubular segments. Intracellular signaling pathways were studied by a variety of different techniques including Western blot using phosphospecific antibodies, immunoprecipitation and biotinylation assays. We found that dopamine and prolactin regulated Na(+), K(+)-ATPase activity via similar signaling pathways, including protein kinase A, protein kinase C and phosphoinositide - 3- kinase activation. The cross talk between prolactin and dopamine 1 like receptors was explained by a heterologous recruitment of dopamine 1 like receptors to the plasma membrane in renal proximal tubular cells. Prolactin had no effect on Na(+), K(+)-ATPase activity in Spontaneous Hypertensive rats, a rat strain with a blunted response to dopamine. These results further emphasize the central role of the renal dopamine system in the interactive regulation of renal tubular salt balance.

33: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2010 May 6, 167(1)
Prolactin Inhibition at Mid-lactation Influences Adiposity and Thyroid Function in Adult Rats.

[Abstract]Maternal hypoprolactinemia at the end of lactation (a precocious weaning model) increases milk leptin transfer and results in overweight, leptin resistance, and secondary hypothyroidism at adulthood. We studied the effects of prolactin (PRL) inhibition during mid-lactation (a partial malnutrition model) on milk leptin transfer, leptinemia, body composition, and thyroid function. Lactating rats were treated with bromocryptine (BRO, 1 mg/twice daily) or saline on days 7, 8, and 9 of lactation. Offspring were sacrificed 10, 21, and 90 days after birth. After treatment, BRO-treated dams showed hypoprolactinemia and hyperleptinemia, and produced less milk with lower levels of lactose and higher milk triglycerides. Milk leptin levels were lower at weaning. Offspring of BRO-treated dams had lower body weight and length as well as less visceral fat during lactation and adulthood. Total fat was also lower at weaning and adult life, whereas total protein was higher at 90 days-old. BRO offspring presented lower serum T4 and TSH at 10 days-old and weaning, respectively. When adults, these rats exhibited hypoleptinemia, lower levels of thyroid hormones, and higher TSH. Early inhibition of PRL therefore leads to offspring malnutrition and affects subsequent growth. Also, inhibition of PRL during lactation predisposes offspring to hypothyroidism; however, when the inhibition occurs during late lactation, the hypothyroidism is secondary, whereas when it is restricted to mid-lactation, the thyroid hypofunction is primary. The programming effect of milk suppression thus depends on the developmental stage of offspring.

34: Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion, 2010 Apr 29, 82(1-2)
[Mixed prolactin- and ACTH-producing pituitary adenoma.]

[Abstract]We have recently found that dopamine (DA) released from terminals of the hypothalamic neuroendocrine dopamine (NEDA) neurons plays a role not only in prolactin (PRL), but also in adrenocorticotrop hormone (ACTH) secretion, without having any influence on alpha-melanocyte-stimulating hormone (alpha-MSH) release in lactating dams. The aim of our present studies was to further investigate this DAerg regulation of ACTH using consecutively applied physiological stimulation (suckling) and pharmacological inhibition of the rate-limiting enzyme of DA synthesis (tyrosine hydroxylase, TH) by alpha-methyl-p-tyrosine (alpha-MpT) that acutely affect secretion of these pituitary hormones during lactation. Following 4h separation period, two experimental groups were formed. In the first group, lactating rats were assembled with their litters for 60 min prior to alpha-MpT. In the second group, the alpha-MpT was injected first and 60 min later suckling stimulus was applied. Plasma samples were taken in every 15 min during the 90 min experimental period. Concentrations of plasma PRL, ACTH and alpha-MSH were measured by specific RIAs. Both stimuli applied in the first sequence, significantly elevated plasma PRL and ACTH levels in separated lactating dams, without having any effect on alpha-MSH secretion. Suckling applied in the first sequence was able to block the alpha-MpT-induced elevation of ACTH secretion, while PRL response was also significantly attenuated. alpha-MpT pretreatment prevented both PRL and ACTH responses to suckling stimulus. Investigating the dephosphorylation/inactivation of TH in the arcuate nucleus-ME (TIDA) regions, no pTH-immunoreactive perikarya or terminals can be found in continuously suckled dams. In contrast, after 4h separation of the mothers from their litters, pTH-immunoreactivity can be clearly visualized in the external zone of ME. In alpha-MpT pretreated mothers following 4h separation no pTH positive terminals are visible. No changes in the TH immunostaining can be observed in any of these experimental groups. In conclusion, dephosphorylation/inactivation of TH (the rate-limiting enzyme of the DA biosynthesis) in NEDA neurons is required for suckling-induced PRL and ACTH responses.

35: American journal of respiratory and critical care medicine, 2010 Apr 22, 271(1-2)
Effects of Prolactin on TSC2-null Eker Rat Cells and in Pulmonary Lymphangioleiomyomatosis (LAM).

[Abstract]RATIONALE: Lymphangioleiomyomatosis, a cystic lung disease of women, is characterized by proliferation of smooth muscle-like lymphangioleiomyomatosis cells, which possess mutations in the tuberous sclerosis complex genes, TSC1/TSC2. Growth factors involved in LAM cell proliferation are unknown. Prolactin, an important reproductive hormone in women, is known to promote cell proliferation and survival in other tissues. OBJECTIVE: To determine the role of prolactin on signaling and proliferation in lymphangioleiomyomatosis. METHODS: Prolactin levels in lymphangioleiomyomatosis patient sera were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real time RT-PCR and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro. MEASUREMENTS AND MAIN RESULTS: Higher prolactin levels in sera of lymphangioleiomyomatosis patients were associated with a faster rate of decline in FEV1 and an increased history of pneumothorax (P<0.01). Higher levels of prolactin and prolactin receptor mRNA and immunoreactivity were found in lymphangioleiomyomatosis lesions when compared with vascular smooth muscle cells in the same region of tissue. This was accompanied by evidence of activation of STAT1, STAT3, p44/42, and p38 MAPK. Tsc2-/- Eker rat embryonic fibroblasts expressed more prolactin receptor than did Tsc2+/+ cells, and responded to prolactin with increased proliferation and activation of the same signaling pathways seen in vivo. CONCLUSIONS: Prolactin may be an important growth factor in the pathogenesis of lymphangioleiomyomatosis.

36: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2010 Apr 21, 271(1-2)
Suppression of Prolactin Expression by Cabergoline Requires Prolactin Regulatory Element-binding Protein (PREB) in GH3 Cells.

[Abstract]The prolactin regulatory element-binding protein (PREB) is a transcriptional factor that regulates prolactin (PRL) promoter activity in the anterior pituitary. Prolactinomas are the most common pituitary tumors. Administration of cabergoline, a selective dopamine D2-receptor agonist, has become the initial therapy of choice for most patients with prolactinomas. Although activation of the D2 receptor results in the inhibition of PRL synthesis, the details of the underlying mechanisms remain unknown. Samples of ten prolactinomas and ten nonfunctioning pituitary adenomas were analyzed by immunohistochemistry to detect the expression of PREB. The effect of cabergoline on PREB expression was assessed by western blotting and real-time polymerase chain reaction (PCR) analysis. Reporter gene analysis of PRL was employed to examine the role of PREB on cabergoline-induced suppression of PRL transcription. Immunohistochemical analysis revealed strong positive PREB expression in the prolactinoma tissue, but extremely weak or undetected expression in the nonfunctioning pituitary tumor tissue. Western blots probed with a PREB-specific antiserum revealed that the relative abundance of the PREB protein in the GH3 cells decreased in a dose-dependent manner in response to cabergoline treatment, as did the relative abundance of PREB mRNA. Although cabergoline inhibited the activity of the PRL promoter, mutation of PREB-binding site within the promoter abrogated the ability of cabergoline to inhibit the PRL promoter activity. We have demonstrated that PREB is expressed in prolactinomas and that the suppression of PRL expression by cabergoline requires the transcriptional factor PREB.

37: Endocrinology, 2010 Apr 21, 271(1-2)
Kisspeptin Regulates Prolactin Release through Hypothalamic Dopaminergic Neurons.

[Abstract]Prolactin (PRL) is tonically inhibited by dopamine (DA) released from neurons in the arcuate and periventricular nuclei. Kisspeptin plays a pivotal role in LH regulation. In rodents, kisspeptin neurons are found mostly in the anteroventral periventricular and arcuate nuclei, but the physiology of arcuate kisspeptin neurons is not completely understood. We investigated the role of kisspeptin in the control of hypothalamic DA and pituitary PRL secretion in adult rats. Intracerebroventricular kisspeptin-10 (Kp-10) elicited PRL release in a dose-dependent manner in estradiol (E2)-treated ovariectomized rats (OVX+E2), whereas no effect was found in oil-treated ovariectomized rats (OVX). Kp-10 increased PRL release in males and proestrous but not diestrous females. Associated with the increase in PRL release, intracerebroventricular Kp-10 reduced Fos-related antigen expression in tyrosine hydroxylase-immunoreactive (ir) neurons of arcuate and periventricular nuclei in OVX+E2 rats, with no effect in OVX rats. Kp-10 also decreased 3,4-dihydroxyphenylacetic acid concentration and 3,4-dihydroxyphenylacetic acid-DA ratio in the median eminence but not striatum in OVX+E2 rats. Double-label immunofluorescence combined with confocal microscopy revealed kisspeptin-ir fibers in close apposition to and in contact with tyrosine hydroxylase-ir perikarya in the arcuate. In addition, Kp-10 was not found to alter PRL release from anterior pituitary cell cultures regardless of E2 treatment. We provide herein evidence that kisspeptin regulates PRL release through inhibition of hypothalamic dopaminergic neurons, and that this mechanism is E2 dependent in females. These findings suggest a new role for central kisspeptin with possible implications for reproductive physiology.

38: General and comparative endocrinology, 2010 Apr 17, 271(1-2)
PRL and GH synthesis and release from the sea bream (Sparus auratus L) pituitary gland in vitro in response to osmotic challenge.

[Abstract]The endocrine factors prolactin (PRL) and growth hormone (GH) are believed to have counteracting effects in the adaption of fish to changes in environmental salinity. In order to further investigate this interaction sea bream were challenged with full seawater (SW) or freshwater (FW) for 7 days and the response of pituitary glands cultured in vitro to an osmotic challenge (230, 275 and 320mOsm/kg) was assessed. In vitro PRL secretion from pituitaries of SW adapted fish was unaltered in response to an osmotic challenge, while GH secretion increased in the lowest osmolality (230 mOsm/kg). In contrast, both GH and PRL secretion by pituitaries from FW challenged fish was significantly increased (p<0.01) over that of pituitaries from SW fish at the highest osmolality (320mOsm/kg). After FW challenge pituitary PRL content and de novo synthesised and released PRL were significantly increased (p<0.01), while total PRL secretion was not different from SW animals. GH pituitary content decreased in FW animals while total secretion and secretion of de novo synthesised protein were significantly increased (p<0.01). In addition, after transfer of fish to FW expression of PRL and GH increased 3- and 2-fold respectively. Despite the increase in PRL expression, no increase in total PRL secretion occurred and although in gills a 2-fold increase in the osmoregulatory marker, Na(+)/K(+) ATPase activity was detected, profound haemodilution and a cumulative mortality of 40% occurred in sea bream placed in FW. Taken together the results suggest that the sea bream pituitary gland fails to respond appropriately to the osmotic challenge caused by low salinity and the physiological response evoked in vivo is not enough to allow this species to withstand and adapt to FW.

39: Pediatrics, 2010 Apr 19, 271(1-2)
Breastfeeding and Prolactin Levels in Lactating Women With a Family History of Alcoholism.

[Abstract]Objective: Many motivated new mothers fail to reach public health goals for breastfeeding, highlighting the need to identify risk factors. Because having a family history of alcoholism is associated with blunted prolactin responses to an alcohol challenge in nonlactating individuals, this study aimed to identify associations in family history of alcoholism, prolactin, and breastfeeding behaviors in lactating women. Methods: This was a 2-day experimental study that used within-subject alcohol or control beverage consumption and between-subject family history of alcoholism factors. The participants were non-alcohol-dependent lactating women; 7 were family history-positive (FHP) for alcohol dependence, and 21 were family history-negative (FHN). Consumption of 0.4 g/kg alcohol or nonalcoholic beverage occurred in separate randomized sessions, followed by use of a breast pump. Basal and suckling-induced prolactin, blood alcohol concentrations, milk yield, self-reported drug effects, neophobia, and breastfeeding patterning were measured. Results: Although no group differences in alcohol pharmacokinetics were detected, FHP women exhibited blunted prolactin to breast stimulation after drinking the control and alcohol beverage and felt more of the stimulant-like effects of alcohol than did FHN women. FHP women reported more frequent daily breastfeeding than did FHN women. Conclusions: This is the first evidence that family history of alcoholism is associated with a blunted magnitude, rapidity, and duration of the prolactin response to breast stimulation and an alcohol challenge in lactating women. More frequent breastfeeding by FHP women suggests behavioral compensation for perceived and/or actual poor lactation. Alcohol did not enhance lactational performance, further disputing the lore that alcohol is a galactagogue.

40: Hormones and behavior, 2010 Apr 15, 44(4)
Prolactin, oxytocin, and the development of paternal behavior across the first six months of fatherhood.

[Abstract]Animal studies have implicated the neuropeptides Prolactin (PRL) and Oxytocin (OT) in processes of maternal bonding and PRL has similarly been shown to play a role in the neurophysiology of fatherhood. Yet, very little is known on the involvement of PRL and OT in human fathering. Forty-three fathers and their first-born infant were seen twice: in the second and sixth postpartum months. Paternal plasma PRL and OT were sampled at both time-points and analyzed with ELISA methods. At six months fathers were videotaped interacting with their child in social and exploratory play contexts and interactions were micro-analyzed for father-infant affect synchrony and father facilitation of child toy exploration. PRL and OT showed high individual stability across time and were correlated at the second observation. PRL was related to father-infant coordinated exploratory play in the toy context whereas OT was associated with father-infant affect synchrony in the social context. Results point to the role of PRL and OT in the development of human fathering and underscore their differential relations with patterns of paternal care.

41: Domestic animal endocrinology, 2010 Aug, 39(2)
Pleiotropic effects of the goat prolactin receptor genotype on milk fatty acid composition.

[Abstract]In the lactating mammary gland, prolactin (PRL) stimulates the synthesis of lactose as well as fatty acid uptake, lipogenesis, and triacylglycerol synthesis. Associations between bovine PRL receptor (PRLR) genotype and fat yield have been reported, which illustrates the role of PRL in conveying lipids toward the udder as well as in stimulating their local synthesis during lactation. Conversely, and to the best of our knowledge, the effects of PRLR genotype on milk fatty acid content have not been studied so far in any mammalian species. In this study, we sequenced most of the coding region of the caprine PRLR gene in several individuals from the Malague?a and Murciano-Granadina breeds. This approach allowed us to identify 2 long and short mRNA isoforms, produced by alternative splicing, and 4 single-nucleotide polymorphisms (SNPs), namely, c.177T>C, c.1131G>A, c.1201G>A and c.1355C>T. Two of these SNPs are nonsynonymous and involve G401R (c.1201G>A) and T452I (c.1355C>T) amino acid substitutions in the cytoplasmic domain of PRLR, which plays a fundamental role in signal transduction. Performance of an association analysis with milk composition traits in a Murciano-Granadina goat population revealed highly suggestive effects on palmitoleic acid content, whereas suggestive effects were detected for other fatty acids, such as palmitic and linoleic. These results are consistent with the pleiotropic effects of PRL on mammary gland lipid metabolism and milk composition.

42: Human psychopharmacology, 2010 Apr, 25(3)
Prolactin fluctuation over the course of a day during treatments with three atypical antipsychotics in schizophrenic patients.

[Abstract]Hyperprolactinemia is a frequent consequence of treatment with some antipsychotic agents. Although prolactin secretion varies over the course of a day and during psychological circumstances, there is little information in the literature regarding the time dependence of the prolactin response to antipsychotics. We evaluated prolactin levels in schizophrenic patients receiving risperidone (3 mg twice daily), olanzapine (10 mg twice daily), or perospirone (16 mg twice daily) for at least 4 weeks. The subjects were compared to matched healthy controls. Plasma sample collection for quantification of drug and prolactin levels was conducted before and 2, 4, 6, 8, and 12 h after the morning dosing. Prolactin concentrations before dosing during risperidone treatment were significantly higher than during treatment with olanzapine and perospirone in females. The daily fluctuation of prolactin concentration after perospirone treatment was larger than that observed after risperidone and olanzapine treatments. Areas under the plasma concentration-time curves was greatest in subjects treated with risperidone, followed by perospirone and finally by olanzapine. These findings suggest that daily fluctuations in prolactin concentration after perospirone treatment are larger than following treatment with risperidone and olanzapine. The plasma concentration of prolactin during perospirone treatment therefore depends on the time of sampling.

43: The Journal of endocrinology, 2010 Apr 6, 44(4)
New Concepts in Prolactin Biology.

[Abstract]Human prolactin is currently viewed as a hormone of pituitary origin, whose production (i.e. serum levels) is controlled by dopamine, whose biological actions relate exclusively to lactation and reproductive functions, for which any genetic disorder is yet to be identified, and whose unique associated pathology is hyperprolactinemia. Both experimental studies and human sample/cohort based investigations performed during the past decade have considerably widened our perception of prolactin biology: i) there are now strong epidemiologic arguments supporting the fact that circulating prolactin is a risk factor for breast cancer, ii) in addition to the endocrine hormone, locally-produced prolactin has been documented in several human tissues; there is increasing evidence supporting the tumor-growth potency of local PRL, acting via autocrine/paracrine mechanisms, in both rodent models and human breast and prostate tumors, iii) the first functional germinal polymorphisms of the prolactin receptor were recently identified in patients presenting with breast tumors, which involve single-amino acid substitution variants exhibiting constitutive activity, iv) human prolactin analogs have been engineered, which were shown in experimental models to down-regulate the effects triggered by local prolactin (competitive antagonism) or by the constitutively active receptor variants (inverse agonism). The aim of this review is to discuss these novel concepts in prolactin biology, including their potential pathophysiological outcomes.

44: Progress in neuro-psychopharmacology & biological psychiatry, 2010 Apr 1, 205(1)
The wide variability of perospirone metabolism and the effect of perospirone on prolactin in psychiatric patients.

[Abstract]BACKGROUND: Perospirone was developed in Japan and is used for the treatment of schizophrenia and related illnesses. The authors investigated the relationship between the dosage of perospirone and the plasma levels of perospirone and its active metabolite, ID15036, and also evaluated the impact of the plasma concentrations of perospirone and ID15036 on the plasma prolactin level to examine whether perospirone or ID15036 affected the dopamine D(2) blockade, in psychiatric patients treated with perospirone. METHODS: The subjects consisted of 21 adults treated with perospirone (4-60mg/day). The plasma perospirone and ID15036 levels were measured in 21 patients and serum prolactin levels were investigated in 10 male patients with schizophrenia. RESULTS: The plasma ID15036 level was higher than the plasma perospirone, and a positive correlation was observed between the dosage of perospirone and the ID15036 levels (p=0.032). The 10 male patients showed a positive correlation between the plasma perospirone levels and plasma prolactin levels (r=0.688, p=0.028) and between the plasma ID15036 levels and prolactin levels (r=0.775, p=0.009). CONCLUSION: The plasma levels of ID15036 may have a greater impact on the dopamine D(2) blockade than perospirone in patients treated with perospirone.

45: Rheumatology international, 2010 Mar 30, 205(1)
HLA class II, MICA and PRL gene polymorphisms: the common contribution to the systemic lupus erythematosus development in Czech population.

[Abstract]The genetic components contribute to the systemic lupus erythematosus development. This study for the first time determined the distribution of the polymorphisms and linkage disequilibrium in HLA class II, MICA and PRL gene among patients suffering from SLE and healthy Czech individuals. DNA was obtained from the peripheral blood cells of 123 SLE patients and 96 healthy people. Allele variants of the HLA class II, MICA transmembrane polymorphism and PRL extrapituitary promoter -1149G/T SNP were detected using the sequence-specific primers analysis, PCR-fragment analysis and PCR-RFLP, respectively. In Czech population, only DRB1*03-DQB1*0201 haplotype is significantly associated with increased risk for SLE development: the frequency in SLE group was 44.7% in comparison with 15.2% in controls, P (c) < 0.0001; OR 4.54 CI 95% (2.36-9.09). The MICA-A5.1 allele is present significantly more often in SLE (55.7%) than controls (39.9%), P (c) = 0.005; OR 1.88 CI 95% (1.29-2.77), and the combination of HLA DRB1 *03 together with MICA-A5.1 is strongly associated with SLE [P (c) < 0.000001; OR 9.71 CI 95% (3.4-27.7)]. On the other hand, the MICA-A6 allele is less frequent in SLE patients compared to controls, 10.6% and 19.7%, respectively [P (c) = 0.035; OR 0.48 CI 95% (0.28-0.82)], and the combination of absence both alleles MICA-A6 and HLA DRB*11 seems to be risk for SLE development compared to controls, 84.6 and 70.2%, respectively, [P (c) = 0.0003 OR 2.32 CI 95% (1.47-3.70)]. We found that only G allele of the -1149 G/T SNP is associated with specific clinical manifestation of SLE, arthritis [P (c) = 0.022; OR 2.63, CI 95% (1.45-4.81)]. HLA class II-MICA combinations may increase/decrease a risk for SLE development. Multiple studies focusing on the ethnical differences as well as genetic-epigenetic relationships are necessary for better understanding SLE pathogenesis.

46: Molecular biology reports, 2010 Mar 27, 205(1)
Single nucleotide polymorphisms of the prolactin receptor (PRLR) gene and its association with growth traits in chinese cattle.

[Abstract]Genetic polymorphism of the prolactin receptor (PRLR) gene was detected by PCR-SSCP and DNA sequencing methods in 665 individuals from five Chinese cattle breeds. The results showed that at the P1 locus, three observed genotypes (AA, AB and BB), two linked SNPs (G1267A and T1268C), and one missense mutation (S18N) within a putative signal peptide were determined. The frequencies of haplotypes A and B in the five breeds were 0.596-0.802 and 0.198-0.404, respectively. Polymorphism of the PRLR gene was shown to be significantly associated with growth traits in the Nanyang breed. Individuals with genotype BB had greater hucklebone width, body weight and average daily gain than those with genotype AA at 6 months old (P < 0.01), as well as better body height, body length and heart girth when 6 months (P < 0.05). This study revealed for the first time that the PRLR gene is a promising candidate gene that affects growth traits in cattle.

47: Schizophrenia research, 2010 Mar 25, 205(1)
An abnormal relation between basal prolactin levels and prolactin response to 12.5microg TRH i.v. in drug-na?ve patients with first-episode schizophrenia.

[Abstract]At doses lower than those needed to stimulate prolactin release directly, TRH almost completely antagonizes the inhibitory effect of dopamine on prolactin release. We have previously reported that prolactin response to administration of 12.5microg TRH i.v. correlates with prolactin response to 0.5mg i.m. haloperidol and negatively with 24-h urinary excretion of HVA in normal subjects, suggesting that the response reflects dopamine activity. An association between central dopamine hyperactivity and SANS scores relating to poverty of content of speech and inattention has been suggested by studies utilizing methylphenidate administration in patients with first-episode schizophrenia. The hypothesis that small plasma prolactin responses to administration of 12.5microg TRH i.v. ( prolactin) correlate with SANS scores for these symptoms was tested in 19 drug-na?ve patients with first-episode schizophrenia. Significant negative correlations were found between the response and scores relating to poverty of content of speech (r=-0.55, p=0.014) and inattention (r=-0.52, p=0.022), supporting the hypothesis of increased dopamine activity in association with disorganization symptoms. A significant positive correlation between basal prolactin levels and prolactin response to stimulation by 12.5microg TRH was also found (r=+0.61, p=0.0058). Our previous study in normal subjects found a similar positive correlation between basal prolactin levels and prolactin response to stimulation by 200microg TRH i.v., but not by 12.5microg TRH i.v. As far as we know, this is the first study to report an abnormality in TRH-induced prolactin release in acute schizophrenia.

48: Journal of dairy science, 2010 Apr, 93(4)
Effect of prolactin, beta-lactoglobulin, and kappa-casein genotype on milk yield in East Friesian sheep.

[Abstract]The effect of prolactin (PRL), beta-lactoglobulin (beta-LG), and kappa-casein (CSN3) on milk yield was estimated in an East Friesian dairy sheep population from Old Chatham Sheepherding Company, New York. Genotypes were determined by PCR amplification followed by digestion with HaeIII and RsaI for PRL and beta-LG, respectively, and by PCR amplification for CSN3. Monthly milking records and pedigree information were used to evaluate the effect of each polymorphism on milk yield. Results indicated that PRL genotype had a significant effect on milk yield. Ewes carrying one A allele produced 110.6g more milk per day than ewes with no A alleles. There was no statistical difference between ewes with only one A allele and ewes with 2 A alleles. No association among polymorphisms at the beta-LG and CSN3 loci and milk yield was found. The results presented in this study indicate that the PRL gene is a potential marker that could be used in selection programs for improving milk yield in dairy sheep.

49: Molecular psychiatry, 2010 Mar 23, 205(1)
Exploring functional polymorphisms in the dopamine receptor D2 gene using prolactin concentration in healthy subjects.

[Abstract]At doses lower than those needed to stimulate prolactin release directly, TRH almost completely antagonizes the inhibitory effect of dopamine on prolactin release. We have previously reported that prolactin response to administration of 12.5microg TRH i.v. correlates with prolactin response to 0.5mg i.m. haloperidol and negatively with 24-h urinary excretion of HVA in normal subjects, suggesting that the response reflects dopamine activity. An association between central dopamine hyperactivity and SANS scores relating to poverty of content of speech and inattention has been suggested by studies utilizing methylphenidate administration in patients with first-episode schizophrenia. The hypothesis that small plasma prolactin responses to administration of 12.5microg TRH i.v. ( prolactin) correlate with SANS scores for these symptoms was tested in 19 drug-na?ve patients with first-episode schizophrenia. Significant negative correlations were found between the response and scores relating to poverty of content of speech (r=-0.55, p=0.014) and inattention (r=-0.52, p=0.022), supporting the hypothesis of increased dopamine activity in association with disorganization symptoms. A significant positive correlation between basal prolactin levels and prolactin response to stimulation by 12.5microg TRH was also found (r=+0.61, p=0.0058). Our previous study in normal subjects found a similar positive correlation between basal prolactin levels and prolactin response to stimulation by 200microg TRH i.v., but not by 12.5microg TRH i.v. As far as we know, this is the first study to report an abnormality in TRH-induced prolactin release in acute schizophrenia.

50: Trends in endocrinology and metabolism: TEM, 2010 Mar 19, 205(1)
Is prolactin the cardinal calciotropic maternal hormone?

[Abstract]To produce offspring, mothers require a large amount of calcium for fetal growth and milk production. Increased calcium demand leads to enhanced intestinal calcium absorption and stockpiling of bone calcium in pregnancy prior to demineralization in lactation. These coordinated events must be carefully organized by calciotropic hormone(s), but the classical hormones, namely 1,25-dihydroxyvitamin D(3), parathyroid hormone and calcitonin, do not appear to be responsible. Plasma prolactin (PRL) levels are elevated during pregnancy and, in view of the presence of PRL receptors in gut, bone and mammary glands, as well as recent evidence of the stimulatory effects of PRL on intestinal calcium transport, bone resorption and mammary calcium secretion, we postulate that PRL is the cardinal calciotropic hormone during pregnancy and lactation.

51: The British journal of dermatology, 2010 Mar 10, 285(11)
Immunosuppressive effect of prolactin-induced protein: a new insight into the local and systemic role on chronic allergic contact dermatitis Immunosuppressive effect of prolactin-induced protein.

[Abstract]Summary Background: Prolactin-induced protein (PIP) has been shown to bind to CD4 and is speculated to block CD4-HLA-DR interaction. However, the immunomodulatory effect of PIP on chronic allergic contact dermatitis (ACD) remains to be elucidated. Objectives: The aim of this work was to define the role of PIP during the immunoresponse. Materials and Methods: Using a low dose oxazolone-induced mouse chronic ACD model, expression of PIP was immunohistologically examined. Furthermore, effects of continued exposure of a peptide mimicking the major binding site of PIP (amino acids 106-132) for CD4 was examined in a mouse chronic ACD model. Results: We clarified that keratinocytes, dermal infiltrating cells and infiltrating mononuclear cells into the spleen are positively stained with anti-PIP antibody. The PIP peptide significantly down-regulated oxazolone-induced mouse ACD compared to the controls. We also found that inflammation of PIP-non-applied control ear was also suppressed in a synchronized manner in late phase of the PIP peptide applied mouse. Conclusions: These findings suggest that PIP might have a local and systemic immunosuppressive effect in mouse chronic ACD.

52: The British journal of dermatology, 2010 May, 162(5)
Thyrotropin-releasing hormone and oestrogen differentially regulate prolactin and prolactin receptor expression in female human skin and hair follicles in vitro.

[Abstract]BACKGROUND: Human skin and scalp hair follicles are both a nonclassical target and an extrapituitary source of prolactin (PRL), which is a potent hair growth modulator. However, how the expression of PRL and PRL receptor (PRLR) is regulated in human skin is unknown. OBJECTIVES: To investigate whether two key stimulators of pituitary PRL secretion, thyrotropin-releasing hormone (TRH) and oestrogen, also regulate cutaneous PRL and PRLR expression. METHODS: Female scalp skin and/or microdissected hair follicles were treated for 6 days in serum-free organ culture with oestrogen (100 nmol L(-1)), TRH (1-10 ng mL(-1), 3-30 nm) or vehicle control. Quantitative immunohistomorphometry of skin and hair follicle sections was complemented with quantitative polymerase chain reaction for PRL and PRLR in cultured hair follicles and/or female human outer root sheath (ORS) keratinocytes. RESULTS: Oestrogen treatment significantly upregulated PRL and PRLR immunoreactivity in selected skin and hair follicle compartments, at the gene and protein level (P < 0.05). TRH significantly increased PRL immunoreactivity and transcription in hair follicles (P < 0.05); however, while it also increased PRLR transcription in hair follicles, it downregulated PRLR immunoreactivity in the hair follicle ORS (P < 0.05). CONCLUSIONS: Our pilot study shows that two key endocrine controls of pituitary PRL secretion, oestrogen and TRH, also regulate PRL and PRLR expression in human skin. This provides novel insights into the regulation of extrapituitary PRL and PRLR expression, and invites exploration of oestrogen and TRH as novel therapeutic agents in the management of skin and hair diseases characterized by aberrant PRLR-mediated signalling.

53: Molecular and cellular endocrinology, 2010 Mar 15, 93(5)
Cleaved bovine prolactin-related protein-I proliferates vascular endothelial cells.

[Abstract]Prolactin-related protein-I (PRP1) is a member of a non-classical prolactin (PRL)/growth hormone family in cattle. However, its function is still unknown. PRL, when cleaved by cathepsin D and matrix metalloproteinases (MMPs), resulted in cleaved N-terminal 16kDa fragments (16K-PRL) that have antiangiogenetic properties in human and rodents. We examined the possibility of similar activity of bovine PRP1. PRP1 (normally 33kDa) was cleaved by cathepsins (CTSs), MMPs, and bovine cotyledonary-conditioned medium (BCCM), and generated mainly 26kDa N-terminal fragments. Two specific enzyme families, CTSs and MMPs cleaved intact PRP1, and BCCM also contained PRP1 cleavage activity. Bioactivity for pro- or anti-angiogenesis of the cleaved PRP1 was examined in a cell proliferation assay using bovine brain vascular endothelial cells. The cleaved PRP1 proliferated the endothelial cells in vitro. The endothelial cell proliferation activity of cleaved PRP1 may be shared in specific bovine placentomal angiogenesis.

54: Journal of neuroendocrinology, 2010 Mar 8, 285(11)
Stress response of prolactin-releasing peptide knockout mice as to glucocorticoid secretion.

[Abstract]Abstract Prolactin-releasing peptide (PrRP) is known to have functions in such as prolactin secretion, stress responses, cardiovascular regulation and food intake suppression. In addition PrRP-KO male mice showed obesity from the age of 22 weeks and increased food intake. The plasma concentrations of insulin, leptin, cholesterol and triglyceride were also increased in obese PrRP-KO mice. Fatty liver, hypertrophied white adipose tissue, decreased uncoupling protein 1 (UCP1) mRNA expression in brown adipose tissue and glucose intolerance were observed in obese PrRP-KO mice. As we reported previously, PrRP stimulates corticotrophin-releasing factor (CRF) and regulates the hypothalamo-pituitary-adrenal axis. Therefore, it is speculated that PrRP regulates both food intake and metabolism as a stress responses. In this study, we compared the blood glucose and plasma glucocorticoid concentrations in PrRP-KO mice, finding that PrRP-KO mice showed higher concentrations of blood glucose and corticosterone compared with wild type (WT) mice after restraint stress. In contrast, there was no difference in c-Fos expression in the paraventricular hypothalamic nucleus (PVN) or plasma ACTH concentration between the two groups. These results suggest that the different stress responses as to glucocorticoid secretion may be induced by different responses of the adrenal glands between WT and PrRP-KO mice. Thus we conclude that PrRP-KO mice become obese due to increased food intake, a change in metabolism, and abnormal stress responses as to glucose concentration and glucocorticoid secretion.

55: Endocrinology, 2010 Mar 10, 285(11)
Prolactin Increases the Synthesis of 7{alpha}-Hydroxypregnenolone, a Key Factor for Induction of Locomotor Activity, in Breeding Male Newts.

[Abstract]We recently found that the Japanese red-bellied newt, Cynops pyrrhogaster, actively produces 7alpha-hydroxypregnenolone, a previously undescribed amphibian neurosteroid. 7alpha-Hydroxypregnenolone stimulates locomotor activity of male newts. Locomotor activity of male newts increases during the breeding period as in other wild animals, but the molecular mechanism for such a change in locomotor activity is poorly understood. Here we show that the adenohypophyseal hormone prolactin (PRL) stimulates 7alpha-hydroxypregnenolone synthesis in the brain, thus increasing locomotor activity of breeding male newts. In this study, cytochrome P4507alpha (CYP7B), a steroidogenic enzyme catalyzing the formation of 7alpha-hydroxypregnenolone, was first identified to analyze seasonal changes in 7alpha-hydroxypregnenolone synthesis. Only males exhibited marked seasonal changes in 7alpha-hydroxypregnenolone synthesis and CYP7B expression in the brain, with a maximum level in the spring breeding period when locomotor activity of males increases. Subsequently we identified PRL as a key component of the mechanism regulating 7alpha-hydroxypregnenolone synthesis. Hypophysectomy decreased 7alpha-hydroxypregnenolone synthesis in the male brain, whereas administration of PRL but not gonadotropins to hypophysectomized males caused a dose-dependent increase in 7alpha-hydroxypregnenolone synthesis. To analyze the mode of PRL action, CYP7B and the receptor for PRL were localized in the male brain. PRL receptor was expressed in the neurons expressing CYP7B in the magnocellular preoptic nucleus. Thus, PRL appears to act directly on neurosteroidogenic magnocellular preoptic nucleus neurons to regulate 7alpha-hydroxypregnenolone synthesis, thus inducing seasonal locomotor changes in male newts. This is the first report describing the regulation of neurosteroidogenesis in the brain by an adenohypophyseal hormone in any vertebrate.

56: Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 2010 Mar 10, 285(11)
The influence of other than prolactin hormones on bone mineral density in women with hyperprolactinaemia of various origins.

[Abstract]Objective. Hyperprolactinaemia may lead to bone loss, both due to hypogonadism and other hormonal disturbances. Aim of the case-control study was the analysis of influences of hormonal profiles associated with hyperprolactinaemia on the bone mineral density (BMD) in women with hyperprolactinaemia of various origin. Material and methods. The subjects were 32 patients with prolactinoma, 43 ones with functional hyperprolactinaemia and 29 healthy controls. All of them were studied for BMD (lumbar spine, proximal femur, forearm, total body) by dual-energy X-ray absorptiometry and their correlations with hormones levels (prolactin, oestradiol, luteinising hormone, follicle stimulating hormone, sex hormone binding globulin (SHBG), testosterone, dehydroepiandrosterone sulphate (DHEA-S), insulin-like growth factor-1 and intact parathyroid hormone) using Spearman correlation analysis and multiple regression analysis model. Results. Correlation analysis revealed the anabolic influence of PTH on lumbar spine in women with prolactinoma, and on ultradistal radius in functional hyperprolactinaemia. In multiple regression analysis, oestradiol had greatest influence on lumbar spine and total body BMD. Moreover, positive influence of testosterone, SHBG on spine BMD, and of oestradiol, testosterone, SHBG and DHEA-S on total body BMD were observed in patients with prolactinoma. Conclusion. Hormonal disturbances associated with hyperprolactinaemia influence BMD more in patients with prolactinoma than in ones with functional hyperprolactinaemia.

57: Endocrinology, 2010 Mar 9, 285(11)
Episodes of Prolactin Gene Expression in GH3 Cells Are Dependent on Selective Promoter Binding of Multiple Circadian Elements.

[Abstract]Prolactin (PRL) gene expression in mammotropes occurs in pulses, but the mechanism(s) underlying this dynamic process remains obscure. Recent findings from our laboratory of an E-box in the rat PRL promoter (E-box133) that can interact with the circadian factors, circadian locomoter output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, and was necessary for pulse activity raised the intriguing possibility that the circadian system may be central to this oscillatory process. In this study, we used serum-shocked GH3 cells, established previously to synchronize PRL pulses between cells in culture, to reveal that pulses of PRL mRNA are linked temporally to the expression of bmal1, cry1, per1, and per3 mRNA in these cells. Moreover, we found that each of these circadian factors binds to the rat PRL promoter by chromatin immunoprecipitation analysis. Using EMSA analysis, we observed that two sites present in the proximal promoter region, E-box133 and E-box10, bind circadian factors differentially (E-box133 interacted with BMAL1, cryptochrome-1, period (PER)-1, and PER3 but not PER2 and E-box10 bound BMAL1, cryptochrome-1, PER2, PER3 but not PER1). More importantly, down-regulation of any factor binding E-box133 significantly reduced PRL mRNA levels during pulse periods. Our results demonstrate clearly that certain circadian elements binding to the E-box133 site are required for episodes of PRL mRNA expression in serum-shocked GH3 cultures. Moreover, our findings of binding-related differences between functionally distinct E-boxes demonstrate not only that E-boxes can bind different components but suggest that the number and type of circadian elements that bind to an E-box is central in dictating its function.

58: Biotechnology letters, 2010 Mar 7, 285(11)
Bovine prolactin promotes the expression of human transferrin in the milk of transgenic mice.

[Abstract]The bovine prolactin vector was injected directly into the mammary glands of mice carrying the human transferrin transgene to investigate its effect on the production of human transferrin in milk. The mean levels of human transferrin in two experimental groups were increased by approx. 60% compared with the control group: 1143 +/- 196 ng/ml (experimental group 1; two injections) and 1160 +/- 189 ng/ml (experimental group 2; three injections) versus 714 +/- 75 ng/ml (control group). These findings suggest the potential utility of the prolactin vector for efficient expression of valuable pharmaceutical proteins in transgenic animal mammary glands.

59: Cell and tissue research, 2010 Mar 3, 166(2)
Involvement of insulin-like growth factor-I for the regulation of prolactin synthesis by estrogen and postnatal proliferation of lactotrophs in the mouse anterior pituitary.

[Abstract]Estradiol (E2) stimulates not only secretion of prolactin (PRL) and proliferation of PRL-producing cells (PRL cells) in the anterior pituitary, but also the expression of growth factors. In insulin-like growth factor-I (IGF-I) knockout (KO) mice, the number of PRL cells is decreased and administration of IGF-I does not increase either the number of PRL cells or plasma PRL levels, indicating that IGF-I plays a pivotal role in PRL cells. The effect of E2 on PRL cells in KO mice was investigated by immunohistochemistry and real-time RT-PCR. The number of PRL cells in KO mice was significantly lower than in the wild-type (WT) control mice. E2 increased the PRL mRNA in WT and KO mice; however, an increase of PRL mRNA in KO was less than that in WT. In addition, no vasoactive intestinal peptide (VIP)-immunoreactive cells were found in KO mice, therefore IGF-I is essential for VIP expression. To investigate the roles of IGF-I on PRL cells in the postnatal development, double-immunostaining with PRL and BrdU was performed in WT and KO mice from days 5-20. The percentages of PRL cells and BrdU-labeled cells in the anterior pituitary of KO mice were lower than in WT mice. Thus, IGF-I may be responsible for proliferation and differentiation of PRL cells in this postnatal period. Differentiation and the proliferation of PRL cells are controlled by IGF-I during the postnatal development, and IGF may be a mediator of E2 action through VIP induction in PRL cells of adults.

60: Cell and tissue research, 2010 Feb 25, 95(1)
Oleate and linoleate stimulate degradation of beta-casein in prolactin-treated HC11 mouse mammary epithelial cells.

[Abstract]Although virtually all cells store neutral lipids as cytoplasmic lipid droplets, mammary epithelial cells have developed a specialized function to secrete them as milk fat globules. We have used the mammary epithelial cell line HC11 to evaluate the potential connections between the lipid and protein synthetic pathways. We show that unsaturated fatty acids induce a pronounced proliferation of cytoplasmic lipid droplets and stimulate the synthesis of adipose differentiation-related protein. Unexpectedly, the cellular level of beta-casein, accumulated under lactogenic hormone treatment, decreases following treatment of the cells with unsaturated fatty acids. In contrast, saturated fatty acids have no significant effect on either cytoplasmic lipid droplet proliferation or cellular beta-casein levels. We demonstrate that the action of unsaturated fatty acids on the level of beta-casein is post-translational and requires protein synthesis. We have also observed that proteasome inhibitors potentiate beta-casein degradation, indicating that proteasomal activity can destroy some cytosolic protein(s) involved in the process that negatively controls beta-casein levels. Finally, lysosome inhibitors block the effect of unsaturated fatty acids on the cellular level of beta-casein. Our data thus suggest that the degradation of beta-casein occurs via the microautophagic pathway.

61: The Journal of veterinary medical science / the Japanese Society of Veterinary Science, 2010 Feb 24, 95(1)
Prolactin Secretion and Ovarian Function in Cycling and Non-Cycling African Female Elephants (Loxodonta africana).

[Abstract]Reproduction of captive elephants in zoos has shown a low fecundity and requires improvement. One of reasons of low fecundity is ovarian dysfunction in many female elephants. To investigate whether prolactin has correlation with ovarian function in female elephants, serum concentrations of prolactin, progesterone and estradiol-17beta in four African female elephants (one cycling female and three non-cycling female elephants) were measured. Cyclic pattern of prolactin and estradiol-17beta were observed in a cycling female elephant, which tended to high during the follicular phase and low during the luteal phase. On the other hands, cyclic pattern of prolactin was not observed in non-cycling female elephants. One out of three non-cycling females (Mako) had the developed breast and showed significantly higher average levels of prolactin than those of the other female elephants. These results suggested that high concentrations of circulating estradiol-17beta during the follicular phase stimulated prolactin secretion. These results also suggested that hyperprolactinemia in Mako was one of the causes of developed mammary glands and ovarian dysfunction.

62: The Journal of membrane biology, 2010 Feb 23, 95(1)
Intermediate Ca(2+)-Sensitive K (+) Channels are Necessary for Prolactin-Induced Proliferation in Breast Cancer Cells.

[Abstract]Prolactin (PRL) is a polypeptidic hormone which acts both systemically and locally to cause lactation by interacting with the PRL receptor, a Janus kinase (JAK2)-coupled cytokine receptor family member. Several studies have reported that serum PRL level elevation is associated with an increased risk for breast cancer, and evidence has suggested that PRL is one actor in the pathogenesis and progression of this cancer. We previously reported the involvement of hIKCa1 in breast cell cycle progression and cell proliferation. However, mechanisms by which PRL cooperates with these channels to modulate breast epithelial cell proliferation remain unknown. Our results showed that, in the MCF-7 breast cancer cell line, PRL increased hIKCa1 current density. These channels were functional and regulated the resting membrane potential. The PRL effects were inhibited by TRAM-34 and clotrimazole, the most used hIKCa1 blockers. Moreover, PRL increased proliferation in a dose-dependent manner without overexpressing hIKCa1. To determine whether PRL-induced proliferation and hIKCa1 activity involved the JAK2 pathway, we used pharmacological JAK2 inhibitors (AG490 and JAK inhibitor I). Indeed, PRL-induced JAK2 phosphorylation was required for both cell proliferation and hIKCa1 activity. In the presence of either hIKCa1 blockers or siRNA-hIKCa1, PRL failed to increase cell proliferation and hIKCa1 activity. Taken together, our results demonstrate that PRL plays a role in breast cancer cell proliferation by increasing hIKCa1 activity through the JAK2 signaling pathway.

63: Domestic animal endocrinology, 2010 Jul, 39(1)
Characteristics of prolactin-releasing response to salsolinol in vivo in cattle.

[Abstract]The aims of the present study were to clarify the effect of salsolinol (SAL), a dopamine (DA)-derived endogenous compound, on the secretion of prolactin (PRL) in cattle. The experiments were performed from April to June using calves and cows. A single intravenous (i.v.) injection of SAL (5mg/kg body weight [BW]) or sulpiride (a DA receptor antagonist, 0.1mg/kg BW) significantly stimulated the release of PRL in male and female calves (P<0.05), though the response to SAL was smaller than that to sulpiride. The secretory pattern of PRL in response to SAL or sulpiride in female calves resembled that in male calves. A single i.v. injection of SAL or sulpiride significantly stimulated the release of PRL in cows (P<0.05). There was no significant difference in the PRL-releasing response between the SAL- and sulpiride-injected groups in cows. A single intracerebroventricular injection of SAL (10mg/head) also significantly stimulated the release of PRL in castrated calves (P<0.05). These results show that SAL is involved in the regulatory process for the secretion of PRL, not only in male and female calves, but also in cows. The results also suggest that the potency of the PRL-releasing response to SAL differs with the physiological status of cattle.

64: Brain research bulletin, 2010 Feb 16, 11(1)
Dephosphorylation/inactivation of tyrosine hydroxylase at the median eminence of the hypothalamus is required for suckling-induced prolactin and adrenocorticotrop hormone responses.

[Abstract]We have recently found that dopamine (DA) released from terminals of the hypothalamic neuroendocrine dopamine (NEDA) neurons plays a role not only in prolactin (PRL), but also in adrenocorticotrop hormone (ACTH) secretion, without having any influence on alpha-melanocyte stimulating hormone (alpha-MSH) release in lactating dams. The aim of our present studies was to further investigate this DAerg regulation of ACTH using consecutively applied physiological stimulation (suckling) and pharmacological inhibition of the rate limiting enzyme of DA synthesis (tyrosine hydroxylase, TH) by alpha-methyl-p-tyrosine (alpha-MpT) that acutely affect secretion of these pituitary hormones during lactation. Following 4hours separation period, two experimental groups were formed. In the first group, lactating rats were assembled with their litters for 60min prior to alpha-MpT. In the second group, the alpha-MpT was injected first and 60min later suckling stimulus was applied. Plasma samples were taken in every 15min during the 90min experimental period. Concentrations of plasma PRL, ACTH and alpha-MSH were measured by specific RIAs. Both stimuli applied in the first sequence, significantly elevated plasma PRL and ACTH levels in separated lactating dams, without having any effect on alpha-MSH secretion. Suckling applied in the first sequence was able to block the alpha-MpT-induced elevation of ACTH secretion, while PRL response was also significantly attenuated. alpha-MpT pretreatment prevented both PRL and ACTH responses to suckling stimulus. Investigating the dephosphorylation/inactivation of TH in the arcuate nucleus-ME (TIDA) regions, no pTH-immunoreactive perikarya or terminals can be found in continuously suckled dams. In contrast, after 4h separation of the mothers from their litters, pTH-immunoreactivity can be clearly visualized in the external zone of ME. In alpha-MpT pretreated mothers following 4h separation no pTH positive terminals are visible. No changes in the TH immunostaining can be observed in any of these experimental groups. In conclusion, dephosphorylation/inactivation of TH (the rate-limiting enzyme of the DA biosynthesis) in NEDA neurons is required for suckling-induced PRL and ACTH responses.

65: Progress in neuro-psychopharmacology & biological psychiatry, 2010 Feb 16, 11(1)
Gender-specific prolactin response to antipsychotic treatments with risperidone and olanzapine and its relationship to drug concentrations in patients with acutely exacerbated schizophrenia.

[Abstract]Hyperprolactinemia is a frequent consequence of treatment with antipsychotic agents, partially because the prolactin response to antipsychotics is related to dopamine blockade. Recent studies have suggested that the prolactin response to olanzapine is weaker than that to risperidone. Thus, we studied the effects of various factors on the elevated plasma prolactin levels caused by these medications. The subjects were 94 patients with acutely exacerbated schizophrenia (46 males, 48 females). For four weeks, they received 6mg of risperidone and 20mg of olanzapine daily. Plasma samples were collected before the medications were given and 12h after the bedtime dosing each week. Treatment with either risperidone or olanzapine boosted plasma prolactin levels above baseline in both males and females. Prolactin levels were significantly higher in females than in males at all sampling points in both treatments. Risperidone increased prolactin significantly more than did olanzapine in both males and females. Delta prolactin (prolactin level at four weeks minus the baseline prolactin level) during olanzapine treatment significantly correlated with olanzapine concentration at 4th week (r=-0.518, p<0.01) only in males. Multiple regression analyses showed that delta prolactin during risperidone was significantly correlated with gender (p<0.001) and age (p<0.05) and that delta prolactin during olanzapine significantly correlated with gender (p<0.001) and drug concentration (p<0.01). The present study suggests that the predominant factors influencing hyperprolactinemia are young female for risperidone treatment, and being female and lower drug concentration as a predictor for hyperprolactinemia under olanzapine.

66: The Journal of clinical endocrinology and metabolism, 2010 Feb 17, 11(1)
Prognostic Factors in Prolactin Pituitary Tumors: Clinical, Histological, and Molecular Data from a Series of 94 Patients with a Long Postoperative Follow-Up.

[Abstract]Context and Objective: Predicting pituitary tumor behavior remains a challenge. This multiparameter investigation aimed to identify markers for recurrence and progression in prolactin tumors. Design: From a cohort of patients treated for prolactin tumors by surgery, we retrospectively studied clinical data, tumor characteristics, clinical outcome, and the expression of nine genes by quantitative RT-PCR. Results: This study included 94 patients (62 females and 32 men), with long postoperative follow-up periods (mean, 138 +/- 46 months); 54.3% of patients had a macro or giant adenoma. Tumors were classified into three pathological groups based on their radiological and histological characteristics (noninvasive, 61; invasive, 22; and aggressive-invasive, 11). Immediately after surgery, 60 patients (63.8%) went into remission (prolactin level normalization). Persistently elevated prolactin levels (36.2%) were associated with increasing age, male sex, high preoperative prolactin levels, large tumor size on univariate analysis, and invasion and pathological classification on univariate and multivariate (P = 8 x 10(-10) and 3 x 10(-8)) analysis. During follow-up, 19 patients (20%) had tumors that recurred or progressed under dopamine agonist treatment. Invasion and pathological classification were associated with recurrence or progression on univariate analysis. Seven genes (ADAMTS6, CRMP1, PTTG, ASK, CCNB1, AURKB, and CENPE) were associated with tumor recurrence or progression and five of these (ADAMTS6, CRMP1, ASK, CCNB1, and CENPE) were associated with the pathological classification. Conclusion: This study identifies both the clinical and histological factors that relate to prolactin tumor recurrence or progression. Molecular markers give additional information for prognosis of such tumors. Altogether, our results could influence the management of patients with pituitary tumors.

67: BMC musculoskeletal disorders, 2010 Feb 17, 11(1)
Effects of plasma magnesium and prolactin on quantitative ultrasound measurements of heel bone among schizophrenic patients.

[Abstract]ABSTRACT: BACKGROUND: Osteoporosis is a bone disease that can reduce both bone mass and bone strength. It can cause serious fractures of bones, along with causing significant and even devastating physical, psychological and financial consequences for patients and their family members. Many reports have revealed that the prevalence of decreased bone density is higher in schizophrenic patients than in the non-psychological diseased population. The previous report of our group revealed that chronic schizophrenia patients have poorer BUA levels since they were young as compared to the general community population. Hyperprolactinemia and antipsychotics are reported to be among the risk factors for osteoporosis in chronic schizophrenic patients. METHODS: 93 schizophrenic patients with severely poor adjusted BUA values and 93 age and gender matched patients with normal adjusted BUA values from a previous survey study were selected. Data were collected via questionnaires and via reviews of antipsychotic medications. Blood samples were drawn, and serum levels of prolactin, estradiol, testosterone, magnesium, calcium, phosphate, osteocalcin, Cross-linked N-teleopeptide of type I collagen (NTX), thyroid hormone and parathyroid hormone were checked. The association between BUA levels and serum levels of the above items, along with the type of received antipsychotic medication, was evaluated. RESULTS: There was no significant association found between reduced BUA levels and serum prolactin, calcium, phosphate, osteocalcin, NTX, thyroid stimulating hormone and parathyroid hormone levels. There was also no association between BUA levels and types of currently received antipsychotics. There was no association between BUA levels and menstruation condition in female patients. Hypermagnesemia had a borderline association with classical and combined (classical and atypical) antipsychotic medications in male patients. Nevertheless, hypermagnesemia is a significant protective factor of reduced BUA levels in female patients. Hyperprolactinemia had a borderline significant association with classical and combined antipsychotic medications in female patients. Hyperprolactinemia, however, provides a protective effect on reduced BUA levels in male patients. There was no significant association found between serum prolactin level and the type of antipsychotic medication received. CONCLUSIONS: The results of this study are in contrast with literature that has reported an association between bone mass and serum prolactin levels, serum magnesium levels and type of received antipsychotics. Further study to investigate the pathophysiological process and the association between bone mass and serum prolactin level, serum magnesium level and specific antipsychotics is necessary.

68: General and comparative endocrinology, 2010 Feb 9, 145(4)
Seasonal changes in concentrations of plasma LH and prolactin associated with the advance in the development of photorefractoriness and molt by high temperature in the starling.

[Abstract]In a study on starlings (Sturnus vulgaris) kept on a simulated annual cycle in photoperiod, temperature had no effect on the timing or rate of testicular maturation but high temperature resulted in an advance in the timing of testicular regression and molt (Dawson, 2005). This study asks whether the earlier gonadal regression in response to higher temperature represents a central neuroendocrine response to temperature, and secondly, whether prolactin plays a role in the earlier regression. Castrated starlings were kept on a simulated annual cycle of photoperiod at either 8 degrees C or 18 degrees C. Circulating LH and prolactin concentrations were measured and the progress of the post-nuptial molt was recorded as an external indicator of the development of photorefractoriness. Additionally plasma prolactin was measured in samples taken from intact male and female starlings in the 2005 study. In castrated birds, LH concentrations decreased three weeks earlier at 18 degrees C. These birds also showed the same three week advance in molt as males and females in the earlier study. This demonstrates that the advance in regression caused by higher temperatures probably results from a central neuroendocrine mechanism, i.e. an advance in photorefractoriness, rather than an effect at the level of the gonads. Temperature had a highly significant effect on the changes in prolactin - peak prolactin occurred three weeks earlier at 18 degrees C. However, there was no clear consistent significant difference in prolactin between the two temperatures in advance of the onset of photorefractoriness, so the advance in photorefractoriness may not be mediated by prolactin. The higher temperature resulted in a significantly earlier decrease in prolactin and this may be causally related to the advance in molt.

69: Journal of affective disorders, 2010 Feb 9, 130(3)
Growth hormone, prolactin and cortisol response to exercise in patients with depression.

[Abstract]BACKGROUND: A blunted growth hormone and prolactin response to pharmacological stress test have previously been found in depressed patients, as well as an increased cortisol response to psychosocial stress. This study investigated these hormones in response to acute exercise using an incremental bicycle test. METHOD: A cross-sectional comparison of cortisol, growth hormone, and prolactin in depressed (n=137) and healthy (n=44) subjects during rest and in response to an incremental bicycle test. Secondly, we tested the depressed patients again after a 4-month randomized naturalistic exercise intervention. RESULTS: Resting plasma levels of growth hormone (GH), cortisol, or prolactin (PRL) did not differ between depressed and healthy subjects (all p-values>.12). In response to an incremental bicycle test the GH (p=.02) and cortisol (p=.05) response in depressed was different compared to healthy controls. The effect of acute exercise stress on PRL (p=.56) did not differ between depressed and healthy subjects. Apart from a decrease in GH response in the strength-training group (p=.03) the pragmatic exercise intervention did not affect resting hormonal levels, or the response to acute exercise. CONCLUSIONS: Patients with mild to moderate depression had a different growth hormone and cortisol response to acute exercise stress compared to healthy controls. Strength training was able to reduce the growth hormone response to acute exercise stress in this patient population. Studies with more rigorous inclusion criteria and higher exercise frequencies are needed to evaluate and confirm the possible effect of exercise in depressed subjects.

70: Trends in endocrinology and metabolism: TEM, 2010 Feb 8, 130(3)
Impact of prolactin receptor isoforms on reproduction.

[Abstract]Prolactin is a hormone involved in growth, development, reproduction, metabolism, water and electrolyte balance, brain and behavior, and immunoregulation. Its actions on reproductive processes represent the largest group of functions identified for this hormone. Besides the classic long form of the prolactin receptor, many short form receptors have been identified in rodents and human tissues. Mouse mutagenesis studies have offered insight into the biology of the prolactin family, providing compelling evidence that different isoforms have independent biological activity. The possibility that short forms mediate cell proliferation is important for a variety of tissues including mammary glands and ovarian follicles. This review summarizes the current knowledge about prolactin signaling and its role in reproduction through either long or short isoform receptors.

71: Journal of cell science, 2010 Feb 1, 123(Pt 3)
Dynamic organisation of prolactin gene expression in living pituitary tissue.

[Abstract]Gene expression in living cells is highly dynamic, but temporal patterns of gene expression in intact tissues are largely unknown. The mammalian pituitary gland comprises several intermingled cell types, organised as interdigitated networks that interact functionally to generate co-ordinated hormone secretion. Live-cell imaging was used to quantify patterns of reporter gene expression in dispersed lactotrophic cells or intact pituitary tissue from bacterial artificial chromosome (BAC) transgenic rats in which a large prolactin genomic fragment directed expression of luciferase or destabilised enhanced green fluorescent protein (d2EGFP). Prolactin promoter activity in transgenic pituitaries varied with time across different regions of the gland. Although amplitude of transcriptional responses differed, all regions of the gland displayed similar overall patterns of reporter gene expression over a 50-hour period, implying overall co-ordination of cellular behaviour. By contrast, enzymatically dispersed pituitary cell cultures showed unsynchronised fluctuations of promoter activity amongst different cells, suggesting that transcriptional patterns were constrained by tissue architecture. Short-term, high resolution, single cell analyses in prolactin-d2EGFP transgenic pituitary slice preparations showed varying transcriptional patterns with little correlation between adjacent cells. Together, these data suggest that pituitary tissue comprises a series of cell ensembles, which individually display a variety of patterns of short-term stochastic behaviour, but together yield long-range and long-term coordinated behaviour.

72: Cancer research, 2010 Feb 2, 22(3)
Prolactin Inhibits BCL6 Expression in Breast Cancer through a Stat5a-Dependent Mechanism.

[Abstract]BCL6 is a transcriptional repressor that recognizes DNA target sequences similar to those recognized by signal transducer and activator of transcriptions 5 (Stat5). BCL6 disrupts differentiation of breast epithelia, is downregulated during lactation, and is upregulated in poorly differentiated breast cancer. In contrast, Stat5a mediates prolactin-induced differentiation of mammary epithelia, and loss of Stat5 signaling in human breast cancer is associated with undifferentiated histology and poor prognosis. Here, we identify the mammary cell growth factor prolactin as a potent suppressor of BCL6 protein expression in human breast cancer through a mechanism that requires Stat5a, but not prolactin-activated Stat5b, MEK-ERK, or PI3K-AKT pathways. Prolactin rapidly suppressed BCL6 mRNA in T47D, MCF7, ZR75.1, and SKBr3 breast cancer cell lines, followed by prolonged reduction of BCL6 protein levels within 3 hours. Prolactin suppression of BCL6 was enhanced by overexpression of Stat5a but not Stat5b, was mimicked by constitutively active Stat5a, but did not require the transactivation domain of Stat5a. Stat5 chromatin immunoprecipitation demonstrated physical interaction with a BCL6 gene regulatory region, and BCL6 transcript repression required histone deacetylase activity based on sensitivity to trichostatin A. Functionally, BCL6 overexpression disrupted prolactin induction of Stat5 reporter genes. Prolactin suppression of BCL6 was extended to xenotransplant tumors in nude mice in vivo and to freshly isolated human breast cancer explants ex vivo. Quantitative immunohistochemistry revealed elevated BCL6 in high-grade and metastatic breast cancer compared with ductal carcinoma in situ and nonmalignant breast, and cellular BCL6 protein levels correlated negatively with nuclear Stat5a (r = -0.52; P < 0.001) but not with Stat5b. Loss of prolactin-Stat5a signaling and concomitant upregulation of BCL6 may represent a regulatory switch facilitating undifferentiated histology and poor prognosis of breast cancer. Cancer Res; 70(4); 1711-21.

73: Trends in endocrinology and metabolism: TEM, 2010 Jan 30, 175(1-2)
Metabolic and stress-related roles of prolactin-releasing peptide.

[Abstract]In the modern world, improvements in human health can be offset by unhealthy lifestyle factors, including the deleterious consequences of stress and obesity. For energy homeostasis, humoral factors and neural afferents from the gastrointestinal tract, in combination with long-term nutritional signals, communicate information to the brain to regulate energy intake and expenditure. Energy homeostasis and stress interact with each other, and stress affects both food intake and energy expenditure. Prolactin-releasing peptide, synthesized in discrete neuronal populations in the hypothalamus and brainstem, plays an important role in integrating these responses. This review describes how prolactin-releasing peptide neurons receive information concerning both internal metabolic states and environmental conditions, and play a key role in energy homeostasis and stress responses.

74: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2010 Jan 26, 41(1)
Prolactin--a novel neuroendocrine regulator of human keratin expression in situ.

[Abstract]The controls of human keratin expression in situ remain to be fully elucidated. Here, we have investigated the effects of the neurohormone prolactin (PRL) on keratin expression in a physiologically and clinically relevant test system: organ-cultured normal human hair follicles (HFs). Not only do HFs express a wide range of keratins, but they are also a source and target of PRL. Microarray analysis revealed that PRL differentially regulated a defined subset of keratins and keratin-associated proteins. Quantitative immunohistomorphometry and quantitative PCR confirmed that PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. PRL also up-regulated K15 promoter activity and K15 protein expression in situ, whereas it inhibited K6 and K31 expression. These regulatory effects were reversed by a pure competitive PRL receptor antagonist. Antagonist alone also modulated keratin expression, suggesting that "tonic stimulation" by endogenous PRL is required for normal expression levels of selected keratins. Therefore, our study identifies PRL as a major, clinically relevant, novel neuroendocrine regulator of both human keratin expression and human epithelial stem cell biology in situ.-Ramot, Y., B��r��, T., Tiede, S. T��th, B. I., Langan, E. A., Sugawara, K., Foitzik, K., Ingber, A., Goffin, V., Langbein, L., Paus, R. Prolactin-a novel neuroendocrine regulator of human keratin expression in situ.

75: General and comparative endocrinology, 2010 Jan 22, 41(1)
Changes in gene expression for GH/PRL/SL family hormones in the pituitaries of homing chum salmon during ocean migration through upstream migration.

[Abstract]Gene expression for growth hormone (GH)/prolactin (PRL)/somatolactin (SL) family hormones in the pituitaries of homing chum salmon were examined, because gene expression for these hormones during ocean-migrating phases remains unclear. Fish were collected in the winter Gulf of Alaska, the summer Bering Sea and along homing pathway in the Ishikari River-Ishikari Bay water system in Hokkaido, Japan in autumn. The oceanic fish included maturing adults, which had developing gonads and left the Bering Sea for the natal river by the end of summer. The absolute amounts of GH, PRL and SL mRNAs in the pituitaries of the maturing adults in the summer Bering Sea were 5- to 20-fold those in the winter Gulf of Alaska. The amount of GH mRNA in the homing adults at the coastal seawater (SW) areas was smaller than that in the Bering fish, while the amount of PRL mRNA remained at the higher level until fish arrived at the Ishikari River. The gill Na(+),K(+)-ATPase activity in the coastal SW fish and the plasma Na(+) levels in the brackish water fish at the estuary were lowered to the levels that were comparable to those in the fresh water (FW) fish. In conclusion, gene expression for GH, PRL and SL was elevated in the pituitaries of chum salmon before initiation of homing behavior from the summer Bering Sea. Gene expression for GH is thereafter lowered coincidently with malfunction of SW adaptability in the breeding season, while gene expression for PRL is maintained high until forthcoming FW adaptation.

76: Environmental toxicology, 2010 Jan 15, 41(1)
Histological alterations in the prolactin cells of a teleost, Heteropneustes fossilis, after exposure to cypermethrin.

[Abstract]Freshwater fish Heteropneustes fossilis (H. fossilis) were subjected to 5.76 mug/L (80% of 96 h LC(50)) and 1.44 mug/L (20% of 96 h LC(50)) of cypermethrin for short-term (96 h) and long-term (28 days) duration, respectively. Plasma calcium of H. fossilis exposed for short term (96 h) to cypermethrin exhibited no change at 24 h. The levels indicate a decrease in plasma calcium at 48 h. This response persists till the close of experiment (96 h). No change has been noticed throughout the experiment in the histological structure and nuclear volume of prolactin cells of short-term cypermethrin treated fish. Long-term exposure of cypermethrin to fish provoked hypocalcemia. The prolactin cells remain unchanged till 7 days following cypermethrin treatment. After 14 days, the nuclear volume exhibits an increase and the cells exhibit degranulation. These changes increase progressively 21 days onwards. Also, few degenerating cells are discerned after 28 days. (c) 2010 Wiley Periodicals, Inc. Environ Toxicol, 2010.

77: The Journal of biological chemistry, 2010 Jan 15, 165(2)
Prolactin enhances IGF-IR phosphorylation by decreasing its association with the tyrosine phosphatase SHP-2 in MCF-7 breast cancer cells.

[Abstract]Normal mammary development requires coordinated interactions of numerous factors, including prolactin (PRL) and insulin-like growth factor-I (IGF-I), both of which have also been implicated in breast cancer pathogenesis and progression. We previously reported that PRL and IGF-I synergize in breast cancer cells to activate ERK1/2 and AKT, leading to increased proliferation, survival, and invasion. Intriguingly, PRL co-treatment with IGF-I augments IGF-I receptor (IGF-IR) phosphorylation two-fold higher than IGF-I alone. Here, we showed the importance of the tyrosine phosphatase, SHP-2, in this crosstalk using pharmacological inhibition and siRNA. SHP-2 recruitment to IGF-IR was significantly attenuated by PRL co-treatment. Src family kinase activity was required for IGF-IR association with SHP-2, ligand-induced IGF-IR internalization, and PRL-enhanced IGF-IR phosphorylation. Inhibition of internalization, via knock-down of the GTPase, dynamin-2, prevented not only IGF-IR dephosphorylation, but also PRL-enhanced IGF-IR phosphorylation. Consistently, PRL diminished IGF-I-induced IGF-IR internalization, which may result from reduced SHP-2 association with IGF-IR, since we demonstrated an essential role for SHP-2 in IGF-IR internalization. Together, these findings describe a novel mechanism of crosstalk between PRL and IGF-I in breast cancer cells, with implications for our understanding of tumor progression and potential therapeutic strategies.

78: The EMBO journal, 2010 Jan 14, 165(2)
PIKE-A is required for prolactin-mediated STAT5a activation in mammary gland development.

[Abstract]PI 3-kinase enhancer A (PIKE-A) is critical for the activation of Akt signalling, and has an essential function in promoting cancer cell survival. However, its physiological functions are poorly understood. Here, we show that PIKE-A directly associates with both signal transducer and activator of transcription 5a (STAT5a) and prolactin (PRL) receptor, which is essential for PRL-provoked STAT5a activation and the subsequent gene transcription. Depletion of PIKE-A in HC11 epithelial cells diminished PRL-induced STAT5 activation and cyclin D1 expression, resulting in profoundly impaired cell proliferation in vitro. To confirm the function of PIKE-A in PRL signalling in vivo, we generated PIKE knockout (PIKE-/-) mice. PIKE-/- mice displayed a severe lactation defect that was characterized by enhanced apoptosis and impaired proliferation of mammary epithelial cells. At parturition, STAT5 activation and cyclin D1 expression were substantially reduced in the mammary epithelium of PIKE-/- mice. The defective mammary gland development in PIKE-/- mice was rescued by overexpression of a mammary-specific cyclin D1 transgene. These data establish a critical function for PIKE-A in mediating PRL functions.

79: Endocrine-related cancer, 2010 Jan 13, 165(2)
Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy.

[Abstract]Resistance to chemotherapy is a major complication in the treatment of advanced breast cancer. Estrogens and prolactin (PRL) are implicated in the pathogenesis of breast cancer but their roles in chemoresistance have been overlooked. A common feature to the two hormones is activation of their receptors by diverse compounds which mimic or antagonize their actions. The PRL receptor (PRLR) is activated by lactogens (PRL, growth hormone or placental lactogen) originating from the pituitary, breast, adipose tissue or the placenta. Estrogen receptors (ERs) exist in multiple membrane-associated and cytoplasmic forms that can be activated by endogenous estrogens, man-made chemicals, and phytoestrogens. Here we review evidence that low doses of PRL, estradiol (E2), and bisphenol A (BPA) antagonize multiple anti-cancer drugs that induce cell death by different mechanisms. Focusing on cisplatin, a DNA-damaging drug which is effective in the treatment of many cancer types but not breast cancer, we compare the abilities of PRL, E2 and BPA to antagonize its cytotoxicity. Whereas PRL acts by activating the glutathione-S-transferase detoxification enzyme, E2 and BPA act by inducing the anti-apoptotic protein Bcl-2. The implications of these findings to patients undergoing chemotherapy are discussed.

80: Journal of biotechnology, 2010 Jan 9, 1307(2)
Synthesis, purification and characterization of recombinant glycosylated human prolactin (G-hPRL) secreted by cycloheximide-treated CHO cells.

[Abstract]Human prolactin (hPRL) is a 199 aminoacid protein hormone with a wide spectrum of biological activities which is best known for its stimulation of lactation and development of mammary gland. This protein contains only one potential asparagine-linked glycosylation site, which is partially (10-30%) occupied when the protein is synthesized in eukaryotic cells. Although the biological activity of glycosylated hPRL (G-hPRL) has been found to be approximately 4-fold lower than that of hPRL, its physiological function is not yet well defined. In order to better characterize and study this hormone variant, we carried out its laboratory scale purification from conditioned medium of genetically modified CHO cells that had been supplemented with cycloheximide. Addition of cycloheximide increased the absolute concentration of G-hPRL approximately 4-fold and the glycosylated versus non-glycosylated hPRL concentration ratio by approximately 9-fold. G-hPRL purification was carried out via a two-step process based on a cationic exchanger and a size-exclusion HPLC (HPSEC) column. Characterization was carried out by HPSEC, Western blotting, MALDI-TOF-MS and in vitro bioassay based on Nb2 and Ba/F3-LLP cells, the biological activity being of the same order (11-15 IU mg(-1)) in the two assays. Our results show that addition of cycloheximide can be an important strategy for increasing glycosylated protein production, facilitating the purification and characterization of these isoforms.

81: Endocrine pathology, 2010 Jan 8, 1307(2)
A Double Pituitary Adenoma Presenting as a Prolactin-secreting Tumor with Partial Response to Medical Therapy. Case report.

[Abstract]Double pituitary adenomas are difficult to recognize pre-operatively as only a single mass may be appreciated on imaging. We present herein a giant prolactin-secreting pituitary adenoma in a middle-aged man that had responded partially to dopamine agonist therapy. The excised specimen demonstrated a double adenoma. The prolactin-producing one displayed the expected morphological changes resulting from medical therapy, while the other, a gonadotroph adenoma, did not. The failure of tumor shrinkage can be attributed to the presence of a double adenoma, a previously unreported cause of failure of medical therapy in prolactinoma.

82: The Journal of biological chemistry, 2010 Jan 6, 159(1-3)
Crystal structure of an affinity-matured prolactin complexed to its dimerized receptor reveals the topology of hormone binding site 2.

[Abstract]We report the first crystal structure of a 1:2 hormone-receptor complex that involves prolactin (PRL) as the ligand, at 3.8 A resolution. Stable ternary complexes were obtained by generating affinity-matured PRL variants harboring an N-terminal tail from ovine placental lactogen, a closely-related PRL receptor (PRLR) ligand. This structure allows to draw up an exhaustive inventory of the residues involved at PRL/PRLR site 2 interface, consistent with all previously reported site-directed mutagenesis data. This description allows to propose an interaction model involving three structural components of PRL site 2 ("three pin plug"): the conserved glycine 129 of helix alpha3, the hydrogen bond network involving surrounding residues (glycine cavity), and the N-terminus. The model provides a molecular basis for the properties of the different PRL analogs designed to date, including PRLR antagonists. Finally, comparison of our 1:2 PRL/PRLR2 structure with those of free PRL and its 1:1 complex indicates that the structure of PRL undergoes significant changes when binding the first, but not the second receptor. This suggests that the second PRLR moiety adapts to the 1:1 complex rather than the opposite. In conclusion, this structure will be a useful guiding tool for further investigations of the molecular mechanisms involved in PRLR dimerization and activation, as well as for the optimization of PRLR antagonists, an emerging class of compounds with high therapeutic potential against breast and prostate cancer.

83: Neuroscience, 2009 Dec 30, 7(1)
Mu and Kappa Opioid Receptor Expression in the Mediobasal Hypothalamus and Effectiveness of Selective Antagonists on Prolactin Release During Lactation.

[Abstract]Endogenous opioid peptides are involved in prolactin release during lactation, in part by decreasing tuberoinfundibular dopaminergic (TIDA) neuronal activity. Both mu and kappa opioid receptors have a role in the suckling-induced prolactin rise after 4-5h pup deprivation. The aim of this study was to investigate effects of mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), and kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on prolactin secretion and TIDA neuronal activity in lactating rats after 18h pup deprivation. After 4h separation from pups, the suckling-induced prolactin rise was abolished by 16 mug nor-BNI and 5 mug beta-FNA, coincident with increased dihydroxyphenylacetic acid (DOPAC):dopamine ratio in the stalk-median eminence (SME). However, after 18h pups separation, these same doses of nor-BNI and beta-FNA did not alter the prolactin surge or DOPAC:dopamine ratios in the SME. Higher doses of nor-BNI (32 mug) and beta-FNA (10 mug) were required to inhibit suckling-induced prolactin secretion. beta-FNA (10 mug) increased the DOPAC:dopamine ratio in the SME, whereas nor-BNI (32 mug) treatment had no effect. The mu and kappa opioid receptor mRNA levels in the mediobasal hypothalamus were similar to suckled control rats after 4h pup deprivation, but increased 1.4-fold after 18h pup deprivation. These data support involvement of endogenous opioidergic systems in the suckling-induced prolactin rise after a prolonged (18h) period of pup deprivation, as well as the shorter (4h) pup deprivation period previously reported. Suppression of TIDA neuronal activity likely played a part in mu opioid receptor input to the suckling-induced prolactin rise after both 4h and 18h separation, whereas non-dopaminergic input was implicated with kappa opioid receptors after 18h pup deprivation. Increased mu and kappa opioid receptors gene expression in the mediobasal hypothalamus may contribute to reduced effectiveness of opioid receptor antagonists to block suckling-induced prolactin release after 18h pup deprivation.

84: Reproductive biology and endocrinology : RB&E, 2009 Dec 31, 7(1)
Excitatory and inhibitory effects of prolactin release activated by nerve stimulation in rat anterior pituitary.

[Abstract]ABSTRACT: BACKGROUND: A series of studies showed the presence of substantial amount of nerve fibers and their close relationship with the anterior pituitary gland cells. Our previous studies have suggested that aside from the classical theory of humoral regulation, the rat anterior pituitary has direct neural regulation on adrenocorticotropic hormone release. In rat anterior pituitary, typical synapses are found on every type of the hormone-secreting cells, many on lactotrophs. The present study was aimed at investigating the physiological significance of this synaptic relationship on prolactin release. METHODS: The anterior pituitary of rat was sliced and stimulated with electrical field in a self-designed perfusion chamber. The perfusate was continuously collected in aliquots and measured by radioimmunoassay for prolactin levels. After statistic analysis, differences of prolactin concentrations within and between groups were outlined. RESULTS: The results showed that stimulation at frequency of 2 Hz caused a quick enhancement of prolactin release, when stimulated at 10 Hz, prolactin release was found to be inhibited which came slower and lasted longer. The effect of nerve stimulation on prolactin release is diphasic and frequency dependent. CONCLUSIONS: The present in vitro study offers the first physiological evidence that stimulation of nerve fibers can affect prolactin release in rat anterior pituitary. Low frequency stimulation enhances prolactin release and high frequency mainly inhibits it.

85: The Journal of reproduction and development, 2009 Dec 25, 139(1)
Profiles of Circulating Steroid Hormones, Gonadotropins, Immunoreactive Inhibin and Prolactin during Pregnancy in Goats and Immunolocalization of Inhibin Subunits, Steroidogenic Enzymes and Prolactin in the Corpus Luteum and Placenta.

[Abstract]The current study was performed to follow up the circulating hormonal changes and to correlate the findings with the physiological activity of the corpus luteum (CL) and placenta during pregnancy in goats. Blood samples were collected weekly from five goats during pregnancy for measuring steroid and protein hormones. A gradual increase was observed in immunoreactive (ir-) inhibin, with maximal levels at the 17th week. The plasma concentrations of estradiol and prolactin (PRL) showed nearly similar patterns during pregnancy, where they declined to basal levels during the first 4 weeks post-breeding and then increased significantly, with the maximal concentration during late pregnancy. The plasma FSH and LH concentrations were maintained at basal levels throughout the gestation period. The plasma progesterone concentration abruptly increased in the first week post-breeding and remained at high values throughout the pregnancy period. Immunohistochemical localization of inhibin alpha, beta(A), beta(B) and steroidogenic enzymes cytochrome P450 aromatase, 3alpha-hydroxysteroid dehydrogenase (3betaHSD), cytochrome 17alpha-hydroxylase P450 and cholesterol side-chain cleavage cytochrome P450 in the cyclic and pregnant goat CL revealed positive immunoreactivity without affinity differences between the luteal and pregnancy stages. The placental syncytiotrophoblasts also showed positive staining, except for inhibin beta(A) and 3betaHSD. The giant binucleate cells of the placenta showed positive immunoreactions to PRL. These results suggest that the high concentrations of ir-inhibin, estradiol and PRL during late pregnancy are of placental origin and that the placenta may have a vital role in the maintenance of pregnancy, regulation of mammary growth and preparation for kidding and lactation in goats.

86: Endocrinology, 2009 Dec 23, 139(1)
Prolactin Exerts a Prosurvival Effect on Human Spermatozoa via Mechanisms that Involve the Stimulation of Akt Phosphorylation and Suppression of Caspase Activation and Capacitation.

[Abstract]The purpose of this study was to examine the impact of prolactin (PRL) on human sperm function, in light of a recent proteomic analysis indicating that these cells express the PRL receptor (PRLR). Immunocytochemical analyses confirmed the presence of PRLR in human spermatozoa and localized this receptor to the postacrosomal region of the sperm head as well as the neck, midpiece, and principal piece of the sperm tail. Nested PCR analysis indicated that these cells possess four splice variants of the PRLR: the long form and three short isoforms, one of which is reported for the first time. A combination of Western blot analyses and immunocytochemistry demonstrated that PRL inhibited sperm capacitation in a dose-dependent manner, suppressing SRC kinase activation and phosphotyrosine expression, two hallmarks of this process. The suppression of sperm capacitation was accompanied by a powerful prosurvival effect, supporting the prolonged motility of these cells and preventing the formation of spontaneous DNA strand breaks via mechanisms that involved the concomitant suppression of caspase activation. Western blot analyses indicated that the prosurvival effect of PRL on human spermatozoa involved the stimulation of Akt phosphorylation, whereas inhibitors of phosphatidylinositol-3-OH kinase and Akt negated this effect, as did the direct induction of sperm capacitation with cAMP analogues. We conclude that PRL is a prosurvival factor for human spermatozoa that prevents these cells from defaulting to an intrinsic apoptotic pathway associated with cell senescence. These findings have implications for preservation of sperm integrity in vivo and in vitro.

87: Rheumatology international, 2009 Dec 19, 139(1)
Polymorphism of the extrapituitary prolactin promoter and systemic sclerosis.

[Abstract]The purpose of this study was to examine the impact of prolactin (PRL) on human sperm function, in light of a recent proteomic analysis indicating that these cells express the PRL receptor (PRLR). Immunocytochemical analyses confirmed the presence of PRLR in human spermatozoa and localized this receptor to the postacrosomal region of the sperm head as well as the neck, midpiece, and principal piece of the sperm tail. Nested PCR analysis indicated that these cells possess four splice variants of the PRLR: the long form and three short isoforms, one of which is reported for the first time. A combination of Western blot analyses and immunocytochemistry demonstrated that PRL inhibited sperm capacitation in a dose-dependent manner, suppressing SRC kinase activation and phosphotyrosine expression, two hallmarks of this process. The suppression of sperm capacitation was accompanied by a powerful prosurvival effect, supporting the prolonged motility of these cells and preventing the formation of spontaneous DNA strand breaks via mechanisms that involved the concomitant suppression of caspase activation. Western blot analyses indicated that the prosurvival effect of PRL on human spermatozoa involved the stimulation of Akt phosphorylation, whereas inhibitors of phosphatidylinositol-3-OH kinase and Akt negated this effect, as did the direct induction of sperm capacitation with cAMP analogues. We conclude that PRL is a prosurvival factor for human spermatozoa that prevents these cells from defaulting to an intrinsic apoptotic pathway associated with cell senescence. These findings have implications for preservation of sperm integrity in vivo and in vitro.

88: Medical oncology (Northwood, London, England), 2009 Dec 15, 139(1)
A mimic of phosphorylated prolactin inhibits human breast cancer cell proliferation via upregulation of p21 waf1.

[Abstract]A mimic of phosphorylated prolactin (S179D PRL) inhibits mouse normal mammary HC11 cell proliferation through the upregulation of the vitamin D receptor (VDR) and p21. Here, we investigated whether S179D PRL also inhibited growth of human breast cancer MCF7 cells via VDR and p21. Western blots showed that S179D PRL upregulated VDR and p21 after the cells were incubated with S179D PRL for 3 days. These effects were blocked by the MAP kinase blocker PD98059 (25 muM), indicating that MAPK plays a role in VDR and p21 upregulation. To confirm whether VDR contributes to p21 upregulation, we used two constructs that express luciferase. One (p21 VDRE Luc) has the vitamin D response element (VDRE) in the p21 promoter region; the other (p21 NO-VDRE Luc) does not. The results show that S179D PRL upregulated p21 VDRE Luc activity in p21 VDRE Luc-transfected cells more than in p21 NO-VDRE-transfected cells, indicating that S179D PRL upregulated p21 via VDR. A cell proliferation assay showed that S179D PRL inhibits cell proliferation in a dose-dependent manner.

89: Physiology & behavior, 2009 Dec 4, 1302(1)
Relationships of stress responses with plasma oxytocin and prolactin in heifer calves.

[Abstract]Oxytocin and prolactin are potential candidates for the regulation of behavioral and physiological stress responses in the brain. To investigate the neurobiological basis of individual differences in stress responses in cattle, we examined the association of behavioral and hypothalamopituitary-adrenal axis reactivity to acute stressors and basal and stimulated levels of oxytocin and prolactin. Twenty Holstein heifer calves aged 2weeks were subjected to a 10-minute open-field test (OFT) followed by presentation of a feeding bucket for 15min in the OF. If the calf contacted the bucket, a blast of air was applied to its muzzle (surprise test). Jugular blood samples collected before and after both tests were analyzed for oxytocin, prolactin, and cortisol. Relationships of basal and percent change in oxytocin or prolactin with behavioral responses in each test and percent change in cortisol were analyzed using principal components analysis and Spearman rank correlations. Plasma cortisol and prolactin concentration were significantly elevated by the tests (p<0.005), but plasma oxytocin concentration did not significantly change (p>0.1). Four principal components explained 56.1% of the total variation: curiosity, general activity, fearfulness, and dependence on humans. Curiosity was inversely correlated with basal oxytocin level (rS=-0.683, p<0 .05). General activity was positively correlated with prolactin reactivity (rS=0.448, p<0.05) and inversely with oxytocin reactivity to the novel environment (rS=-0.717, p<0.05). Fearfulness tended to correlate positively with basal oxytocin level (rS=0.583, p<0.1). Dependence on humans correlated with none of the hormonal parameters. The relationships of basal oxytocin level with curiosity and fearfulness for novel environments are of particular interest for future study.

90: Clinical reviews in allergy & immunology, 2009 Nov 24, 24(6)
Prolactin, Systemic Lupus Erythematosus, and Autoreactive B Cells: Lessons Learnt from Murine Models.

[Abstract]The predominant prevalence of autoimmune diseases in women of reproductive age has led to the investigation of the effects of sex hormones on immune regulation and in autoimmune diseases, in particular the prototypic systemic autoimmune disease lupus. The female hormone prolactin has receptors beyond the reproductive axis including immune cells, and it is thought to promote autoimmunity in human and murine lupus. Induced hyperprolactinemia in experimental lupus models, regardless of gender, exacerbates disease activity and leads to premature death. Prolactin treatment in mice that are not prone to develop lupus leads to the development of a lupus-like phenotype. Persistent mild-moderate hyperprolactinemia alters the selection of the na?ve B cell repertoire. Recent studies demonstrate that prolactin impairs all three mechanisms of B cell tolerance induction (negative selection, receptor editing, and anergy) and thereby contributes to the pathogenesis of autoimmunity. The effects of prolactin are genetically determined as shown by the differential response to the hormone in the different mice strains. Bromocriptine, a drug that inhibits prolactin secretion, abrogates some of the immune effects of this hormone. Further research is required to elucidate molecular mechanisms involved in immune effects of prolactin and to develop novel targeted treatments for SLE patients with prolactin-responsive disease.

91: Expert opinion on drug metabolism & toxicology, 2009 Nov 23, 8(1)
Pharmacogenetics of D2 dopamine receptor gene in prolactin-secreting pituitary adenomas.

[Abstract]Importance of the field: Dopamine-agonists are the treatment of choice of prolactin-secreting pituitary adenomas (PRL-omas). Their actions on D2 dopamine receptor (DRD2) and the clinical outcome may be affected by polymorphisms. Areas covered in this review: PRL-omas are well-differentiated endocrine tumors expressing DRD2. The dopamine-agonist cabergoline (CB), normalizes prolactin and reduces tumor size in about 80 - 90% of patients. DRD2 polymorphisms correlate with neuropsychiatric disorders, in particular alcoholism and schizophrenia. This review describes the DRD2 polymorphisms, their functional effects, and their impact on susceptibility and response to dopamine-agonists treatment. Searching PubMed database for pertinent articles we found that some DRD2 polymorphisms, particularly TaqIA, TaqIB and NcoI, are associated with different receptor binding in brain areas. One study carried out in patients with PRL-omas found a correlation between NcoI and TaqIA and resistance to CB. In particular, resistant patients had higher prevalence of NcoI-T allele than the responsive patients, while the commonest haplotype (having TaqIA2 allele) was associated with better response. What the reader will gain: This review deals with the connection between DRD2 polymorphisms and PRL-oma treatment and suggests hypotheses for further studies. Take home message: Only one study was carried out to analyze the role of DRD2 polymorphisms in PRLomas response to CB. Further studies, including pituitary and hypothalamus in vivo determination of DRD2 binding according to DRD2 genotypes, investigation of possible post-receptorial mechanisms involved, as well as population studies in collaboration with psychiatrists and neurologists, are needed.

92: Journal of neuroendocrinology, 2009 Nov 14, 24(6)
Participation of the prolactin-releasing peptide-containing neurons in caudal medulla in conveying hemorrhagic stress-induced signals to the paraventricular nucleus of the hypothalamus.

[Abstract]Abstract The prolactin-releasing peptide (PrRP) has been proposed to be a co-transmitter or modulator of noradrenaline (NA) because it colocalizes with NA in the A1 (in the ventrolateral reticular formation) and A2 [in the nucleus of the solitary tract (NTS)] cell groups in the caudal medulla. The baroreceptor signals, originating from the great vessels, are transmitted primarily to the NTS, and then part of the signals is conveyed to the hypothalamic neuroendocrine neurons via the ascending NA neurons. The hypotensive hemorrhagic paradigm was employed to examine whether the PrRP-containing neurons in the caudal medulla participate in conveying signals to the hypothalamic neuroendocrine neurons. Among the caudal medullary A1 or A2 neurons, the majority of the PrRP-immunoreactive (ir) neurons became c-Fos-ir at 2 h following hypotensive hemorrhage. The hypothalamic corticotropin-releasing hormone-ir neurons and vasopressin-ir neurons became c-Fos positive in parallel with the activation of the medullary PrRP-ir neurons. Following delivery of retrograde tracer fluorogold (FG) to the PVN, part of the PrRP/FG double labeled neurons in the A1 and A2 became c-Fos-ir following hemorrhage, demonstrating that the PrRP-ir neurons participate in conveying the hemorrhagic stress-induced signals from the medulla to the PVN. PrRP and/or NA were microinjected directly to the PVN of conscious rats, and they presented a synergistic action on AVP release, while an additive action was observed for ACTH release. These results suggest that the PrRP-containing NA neurons in the caudal medulla may relay the hemorrhagic stress-induced medullary inputs to the hypothalamic neuroendocrine neurons.

93: Clinical reviews in allergy & immunology, 2009 Nov 13, 24(6)
Prolactin and Autoimmunity.

[Abstract]The relationship between prolactin and the immune system has been demonstrated in the last two decades, opening new windows in the field of the immunoendocrinology. Prolactin has an important role in the innate and adaptive immune response. Increased prolactin levels have been described in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sj?gren syndrome, and systemic sclerosis among others. Hyperprolactinemia is associated with active disease and organ involvement in systemic lupus erythematosus. Therefore, prolactin is an integral member of the immunoneuroendocrinology network and seems to have a role in pathogenesis of autoimmune diseases. Few controlled studies of dopamine agonist treatment in humans with autoimmune disease have been conducted only in systemic lupus erythematosus patients, which support the potential efficacy of such agents even during pregnancy and postpartum. Further studies are necessary to elucidate the mechanisms by which prolactin affects autoimmune disease activity, increase the inflammatory mechanism, and determine the role of anti-prolactinemic drugs to regulate the immune/inflammatory process.

94: The Journal of clinical endocrinology and metabolism, 2009 Nov 6, 24(6)
Characterization of Two Constitutively Active Prolactin Receptor Variants in a Cohort of 95 Women with Multiple Breast Fibroadenomas.

[Abstract]Background: The role of prolactin (PRL) and its receptor (hPRLR) in promoting breast tumors is debated. We recently identified a gain-of-function hPRLR variant (I146L) in four women with multiple breast fibroadenomas (MFA) and no control subject. Objectives: The specific aims were to describe this cohort of women presenting with MFA to identify and functionally characterize germline variants of hPRL/hPRLR genes and compare phenotypes of all patients. Design: Ninety-five patients prospectively underwent clinical examination, breast ultrasonography, magnetic resonance imaging, and hormonal evaluation of gonadal and lactotrope functions. We analyzed hPRL/hPRLR coding sequences and made comparisons with a control population of 194 women. Functional characterization of hPRLR variants was performed. Pathology and immunochemistry were systematically carried out after surgical removal of tumors. Results: One third of patients had a family history of breast disease. No hormonal imbalance was observed, except 30.7% of explosive stimulated PRL. Prolactin receptor variants were identified in exon 5 (I76V: 10 patients, eight controls) and exon 10 (one patient, no control). Both I146L and I76V variants exhibited constitutive activity. Pathology showed common fibroadenomas and identified six benign phyllodes tumors. Estrogen and progesterone receptors were detected in 85 and 98% of samples, respectively. Ki-67 median staining was less than 5%. No phenotypic difference was observed between carriers and noncarriers of either hPRLR variant. Conclusion: We present the largest population with MFA ever described, 15% of which had a hPRLR exhibiting basal activity in vitro. This questions the involvement of the hPRLR in MFA etiology and the potential relevance of therapeutic inhibition of PRLR signaling in patients.

95: Psychiatry research, 2009 Nov 4, 24(6)
Genetic associations of prolactin increase in olanzapine/fluoxetine combination-treated patients.

[Abstract]In patients from two clinical trials, we investigated the associations of single nucleotide polymorphisms (SNPs) in candidate genes with prolactin level changes during treatment with olanzapine/fluoxetine combination. In both cohorts, three dopamine receptor D2 (DRD2) SNPs were associated with prolactin changes. DRD2 may influence susceptibility to hyperprolactinemia associated with antipsychotic treatment.

96: Neoplasma, 2010, 57(1)
Relationship between plasma progesterone, estradiol and prolactin concentrations and breast cancer in pre and postmenopausal women.

[Abstract]Hormones such as estrogen, progesterone and prolactin are implicated in anumber of ways as possible causes of breast cancer. Throughout women life cycle, breast development and function depend on complex critical interplay of these hormones. The acknowledged gaps in our understanding concerning progesterone, estrogen and prolactin hormones involvement in human breast cancer has exposed the need to conduct this study for better understanding of the role played by these hormones in breast cancer during pre and post menopause status in order to influence prevention and treatment of breast cancer. Ninety women were enrolled, (80%) of them were breast cancer patients and the other (20%) were breast benign lesion patients. At attending King Hussein Medical Center, blood samples were collected and analyzed for plasma estradiol, prolactin and progesterone. Of the 72 breast cancer patients (66.6% and 33.4%), and of the 18 breast benign patients (27.8% and 72.2%) were in menopause and premenopausal, respectively. Of the breast cancer and benign patients groups, 55.6% of each had an association with either high plasma estradiol, prolactin or progesterone concentrations. Of the breast cancer patients that had association with high plasma hormonal concentrations, 47.5% had high plasma estradiol concentrations (155.0+/-36 pg/ml) and 89.5% of these were in menopause. Of the breast benign patients, 60% had high plasma prolactin concentrations (55.2+/-10.6 ng/ml). Menopausal breast cancer is associated with high plasma estradiol concentrations, while premenopausal breast benign were associated high plasma prolactin concentrations which indicate that high plasma estradiol in menopause is arisk factor for breast cancer development while high prolactin in premenopausal is arisk factor for breast benign. Therefore, breast cancer and benign are highly hormonal dependent. Keywords: breast cancer, premenopausal and postmenopausal, plasma hormones.

97: Cellular signalling, 2009 Nov 2, 24(6)
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling.

[Abstract]The cytokine prolactin (PRL) plays important roles in the proliferation and differentiation of the mammary gland and it has been implicated in tumorigenesis. The prolactin receptor (PRLR) is devoid of catalytic activity and its mitogenic response is controlled by cytoplasmic tyrosine kinases of the Src (SFK) and Jak families. How PRLR uses these kinases for signaling is not well understood. Previous studies indicated that PRLR-induced Jak2 activation does not required SFK catalytic activity in favor of separate signaling operating on this cellular response. Here we show that, nevertheless, PRLR requires Src-SH2 and -SH3 domains for Jak2 signaling. In W53 lymphoid cells, conditional expression of two c-Src non-catalytic mutants, either SrcK295M/Y527F or SrcK, whose SH3 and SH2 domains are exposed, controls Jak2/Stat5 activation by recruiting Jak2, avoiding its activation by endogenous active SFK. In contrast, the kinase inactive SrcK295M mutant, with inaccessible SH3 and SH2 domains, does not. Furthermore, all three mutants attenuate PRLR-induced Akt and p70S6K activation. Accordingly, PRLR-induced Jak2/Stat5 signaling is inhibited in MCF7 breast cancer cells by Src depletion, expression of SrcK295M/Y527F or active Src harboring an inactive SH2 (SrcR175L) or SH3 domain (SrcW118A). Finally, Jak2/Stat5 pathway is also reduced in Src(-/-) mice mammary glands. We thus conclude that, in addition to Akt and p70S6K, SFK regulate PRLR-induced Jak2 signaling through a kinase-independent mechanism.

98: The Journal of investigative dermatology, 2009 Nov 5, 24(6)
Mind the (Gender) Gap: Does Prolactin Exert Gender and/or Site-Specific Effects on the Human Hair Follicle?

[Abstract]INTRODUCTION: Mouse prolactin-inducible protein (mPIP) is secreted in mouse saliva and has been found to bind oral bacteria, showing the highest affinity for streptococci. Comparisons between the oral flora of mPIP knockout mice and their wild-type controls showed differences in the genera colonizing the two groups of mice. These findings suggested a role for mPIP in the colonization of the mouse oral cavity, possibly modulating the oral flora. In this in vitro study, we focused on the contribution of this protein to aggregation of oral bacteria, a process thought to promote the clearance of bacteria from the oral cavity, and one that could influence the composition of the oral bacterial community. METHODS: The aggregation of selected human and mouse oral streptococci was measured spectrophotometrically. The aggregation of oral bacteria by saliva from mPIP knockout mice, which lack mPIP, was compared with that of saliva from wild-type mice. RESULTS: Both wild-type saliva and mPIP knockout mouse saliva induced aggregation of human strain Streptococcus gordonii SK120 and mouse streptococci strains M105/6 and M106/2. Bacterial aggregation induced by the saliva of wild-type mice was significantly higher than the aggregation induced by saliva from mPIP knockout mice for all the bacterial strains. CONCLUSION: In this study it was confirmed that mPIP plays a role in the aggregation of oral bacteria. The salivary components promoting aggregation of oral bacteria are considered to be part of the oral defense mechanisms so these findings provide insight into a possible function of mPIP in host defense by promoting aggregation of oral bacteria.

99: Molecular endocrinology (Baltimore, Md.), 2009 Nov 3, 24(6)
A Pit-1 Threonine 220 Phosphomimic Reduces Binding to Monomeric DNA Sites to Inhibit Ras and Estrogen Stimulation of the Prolactin Gene Promoter.

[Abstract]Pit-1 is a POU-homeodomain transcription factor that dictates the ontogeny of pituitary somatotrophs, lactotrophs, and thyrotrophs through regulation of their respective protein hormone genes: GH, prolactin (PRL), and TSHbeta. Although Pit-1 threonine 220 (T220) and serine 115 are protein kinase phospho-acceptor sites, the transcriptional role of Pit-1 phosphorylation remains unclear. In the rat PRL promoter (rPRL), Ras-stimulated transcription is mediated by binding of Ets-1 and Pit-1 at a composite site (FPIV). Ets-1 and Pit-1 physically interact, and Pit-1 T220 is a major Ets-1 contact point. T220 was mutated to aspartic acid (D, to mimic phosphorylation) or a neutral alanine (A), and DNA binding and transcriptional activity were tested. The Pit-1 T220D mutation reduced binding at monomeric Pit-1 sites (FPIV, PRL-1d), but not dimeric Pit-1 sites (FPI). Pit-1 T220A bound all sites with wild-type (WT) affinity. In transfections of HeLa cells, each Pit-1 mutant transcriptionally activated the -425rPRL promoter and cooperated with Ets-1 to WT levels. In contrast, Pit-1-mediated Ras activation of the -425 rPRL promoter was significantly inhibited by T220D. Finally, Pit-1 synergistic activation of the 2500-bp rPRL promoter with estrogen receptor was reduced by T220D compared with T220A and WT Pit-1. Thus, phosphorylation of Pit-1 T220 reduces binding to monomeric sites blunting Ras and estrogen/estrogen receptor stimulation of the rPRL gene promoter. Consequently, T220 phosphorylation of Pit-1 by protein kinase A, protein kinase C, or cell cycle-dependent kinases appears to serve as a regulatory switch, inhibiting Ras and estrogen/estrogen receptor regulatory pathways, while enhancing the cAMP/protein kinase A response, thus allowing a more precise integration of pituitary responses to distinct signaling stimuli.

100: The journal of physiological sciences : JPS, 2009 Nov 3, 24(6)
Transepithelial calcium transport in prolactin-exposed intestine-like Caco-2 monolayer after combinatorial knockdown of TRPV5, TRPV6 and Ca(v)1.3.

[Abstract]The milk-producing hormone prolactin (PRL) increases the transcellular intestinal calcium absorption by enhancing apical calcium uptake through voltage-dependent L-type calcium channel (Ca(v)) 1.3. However, the redundancy of apical calcium channels raised the possibility that Ca(v)1.3 may operate with other channels, especially transient receptor potential vanilloid family calcium channels (TRPV) 5 or 6, in an interdependent manner. Herein, TRPV5 knockdown (KD), TRPV5/TRPV6, TRPV5/Ca(v)1.3, and TRPV6/Ca(v)1.3 double KD, and TRPV5/TRPV6/Ca(v)1.3 triple KD Caco-2 monolayers were generated by transfecting cells with small interfering RNAs (siRNA). siRNAs downregulated only the target mRNAs, and did not induce compensatory upregulation of the remaining channels. After exposure to 600 ng/mL PRL, the transcellular calcium transport was increased by ~2-fold in scrambled siRNA-treated, TRPV5 KD and TRPV5/TRPV6 KD monolayers, but not in TRPV5/Ca(v)1.3, TRPV6/Ca(v)1.3 and TRPV5/TRPV6/Ca(v)1.3 KD monolayers. The results suggested that Ca(v)1.3 was the sole apical channel responsible for the PRL-stimulated transcellular calcium transport in intestine-like Caco-2 monolayer.

101: Saudi medical journal, 2009 Nov, 30(11)
Serum protein and prolactin as diagnostic markers.

[Abstract]OBJECTIVE: To evaluate the use of serum prolactin and total protein as a tumor marker in diagnosing uterine fibroid(s). METHODS: A case control study was carried out from March 2004 to October 2005 at Al-Kharch Hospital in Baghdad, Iraq. Thirty-two patients with uterine fibroid(s) and 30 healthy normal women were involved in the study. Blood was collected from uterine fibroid patients before and after surgery. The serum total protein was measured by the Biuret method, and prolactin by the mini VIDAS ELFA technique (enzyme linked fluorescent assay). RESULTS: The serum of patients with uterine fibroids before surgery showed an elevated prolactin level (169.64 +/- 133.11 ng/ml), compared with their prolactin after surgery (19.69+/-9.54 ng/ml), and with the control group (18.93 +/- 5.16 ng/ml). This also increased with increasing fibroid number independently of the site, or the size of the fibroid. Serum total protein was relatively low in the patient group before surgery (5.56+/-9.66 g/dl), and returned to a healthy reference level after they underwent surgery (6.83 +/- 0.9 g/dl), similar to the control group level (7.18+/-0.75 g/dl). CONCLUSION: Serum prolactin and serum total protein can be used as an adjuvant biochemical marker to confirm the diagnosis of uterine fibroids.

102: General and comparative endocrinology, 2009 Oct 22, 7(1)
Production, characterization, and applications of mouse monoclonal antibodies against gonadotropin, somatolactin, and prolactin from common carp (Cyprinus carpio).

[Abstract]The gonadotropin alpha subunit (cGTHalpha), gonadotropinIIbeta subunit (cGTHIIbeta), somatolactin (cSL), and prolactin (cPRL) were isolated from the pituitaries of common carps, purified by traditional chromatographic analysis, identified by mass-chromatographic analysis, and used as immunogens in the B-lymphocyte hybridoma technique. Totally, 7, 11, 17, and 8 hybridoma cell lines were established, which were able to stably secrete monoclonal antibodies (mAbs) against cGTHalpha, cGTHIIbeta, cSL, and cPRL, and designated as FMU-cGTHalpha1-7, FMU-cGTHIIbeta1-11, FMU-cSL 1-17, and FMU-cPRL 1-8, respectively. The isotype, titer, and specificity were identified by enzyme-linked immunosorbent assay (ELISA), Western blot, and immunohistochemical staining, respectively, and application of these mAbs in the aforementioned tests has been proved. Furthermore, sensitive sandwich-ELISA systems for quantitative detection of the hormones mentioned above were also developed.

103: Brain research, 2009 Oct 20, 7(1)
Effects of a structural analogue of salsolinol, 1-MeDIQ, on pituitary prolactin release and dopaminergic activity in the mediobasal hypothalamus in nursing sheep.

[Abstract]The prolactin release caused by salsolinol (a derivative of dopamine, DA) in rats could be prevented by its structural analogue 1-methyl-3,4-dihydroisoqinoline (1-MeDIQ). To study the participation of salsolinol in the neural stimulatory mechanism of prolactin release in lactating sheep we tested whether 1-MeDIQ, acting at the central nervous system (CNS) level, would diminish basal prolactin release and reduce prolactin surge induced by suckling. A series of intracerebroventricular (icv) infusions of 1-MeDIQ (5x60mug/60mul/ 30min, at 30-min intervals) were performed in nursing ewes (n=8) during the fifth week of lactation. Additionally, by combining these infusions with push-pull perfusion, we studied the concentration of dopaminergic components i.e. salsolinol, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) within the infundibular nucleus/median eminence (IN/ME) in four of the ewes. Treatment with 1-MeDIQ significantly (P<0.001) reduced either the basal prolactin release during the non-suckling period or the suckling-induced prolactin surge. Specifically, the suppressive effect occurred gradually, affecting both the duration and amplitude of the prolactin surge. In the control ewes, the perfusate salsolinol concentration increased significantly (P<0.001) during suckling, while in the ewes treated with 1-MeDIQ only vestigial amounts of this compound were found during the non-suckling period. No DA was detected in the perfusates collected from the IN/ME of control and 1-MeDIQ-treated groups and no significant differences were found in the DOPAC concentrations between these groups. In conclusion, 1-MeDIQ is able to inhibit prolactin secretion in lactating sheep, acting at the CNS level. In addition, one of the way of 1-MeDIQ action may be directed to the local salsolinol release within the mediobasal hypothalamus.

104: Pediatric rheumatology online journal, 2009 Oct 23, 7(1)
Galactorrhea associated with juvenile systemic lupus erythematosus: a review of the role of prolactin.

[Abstract]ABSTRACT: This case report is based on the clinical observation of a patient with juvenile systemic lupus erythematosus (SLE) who developed transient galactorrhea. The subsequent literature review documented an interesting association between prolactin and rheumatic diseases and in particular, hyperprolactinemia and SLE. The discussion that follows the case report explores this relationship and proposes a hypothesis regarding why this patient with juvenile SLE developed galactorrhea.

105: Fertility and sterility, 2010 Sep, 94(4)
Blockage of ghrelin-induced prolactin secretion in women by bromocriptine.

[Abstract]OBJECTIVE: To investigate the effect of bromocriptine on ghrelin-induced PRL secretion in women. DESIGN: Longitudinal study. SETTING: University hospital. PATIENT(S): Ten healthy, normally cycling women. INTERVENTION(S): The women were injected IV on day 3 of three cycles with a single dose of normal saline (cycle 1) or ghrelin (1 mug/kg) after pretreatment for 2 days either with placebo (cycle 2) or with bromocriptine (cycle 3) per os. Blood samples were taken before and frequently after drugs administration for 120 minutes. MAIN OUTCOME MEASURE(S): The PRL and GH responses to ghrelin were assessed. RESULT(S): Bromocriptine suppressed basal PRL levels significantly. The injection of ghrelin stimulated a significant increase in serum PRL levels in cycle 2 but not in cycle 3, in which PRL levels remained stable. The response of GH to gherlin was significantly attenuated in cycle 3 as compared with cycle 2. CONCLUSION(S): The present study demonstrates for the first time that bromocriptine blocked the stimulating effect of ghrelin on PRL release and attenuated the GH response to the same stimulus. The mechanism of these interactions needs to be clarified.

106: The Journal of endocrinology, 2009 Dec, 203(3)
Improving the pharmacokinetics/pharmacodynamics of prolactin, GH, and their antagonists by fusion to a synthetic albumin-binding peptide.

[Abstract]To prolong the circulation half-life of human prolactin (hPRL), human GH (hGH), and their competitive antagonists, hPRL-G129R and hGH-G120R, we examined the effects of fusing a serum albumin-binding peptide (SA20) to their amino- or carboxyl-terminus. Fusion of the SA20 peptide to the amino-terminus of the ligands was less detrimental upon their ability to induce or inhibit signal transduction and cell proliferation in vitro than fusion to the carboxyl-terminus. Pharmacokinetic (PK) studies in mice revealed that the half-life of SA20-hPRL and SA20-hGH was prolonged and their clearance was reduced in comparison with hPRL and hGH. Pharmacodynamic (PD) studies in 8-week-old female mice revealed that lobuloalveolar development in mammary glands was greater in all three groups (daily, every 2 days, or every third day over a 12-day period) of mice treated with SA20-hPRL (4 mg/kg) compared with hPRL (3.59 mg/kg). Similarly, daily administration (i.p.) of SA20-hGH (8 mg/kg) or hGH (7.15 mg/kg) to 23-day-old female mice over a 40-day period revealed the superiority of SA20-hGH over hGH as measured by weight gain, body length, and lobuloalveolar development in the mammary glands. These findings indicate that SA20 modification of hPRL, hGH, and their respective antagonists improves their PK/PD properties.

107: Brain research, 2009 Dec 11, 1302
Prolactin induces Egr-1 gene expression in cultured hypothalamic cells and in the rat hypothalamus.

[Abstract]Prolactin (PRL), the major lactogenic hormone, acts also as neuromodulator and regulator of neuronal and glial plasticity in the brain. There is an increase in synthesis and release of PRL within the hypothalamus during peripartum and in response to stress. To identify mechanisms by which PRL induces neuroplasticity, we studied the ability of PRL to induce the transcription factor Egr-1 in the hypothalamic cell line, 4B, in vitro, and in specific neuronal cell types of the hypothalamus in vivo. PRL induced Egr-1 mRNA expression in 4B cells, an effect which was prevented by the MEK inhibitor, U0126. In vivo, intracerebroventricular PRL (1 microg) increased Egr-1 mRNA levels in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) of female rats. The increase in mRNA paralleled elevated Egr-1 protein expression in the PVN and SON. Double staining immunohistochemistry revealed Egr-1 localization in oxytocin neurons of the PVN and SON, but not in vasopressin neurons in these regions. In the dorsomedial PVN, a population of non-oxytocin or vasopressin cells localized in a region corresponding to corticotropin-releasing hormone neurons also showed marked Egr-1 immunoreactivity. The data suggest that PRL modulates plasticity in oxytocinergic neurons, through MAP kinase-dependent induction of Egr-1.

108: Fish physiology and biochemistry, 2010 Jun, 36(2)
The second prolactin receptor in Nile tilapia (Oreochromis niloticus): molecular characterization, tissue distribution and gene expression.

[Abstract]Prolactin (PRL) is one of the most versatile hormones found in the pituitary of vertebrates and exerts its actions through binding to a specific PRL receptor (PRLR). Here we describe the cloning and characterization of a second prolactin receptor (ntPRLR2), isolated from the ovary of Nile tilapia (Oreochromis niloticus). The newly identified PRLR cDNA was 2011 bp in length and encoded 529 amino acids. It shared 31.6% identity in nucleotide sequence and 29.2% in deduced amino acid sequence with the first PRLR identified in Nile tilapia (ntPRLR1). Both of these ntPRLRs resemble the long form mammalian PRLRs. The nominated ntPRLR2 was further confirmed as a real prolactin receptor based on its competence to transactivate the beta-casein and c-fos promoters in the transiently ntPRLR2-transfected HEK293 cells. The ntPRLR2 gene also found to encode a 864-bp short form transcript in the ovary, which was confirmed by Northern blot analysis. A tissue distribution study by real-time PCR revealed that the mRNA of both receptors (ntPRLR1 and ntPRLR2) was widely expressed in different tissues, with an extremely high abundance in the osmoregulatory organs, including the gills, intestine and kidney. ntPRLR1 mRNA was more abundant than ntPRLR2 in the testis, while the reverse expression pattern was found in the ovary. In the ovary, ntPRLR2 mRNA demonstrated a distinct gonadal development-dependent expression profile, with significantly higher levels at a sexual mature stage than at sexual recrudescent and sexual regressed stages. When challenged with estradiol, ntPRLR2 mRNA expression was up-regulated by E2, whereas E2 had no significant effect on ntPRLR1.

109: Medical hypotheses, 2010 Feb, 74(2)
Prolactin fragmentation by trophoblastic matrix metalloproteinases as a possible contributor to peripartum cardiomyopathy and pre-eclampsia.

[Abstract]Although peripartum cardiomyopathy (PPCM) is a rare disease, it has very serious consequences for both mother and child. No single cause has been held responsible for the pathogenesis. Recent studies have indicated that increased proteolytic cathepsin D activity in cardiomyocytes results in16kDa prolactin fragments with anti-angiogenic and apoptotic properties, which may contribute to the development of PPCM. In support of these findings, lowering full-length prolactin production by bromocriptine therapy has been reported to prevent impairment of cardiac function. PPCM is associated with an increased co-existence of pre-eclampsia, however, a causal relationship has been disputed. We hypothesize that the pathophysiology of PPCM and pre-eclampsia share the same molecular pathway: increased activity of trophoblastic matrix metalloproteinases at the feto-maternal interface may aggravate proteolysis of full-length prolactin, and subsequently the formed 16kDa prolactin fragments may contribute to deterioration of PPCM and pre-eclampsia. Therefore, we argue that it may be worthwhile to explore wether prolactin inhibition is not only beneficial for PPCM patients, but also for the much more prevalent pre-eclamptic women.

110: Domestic animal endocrinology, 2010 Jan, 38(1)
Heat stress abatement during the dry period influences prolactin signaling in lymphocytes.

[Abstract]Heat stress perturbs prolactin (PRL) release and affects dairy cow lactational performance and immune cell function. We hypothesized that greater PRL concentration in plasma of heat-stressed cows relative to cooled cows would decrease expression of prolactin receptor (PRL-R) mRNA and increase mRNA expression of suppressors of cytokine signaling (SOCS) in lymphocytes, altering their cytokine production. To test this hypothesis, multiparous Holstein cows were dried off 46 d before their expected calving date and assigned randomly to heat stress (HT; n=9) or cooling (CL; n=7) during the entire dry period. A second study was conducted the following year with an additional 21 cows (12 HT; 9 CL). Lymphocytes were isolated from cows at -46, -20, +2, and +20 d relative to expected calving date and mRNA expression of PRL-R, SOCS-1, SOCS-2, SOCS-3, cytokine-inducible SH2-containing protein (CIS), and heat shock protein 70 KDa A5 (HSPA5), and housekeeping genes hydroxymethylbilane synthase (HMBS), ATP synthase, H+ transporting mitochondrial F1 complex, beta subunit (ATP5B), and ribosomal protein S9 (RPS9) was analyzed by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Cows exposed to HT had greater PRL concentration in plasma compared with CL cows. Measurement of lymphocyte proliferation indicated that lymphocytes of CL cows proliferated more than those from HT cows and exressed more PRL-R mRNA and less SOCS-1 and SOCS-3 mRNA relative to HT cows. Further, lymphocytes from CL cows produced more tumor necrosis factor-alpha (TNF-alpha) than those from HT cows. These results suggest that changes in PRL-signaling pathway genes during heat stress are associated with differential cytokine secretion by lymphocytes and may regulate lymphocyte proliferation in dairy cows.

111: Journal of vascular research, 2010, 47(1)
Prolactin in Ovarian Follicular Fluid Stimulates Endothelial Cell Proliferation.

[Abstract]Angiogenesis is essential for the growth and maturation of the ovarian follicle and its transition into the corpus luteum. In addition to the main proangiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), follicular fluid (FF) contains the hormone prolactin (PRL), which is known to promote angiogenesis in vivo. Here, we show that FF from large follicles, which contains twice the PRL level of FF from small follicles, stimulates endothelial cell proliferation to a greater extent than the latter, and that immunoneutralization of PRL prevents FF from stimulating endothelial cell proliferation. Notably, the FF increases the expression of the short and long PRL receptor isoforms in endothelial cells, and a purified PRL standard stimulates endothelial cell proliferation but only after the cells have been pretreated with FF. However, purified PRL activates the JAK2/STAT3 pathway in endothelial cells in the absence of pretreatment with FF. In summary, PRL present in the FF stimulates the proliferation of endothelial cells. This effect likely involves the upregulation of the short and long PRL receptor isoforms and is independent of PRL-induced JAK2/STAT3 signaling.

112: Regulatory peptides, 2010 Jan 8, 159(1-3)
Prolactin-releasing peptide regulates cardiac contractility.

[Abstract]High levels of specific prolactin-releasing peptide (PrRP) binding sites have been found in the myocardium; however, the functional importance of PrRP in the regulation of cardiac function is unknown. In isolated perfused rat hearts, infusion of PrRP (1-100 nM) induced a dose-dependent positive inotropic effect. Inhibition of cAMP catabolism by IBMX, a phosphodiesterase inhibitor, failed to augment the contractile effect of PrRP. The protein phosphatase (PP1/PP2A) inhibitor calyculin A increased the inotropic response to PrRP, whereas the PP2A inhibitor okadaic acid had no effect. Ro32-0432, a protein kinase C alpha (PKC alpha) inhibitor, significantly enhanced the inotropic effect of PrRP as well as the phosphorylation of phospholamban at Ser-16. In conclusion, the present data define a hitherto unrecognized role for PrRP in the regulation of cardiovascular system by showing that PrRP exerts a direct positive inotropic effect. Moreover, our results suggest that the cAMP-independent inotropic response to PrRP is suppressed by concurrent activation of PKC alpha and PP1.

113: Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association, 2010 Apr, 118(4)
Associations of anthropometric parameters with serum TSH, prolactin, IGF-I, and testosterone levels: results of the study of health in Pomerania (SHIP).

[Abstract]Obesity is a major risk factor for chronic diseases including cardiovascular disorders. Divergent associations between obesity and hormonal changes have been reported. The objective of the present study was to analyse the associations between anthropometric measurements and hormone levels including serum thyroid stimulating hormone (TSH), prolactin, insulin-like growth factor (IGF) I, and testosterone. Form the cross-sectional Study of Health in Pomerania 1 women and 1 864 men aged 20-79 years were included in the analyses. Serum TSH, prolactin, IGF-I, and testosterone levels were determined by immunochemiluminescent procedures. Body height, weight as well as waist and hip circumferences were measured. Body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were calculated. Our analyses revealed inverse linear associations of waist and hip circumferences, BMI and WHtR with serum TSH levels and linear associations between waist circumference as well as WHtR and serum prolactin levels in women. In men, inverse linear and quadratic associations between anthropometric parameters and serum IGF-I as well as serum testosterone levels were found. Additionally, men with high waist circumference had more often low serum IGF-I or testosterone levels and less often high serum IGF-I or testosterone levels compared to men with low waist circumference. These sex-specific differences should be noted in studies regarding hormones and obesity.

114: Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology, 2009 Feb 26,
Gene and protein expression for Prolactin, Growth hormone and Somatolactin in Sparus aurata: Seasonal variations.

[Abstract]The seasonal variation of PRL, GH and SL gene and protein expression has been analyzed in gilthead sea bream (Sparus aurata) pituitaries using Real Time Q-PCR and Western Blots, respectively. Animals were cultured in earthen ponds under natural photoperiod, temperature and salinity conditions, Samples were taken during winter 2005 (January), spring 2005 (April), summer 2005 (July) and autumn 2005 (October). beta-actin, used as the housekeeping gene both for Q-RT-PCR and Western analysis, did not present significant differences among seasons. Higher expression was observed during spring and autumn for PRL, summer and winter for GH, and spring for SL. Expression of PRL and SL, but not GH, presented seasonal variation, suggesting that these hormones could play a role in the molecular signal transduction of environmental factors (especially of photoperiod and temperature) in eurythermal fish.

115: Autoimmunity reviews, 2009 Feb 24,
Immunomodulatory role of prolactin in diabetes development.

[Abstract]Pituitary hormone and cytokine prolactin (PRL) is one of the mediators of the bidirectional communication between neuroendocrine and immune systems. It participates in many immunomodulatory activities, affects differentiation and maturation of both, B and T lymphocytes and enhances inflammatory responses and production of immunoglobulins. Hyperprolactinemia has been described in many autoimmune diseases, both systemic (SLE, RA, PsA) and organ-specific (T1D, CD and others) and the activity of PRL has been intensively studied. Nevertheless, no data on PRL contribution to pathogenesis of diabetes mellitus is available, although the effect of PRL on beta cells of the pancreas and insulin secretion has been observed.


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