Showing papers on "Prolactin published in 2007"

Initiation of Human Lactation: Secretory Differentiation and Secretory Activation

Abstract: Theories for the origin of milk have been recorded since the time of Ancient Greeks. In those times it was believed that milk was derived from special vessels that connected the uterus to the breasts. The "chyle theory" on the origin of milk was another prominent theory which persisted well into the nineteenth century before the realisation that milk components were derived from blood and some milk constituents were actually synthesized within the breasts. The demonstration that milk ejection was the expulsion of milk that had already been secreted and that milk secretion was a separate continuous process, set the background for the development for the current understanding of milk synthesis and secretion. Today we know that there are two stages in the initiation of lactation- secretory differentiation and secretory activation. Secretory differentiation represents the stage of pregnancy when the mammary epithelial cells differentiate into lactocytes with the capacity to synthesize unique milk constituents such as lactose. This process requires the presence of a 'lactogenic hormone complex' of the reproductive hormones, estrogen, progesterone, prolactin and some metabolic hormones. Secretory activation on the other hand, is the initiation of copious milk secretion and is associated with major changes in the concentrations of many milk constituents. The withdrawal of progesterone triggers the onset of secretory activation but prolactin, insulin and cortisol must also be present. This review describes the works of pioneers that have led to our current understanding of the biochemical and endocrinological processes involved in the initiation of human lactation.

Reproductive role of prolactin

Abstract: The biological actions of prolactin (PRL), a polypeptide hormone, are mostly related to lactation and reproduction. These actions have been clarified by studies of PRL and PRL-deficient receptor mice, which have a clear phenotype of reproductive failure at multiple sites. This review aims to summarize current knowledge about PRL and its receptor, role in reproductive axis and presents information of hyperprolactinemia in reproductive medicine. Our understanding of the physiology and transduction pathway of PRL has largely increased in the past 20 years with the cloning of PRL and its receptor gene.

Clinical implications of antipsychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and current perspectives.

Abstract: Hyperprolactinemia is increasingly studied as a frequent and potentially important consequence of antipsychotic medication treatment. Some individuals presenting with hyperprolactinemia remain asymptomatic, but others may exhibit a wide range of clinical symptoms resulting from either the direct effects of prolactin on body tissues (galactorrhea, gynecomastia) or endocrine-related secondary effects (sexual and reproductive dysfunction in the short term, and possibly the risk of tumorigenesis and osteoporosis in the longer term). Short-term side effects may negatively impact medication compliance, and long-term effects have the potential for serious health consequences. Antipsychotic medications have differing propensities to cause prolactin elevation. The first-generation antipsychotics, as well as the second-generation antipsychotic risperidone and its active metabolite paliperidone, have been shown to cause marked and sustained elevations in prolactin levels, whereas others of the second-generation antipsychotics appear to have little or no effect on prolactin levels or may decrease prolactin. A comprehensive overview of antipsychotics and hyperprolactinemia is presented together with a review of emerging evidence about the short- and long-term health risks of hyperprolactinemia.

Prolactin regulation of gonadotropin-releasing hormone neurons to suppress luteinizing hormone secretion in mice.

Abstract: Hyperprolactinemia causes infertility, but the mechanisms involved are not known. The present study aimed to determine whether and how prolactin may influence LH secretion in the adult female mouse. Using ovariectomized, estrogen-treated (OVX+E) mice, we found that 7 d of intracerebroventricular prolactin potently suppressed serum LH levels (P < 0.05). To examine whether this central action of prolactin may involve the GnRH neurons, the effects of acute and chronic prolactin on cAMP response element-binding protein phosphorylation (pCREB) in GnRH neurons were examined using dual-label immunocytochemistry. In diestrous and OVX+E mice, a single sc injection of ovine prolactin resulted in a significant (P < 0.05) doubling of the number of GnRH neurons expressing pCREB. OVX+E mice treated with five injections of ovine prolactin over 48 h showed a 4-fold increase in the number of GnRH neurons with pCREB. To determine whether GnRH neurons might be regulated directly by prolactin, we examined prolactin receptor (PRL-R) mRNA expression in green fluorescent protein-tagged GnRH neurons by single-cell RT-PCR. As a positive control, PRL-R mRNA was measured in arcuate dopaminergic neurons obtained from green fluorescent protein-tagged tyrosine hydroxylase neurons. Three of 23 GnRH neurons (13%) were identified to express PRL-R transcripts, whereas nine of 11 arcuate dopaminergic neurons (82%) were found to coexpress PRL-R mRNA. These data demonstrate that prolactin suppresses LH levels in the mouse, as it does in other species, and indicate that it acts centrally to regulate intracellular signaling within GnRH neurons. This is likely to occur, at least in part, through the direct regulation of a subpopulation of GnRH neurons.

Age-specific reproductive success in a long-lived bird: do older parents resist stress better?

Abstract: In many vertebrates, reproductive performance increases with advancing age but mechanisms involved in such a pattern remain poorly studied. One potential mechanism may be the hormonal stress response, which shifts energy investment away from reproduction and redirects it towards survival. In birds, this stress response is achieved through a release of corticosterone and is also accompanied by a decrease in circulating prolactin, a hormone involved widely in regulating parental cares. It has been predicted that, when the value of the current reproduction is high relative to the value of future reproduction and survival, as it is expected to be in older adults, the stress response should be attenuated to ensure that reproduction is not inhibited. We tested this hypothesis by measuring the corticosterone and prolactin responses of known-age (8-36 years old) incubating snow petrels (Pagadroma nivea) to a standardized capture/handling stress protocol. We also investigated whether an attenuation of the stress responses will correlate with a lower occurrence of egg neglect, a frequently observed behaviour in snow petrels. The probability of successfully fledging a chick increased from 6 years to 12 years before stabilizing after 12 years of age. Corticosterone response to stress was unaffected by age. Prolactin response to stress, however, was influenced clearly by age: in both sexes older breeders had higher stress-induced prolactin levels than younger ones. This was due to an increasing attenuation of the prolactin response to stress with advancing age in females, and in males this was due to a probably higher intrinsic capacity of older males to secrete prolactin. Moreover, higher stress-induced prolactin levels were correlated with a lower probability of neglecting the egg. In young breeders, the combination of a robust corticosterone increase with a lower ability to maintain prolactin secretion during acute stress is probably one of the functional causes of their lower incubation commitment. We suggest that the ability to maintain a threshold level of prolactin during a stressful situation may be an important physiological mechanism involved in the improvement of reproductive performance with advancing age in long-lived birds.

Chronic intracerebral prolactin attenuates neuronal stress circuitries in virgin rats.

Abstract: Prolactin (PRL) has been shown to promote maternal behaviour, and to regulate neuroendocrine and emotional stress responses. These effects appear more important in the peripartum period, when the brain PRL system is highly activated. Here, we studied the mechanisms that underlie the anti-stress effects of PRL. Ovariectomized, estradiol-substituted Wistar rats were implanted with an intracerebroventricular cannula and treated with ovine PRL (0.01, 0.1 or 1 lg ⁄h; 5 days via osmotic minipumps) or vehicle, and their responses to acute restraint stress was assessed. Chronic PRL treatment exerted an anxiolytic effect on the elevated plus-maze, and attenuated the acute restraint-induced rise in plasma adrenocorticotropin, corticosterone and noradrenaline. At the neuronal level, in situ hybridization revealed PRL effects on the expression patterns of the immediate-early gene c-fos and corticotropin-releasing factor (CRF). Under basal conditions, PRL significantly reduced c-fos mRNA expression within the central amygdala. In response to restraint, the expression of both c-fos mRNA and protein and of CRF mRNA was decreased in the parvocellular part of the paraventricular nucleus (PVN) of PRL-treated compared with vehicle-treated animals. In conclusion, our data demonstrate that chronic elevation of PRL levels within the brain results in reduced neuronal activation within the hypothalamus, specifically within the PVN, in response to an acute stressor. Thus, PRL acting at various relevant brain regions exerts profound anxiolytic and anti-stress effects, and is likely to contribute to the attenuated stress responsiveness found in the peripartum period, when brain PRL levels are physiologically upregulated.

Endocrine and cytokine responses in humans with pulmonary tuberculosis.

Abstract: Endocrine responses during chronic infections such as lung tuberculosis are poorly characterized. Hormonal changes are likely to occur since some of the cytokines produced during this disease could affect endocrine mechanisms that, in turn, influence the course of infectious/inflammatory processes. A main purpose of this work was to study endocrine responses involving pituitary, adrenal, gonadal, and thyroid hormones in parallel to IFN-gamma, IL-10, and IL-6 levels in tuberculosis patients with different degree of pulmonary involvement. We have also studied whether products derived from peripheral immune cells obtained from the patients can affect the in vitro production of adrenal steroids. The population studied comprised HIV-negative newly diagnosed, untreated male patients with mild, moderate, and advanced lung tuberculosis, and matched, healthy controls. IFN-gamma, IL-10, and IL-6 levels were elevated in patients with tuberculosis. Dehydroepiandrosterone and testosterone levels were profoundly decreased and growth hormone levels were markedly elevated in patients, in parallel to modest increases in cortisol, estradiol, prolactin, and thyroid hormone concentrations. Supernatants of peripheral blood mononuclear cells obtained from the patients and stimulated in vitro with Mycobacterium tuberculosis antigens significantly inhibited dehydroepiandrosterone secretion by the human adrenal cell line NCI-H295-R. These results support the hypothesis that at least some of the endocrine changes observed in the patients may be mediated by endogenous cytokines. The endocrine profile of tuberculosis patients would favor a reduction of protective cell-mediated immunity and an exacerbation of inflammation leading to perpetuation of the lung injury and to the hypercatabolic condition that characterizes this disease.

Sexual Function and Gonadal Hormones in Patients Taking Antipsychotic Treatment for Schizophrenia or Schizoaffective Disorder

Abstract: Sexual dysfunction is common in patients taking antipsychotics- more than twice as common as in healthy controls 1;2, and greater in patients taking antipsychotics than unmedicated schizophrenic patients and patients with affective disorders 3-5. The CATIE study has recently highlighted that sexual function is commonly impaired in patients taking atypical as well as typical antipsychotic treatment 6. A number of factors may play a role in impairing sexual dysfunction in patients taking antipsychotic treatment, including ‘negative’ and co-morbid depressive symptoms, the anticholinergic and adrenergic effects of antipsychotics, and higher rates of smoking and physical illness2;7. It has long been supposed, however, that prolactin elevation and low gonadal hormone levels are significant factors underlying the high rates of sexual dysfunction seen in patients treated with antipsychotics8-10. Prolactin may impair sexual function through its actions on the hypothalamic-pituitary-gonadal axis altering sex hormone release. Hyperprolactinemia is associated with hypogonadism and sexual dysfunction11, although a preliminary naturalistic study of women taking antipsychotics found high but similar rates of reproductive dysfunction in normoprolactinemic and hyperprolactinemic groups 12. Low sex hormone levels have been reported in patients taking antipsychotics 13-16. We have previously reported high rates of sexual dysfunction and high rates of hypogonadism in patients taking antipsychotics 1, but no previous studies have investigated the association between the two. We hypothesised that low sex hormone levels are associated with sexual dysfunction in patients taking antipsychotics. We therefore set out to substantiate the finding that rates of sexual dysfunction are higher in patients taking antipsychotics than healthy controls in a larger sample and to test the hypothesis that sexual dysfunction is associated with prolactin, and gonadal hormone levels in patients taking antipsychotic treatment for schizophrenia or schizo-affective disorder.

Prolactin/Leptin Interactions in the Control of Food Intake in Rats

Abstract: Recent evidence suggests that the peptide hormone prolactin (PRL) modulates energy balance through a number of mechanisms, including acting in the brain to increase food intake. In the current studies, we first demonstrated that chronic infusions of PRL into the lateral ventricles increased food intake in cycling rats without disrupting estrous cyclicity. In subsequent experiments the hypothesis that at least part of PRL’s ability to increase food intake resulted from PRL-induced leptin resistance was tested. Female rats given chronic infusions of PRL (5 g/h) into the cerebral ventricles for 10 d did not show a reduction in food intake or body weight after acentralinjectionof4gmurineleptin,whereastheexpected reduction in both of these parameters was seen in vehicleinfused rats. Leptin injections were without effect on these parameters, whether they were administered to free feeding PRL-infused rats or after 24-h food deprivation. This lack of a behavioral response to leptin was accompanied by an attenuation in Fos induction and phosphorylation of signal transducer and activator of transcription 3 after leptin administration in PRL-infused rats in both the ventromedial hypothalamus and paraventricular hypothalamic nucleus. (Endocrinology 148: 5977–5983, 2007)

Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor

Abstract: In addition to classical expression patterns in pituitary and placenta and functions in growth and reproduction, members of the small family of hormones that includes prolactin (PRL), growth hormone (GH), and placental lactogen are expressed by endothelia and have angiogenic effects. In contrast, 16- to 17-kDa proteolytic fragments of these hormones have antiangiogenic effects. Here we show that PRL and GH are bound and processed by members of the bone morphogenetic protein 1 (BMP1) subgroup of extracellular metalloproteinases, previously shown to play key roles in forming extracellular matrix and in activating certain TGFβ superfamily members. BMP1 has previously been suggested to play roles in angiogenesis, as high throughput screens have found its mRNA to be one of those induced to highest levels in tumor-associated endothelia compared with resting endothelia. PRL and GH cleavage is shown to occur in each hormone at a single site typical of sites previously characterized in known substrates of BMP1-like proteinases, and the ≈17-kDa PRL N-terminal fragment so produced is demonstrated to have potent antiangiogenic activity. Mouse embryo fibroblasts are shown to produce both PRL and GH and to process them to ≈17-kDa forms, whereas GH and PRL processing activity is lost in mouse embryo fibroblasts doubly null for two genes encoding BMP1-like proteinases.

Regulation of glucokinase in pancreatic islets by prolactin: a mechanism for increasing glucose-stimulated insulin secretion during pregnancy

Abstract: Glucokinase activity is increased in pancreatic islets during pregnancy and in vitro by prolactin (PRL). The underlying mechanisms that lead to increased glucokinase have not been resolved. Since glucose itself regulates glucokinase activity in beta-cells, it was unclear whether the lactogen effects are direct or occur through changes in glucose metabolism. To clarify the roles of glucose metabolism in this process, we examined the interactions between glucose and PRL on glucose metabolism, insulin secretion, and glucokinase expression in insulin 1 (INS-1) cells and rat islets. Although the PRL-induced changes were more pronounced after culture at higher glucose concentrations, an increase in glucose metabolism, insulin secretion, and glucokinase expression occurred even in the absence of glucose. The presence of comparable levels of insulin secretion at similar rates of glucose metabolism from both control and PRL-treated INS-1 cells suggests the PRL-induced increase in glucose metabolism is responsible for the increase in insulin secretion. Similarly, increases in other known PRL responsive genes (e.g. the PRL receptor, glucose transporter-2, and insulin) were also detected after culture without glucose. We show that the upstream glucokinase promoter contains multiple STAT5 binding sequences with increased binding in response to PRL. Corresponding increases in glucokinase mRNA and protein synthesis were also detected. This suggests the PRL-induced increase in glucokinase mRNA and its translation are sufficient to account for the elevated glucokinase activity in beta-cells with lactogens. Importantly, the increase in islet glucokinase observed with PRL is in line with that observed in islets during pregnancy.

Progesterone Receptor Repression of Prolactin/Signal Transducer and Activator of Transcription 5-Mediated Transcription of the β-Casein Gene in Mammary Epithelial Cells

Abstract: Prolactin (PRL) and glucocorticoids act synergistically to stimulate transcription of the beta-casein milk protein gene. Signal transducer and activator of transcription 5 (Stat5) mediates PRL-dependent trans-activation, and glucocorticoid potentiation occurs through cross talk between glucocorticoid receptor (GR) and Stat5 at the beta-casein promoter. In the mouse, progesterone withdrawal leads to terminal differentiation and secretory activation of the mammary gland at parturition, indicating progesterone's role in repressing milk protein gene expression during pregnancy. To investigate the mechanism of the inhibitory action of progesterone, experiments were performed with cell culture systems reconstituted to express progesterone receptor (PR), the PRL receptor/Stat5 signaling pathway, and GR, enabling evaluation of PR, GR, and Stat5 interactions at the beta-casein promoter. With COS-1, normal murine mammary gland, HC-11, and primary mammary epithelial cells, progestin-PR directly repressed the PRL receptor/Stat5a signaling pathway's mediation of PRL-induced beta-casein transcription. Progestin-PR also inhibited glucocorticoid-GR enhancement of PRL induced trans-activation of beta-casein. Inhibition depended on a functional PR DNA binding domain and specific PR-DNA interactions at the beta-casein promoter. Chromatin immunoprecipitation assays in HC-11 cells revealed recruitment of PR and Stat5a to the beta-casein promoter by progestin or PRL, respectively. Recruitment was disrupted by cotreatment with progestin and PRL, suggesting a mutual interference between activated PR and Stat5a. Without PRL, progestin-PR also recruited Stat5a to the beta-casein promoter, suggesting that recruitment of an unactivated form of Stat5a may contribute to inhibition of beta-casein by progesterone. These results define a negative cross talk between PR and Stat5a/GR that may contribute to the physiological role of progesterone to repress lactogenic hormone induction of the beta-casein gene in the mammary gland during pregnancy.

Loss of mammary epithelial prolactin receptor delays tumor formation by reducing cell proliferation in low-grade preinvasive lesions.

Abstract: Top quartile serum prolactin levels confer a twofold increase in the relative risk of developing breast cancer. Prolactin exerts this effect at an ill defined point in the carcinogenic process, via mechanisms involving direct action via prolactin receptors within mammary epithelium and/or indirect action through regulation of other hormones such as estrogen and progesterone. We have addressed these questions by examining mammary carcinogenesis in transplants of mouse mammary epithelium expressing the SV40T oncogene, with or without the prolactin receptor, using host animals with a normal endocrine system. In prolactin receptor knockout transplants the area of neoplasia was significantly smaller (7 versus 17%; P<0.001 at 22 weeks and 7 versus 14%; P=0.009 at 32 weeks). Low-grade neoplastic lesions displayed reduced BrdU incorporation rate (11.3 versus 17% P=0.003) but no change in apoptosis rate. Tumor latency increased (289 days versus 236 days, P<0.001). Tumor frequency, growth rate, morphology, cell proliferation and apoptosis were not altered. Thus, prolactin acts directly on the mammary epithelial cells to increase cell proliferation in preinvasive lesions, resulting in more neoplasia and acceleration of the transition to invasive carcinoma. Targeting of mammary prolactin signaling thus provides a strategy to prevent the early progression of neoplasia to invasive carcinoma.

Physical activity and inactivity in relation to sex hormone, prolactin, and insulin-like growth factor concentrations in premenopausal women : Exercise and premenopausal hormones

Abstract: An association between physical activity and premenopausal breast cancer risk may be due, in part, to relationships with sex hormones or growth factors Therefore, we assessed whether MET-h/week of total physical activity (moderate-to-vigorous intensity), walking, or vigorous physical activity, and h/week of standing or sitting were associated with plasma concentrations of several hormones We examined levels of estrogens, androgens, progesterone, prolactin, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and growth hormone (GH) in 565 premenopausal women, ages 33-52 years, from the Nurses' Health Study II (NHSII) About 87% of women had both timed follicular and luteal samples; other women had one untimed sample In general we observed few associations between sex hormone or IGF levels and measures of physical activity or inactivity However, free testosterone was modestly inversely associated with total physical activity (p-trend = 002) Luteal estradiol, free estradiol, and estrone also were inversely associated with total physical activity (p-trend = 010, 004, 001, respectively); however, the trend was substantially attenuated when excluding women with anovulatory cycles or irregular cycles These cross-sectional results suggest that physical activity and inactivity have limited associations with premenopausal sex hormone and growth factor levels, except possibly luteal estrogens

Prolactin Enhances Interferon-γ-Induced Production of CXC Ligand 9 (CXCL9), CXCL10, and CXCL11 in Human Keratinocytes

Abstract: Psoriasis vulgaris is an autoimmune dermatosis characterized by type 1 T cell infiltration. Prolactin may be involved in the pathogenesis of psoriasis. CXC ligand 9 (CXCL9), CXCL10, and CXCL11 recruit type 1 T cells, and their production by keratinocytes is enhanced in psoriatic lesions. CXCL9, CXCL10, and CXCL11 production by keratinocytes depends on nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription (STAT)1 and that of CXCL11 depends on interferon (IFN)-regulatory factor (IRF)-1. We examined in vitro effects of prolactin on CXCL9, CXCL10, and CXCL11 production in human keratinocytes. Although prolactin alone was ineffective, it enhanced IFN-gamma-induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of STAT1, NF-kappaB, and IRF-1. Inhibitors of Janus kinase (JAK), p38 MAPK, and MAPK/ERK kinase (MEK) suppressed prolactin- plus IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production and NF-kappaB, STAT1, and IRF-1 activities. Prolactin induced phosphorylation of JAK2 and ERK, whereas IFN-gamma induced phosphorylation of JAK1, JAK2, and p38 MAPK. Prolactin modestly or IFN-gamma greatly induced tyrosine phosphorylation of STAT1, and both were suppressed by JAK inhibitor. Prolactin modestly or IFN-gamma greatly induced serine phosphorylation of STAT1, which was suppressed by MEK or p38 MAPK inhibitor, respectively. Prolactin induced phosphorylation of inhibitory kappaBalpha and NF-kappaB p65, which was suppressed by MEK inhibitor. These results suggest that prolactin may enhance IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in keratinocytes via activation of STAT1, NF-kappaB, and IRF-1 through JAK2 and MEK/ERK pathways. Prolactin may promote type 1 T cell infiltration into psoriatic lesions via these chemokines.

Alveolar progenitor cells develop in mouse mammary glands independent of pregnancy and lactation

Abstract: We have previously described pluripotent, parity-induced mammary epithelial cells (PI-MEC) marked by Rosa26-lacZ expression in the mammary glands of parous females. PI-MEC act as lobule-limited epithelial stem/progenitor cells. To determine whether parity is necessary to generate PI-MEC, we incubated mammary explant cultures from virgin mice in vitro with insulin alone (I), hydrocortisone alone (H), prolactin alone (Prl), or a combination of these lactogenic hormones (IHPrl). Insulin alone activated the WAP-Cre gene. Hydrocortisone and prolactin alone did not. Any combination of hormones that included insulin was effective. Only I, H and Prl together were able to induce secretory differentiation and milk protein synthesis. In addition, EGF, IGF-2 and IGF-1 added individually produced activated (lacZ(+)) PI-MEC in explant cultures. Neither estrogen nor progesterone induced WAP-Cre expression in the explants. None of these positive initiators of WAP-Cre expression in PI-MEC were effective in mammospheres or two-dimensional cultures of mammary epithelium, indicating the indispensability of epithelial-stromal interaction in PI-MEC activation. Like PI-MEC, lacZ(+) cells from virgin explants proliferated and contributed progeny to mammospheres in vitro and to epithelial outgrowths in vivo after transplantation. LacZ(+) cells induced in virgin mouse mammary explants were multipotent (like PI-MEC) in impregnated hosts producing lacZ(+) mammary alveolar structures comprised of both myoepithelial and luminal progeny. These data demonstrate PI-MEC, a mammary epithelial sub-population of lobule-limited progenitor cells, are present in nulliparous female mice before parity and, like the PI-MEC observed following parity, are capable of proliferation, self-renewal and the capacity to produce progeny of diverse epithelial cell fates.

Decidual prolactin silences the expression of genes detrimental to pregnancy.

Abstract: Although the main role of prolactin (PRL) in pregnant rodents is to sustain progesterone production by the corpus luteum, progesterone treatment of PRL or PRL receptor (PRL-R) null mice is unable to prevent fetal loss. We have previously shown that the rat decidua is a site of PRL production and action. In this report, we examined the hypothesis, using PRL null mice and rat decidual cell culture, that the absence of this hormone leads to the expression in the decidua of genes detrimental to pregnancy. The results show that decidual growth is normal in PRL null mice treated with PRL, progesterone, or their combination. However, the decidua of mice treated with progesterone starts expressing IL-6 and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), two proteins absent from the decidua of wild-type mice and involved, respectively, in inflammation and progesterone catabolism. The expression of both IL-6 and 20alpha-HSD is prevented by PRL treatment. Our results further suggest that PRL inhibition of 20alpha-HSD expression is at the level of transcription and that decidual PRL (dPRL) inhibits 20alpha-HSD promoter activity. Inhibitors of Janus kinase 2 (Jak2) but not other kinases prevent dPRL down-regulation of the 20alpha-HSD promoter. Furthermore, cotransfection of the 20alpha-HSD promoter with expression vectors of constitutively active PRL-R, Jak2, or signal transducer and activator of transcription 5b (Stat5b) leads to substantial inhibition of promoter activity. Taken together, our investigation provides an explanation for the inability of progesterone to sustain pregnancy in PRL null mice and suggests that dPRL plays an important role in pregnancy by repressing the expression of IL-6 and 20alpha-HSD in the decidua. The study also demonstrates that PRL signals through the Jak2/Stat5 pathway to down-regulate 20alpha-HSD expression in the decidua.

Impact of proestrous milieu on expression of orexin receptors and prepro-orexin in rat hypothalamus and hypophysis: actions of Cetrorelix and Nembutal

Abstract: Orexins and their receptors OX1 and OX2 regulate energy balance and the sleep-wake cycle. We studied the expression of prepro-orexin (PPO), OX1, and OX2 in brain and pituitary under the influence of the hormonal status in adult rats. Primarily, PPO, OX1, and OX2 expression was determined in Sprague-Dawley female cycling rats during proestrus and in males. Animals were killed at 2-h intervals. Anterior (AH) and mediobasal (MBH) hypothalamus, anterior pituitary (P), and frontoparietal cortex (CC) were homogenized in TRIzol, and mRNAs were obtained for screening of PPO, OX1, OX2 expression by semiquantitative RT-PCR. Main findings were confirmed and extended to all days of the cycle by quantitative real-time RT-PCR. Hormones and food consumption were determined. Finally, OX1, OX2, and PPO were measured by real-time RT-PCR in tissues collected at 1900 of proestrus after treatments at 1400 with ovulation-blocking agents Cetrorelix or pentobarbital. OX1 and OX2 expression increased at least threefold in AH, MBH, and P, but not in CC, between 1700 and 2300 of proestrus, without variations in estrus, diestrus, or in males. PPO in AH and MBH showed a fourfold or higher increase only during proestrus afternoon. Cetrorelix or pentobarbital prevented increases of OX1 and OX2 only in the pituitary and blunted gonadotropin surges, but left OX1, OX2, and PPO brain expression unchanged. Reproduction, energy balance, and sleep-wake cycle are integrated. Here, we demonstrate that, in the physiological neuroendocrine condition leading to ovulation, information to the orexinergic system acts in hypothalamus and pituitary by different mechanisms.

Prolactin induces regional vasoconstriction through the beta2-adrenergic and nitric oxide mechanisms.

Abstract: Prolactin has been associated with many effects and has been implicated in the pathogenesis of pregnancy-related hypertensive disorders, although little is known about its vascular effects. The present study was designed to determine the primary effect of prolactin on regional vascular beds and the mechanisms involved. In 37 anesthetized pigs, the infusion of 0.17 μg/kg·min of prolactin at constant heart rate and arterial pressure decreased coronary, mesenteric, renal, and iliac blood flow. This response was graded in further five pigs by increasing the infused dose of the hormone between 0.017 and 1 μg/kg·min. In 22 of the 37 pigs, blockade of cholinergic receptors (five pigs) and of α-adrenoceptors (five pigs) did not affect the prolactin-induced vascular response, which was abolished by blockade of β2-adrenoceptors (five pigs) and by blockade of vascular nitric oxide (NO) synthase (seven pigs). In 15 of the 37 pigs the increases in measured blood flows caused by iv infusion of isoproterenol (five pigs)...