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PubMed1991

Identification and immunochemical characterization of a major placental secretory protein related to the prolactin-growth hormone family, prolactin-like protein-C.

Trophoblast cells of the rat chorioallantoic placenta synthesize and secrete a number of proteins structurally related to pituitary PRL. During the purification of one member of the placental PRL family, PRL-like protein-A (PLP-A), we identified a major contaminating protein with a similar mol wt but possessing a more acidic pI (5.9-6.1) and different immunoreactivities. After isolation by two-dimensional gel electrophoresis, the more acidic contaminating protein was electroeluted, and its N-terminal amino acid sequence was determined by gas phase sequencing. The N-terminal sequence showed considerable homology with members of the PRL family, including characteristic positioning of cysteine residues at amino acids 4 and 11. The newly identified protein species have been termed PLP-C based on their structural similarity with pituitary PRL. The protein was further characterized by the generation of specific immunological probes. Antibodies were generated to electrophoretically purified protein and to a chemically synthesized peptide representing amino acids 11-32 of its N-terminal sequence. Each antiserum specifically recognized two major species migrating at approximately 25 and 29 kDa, respectively. The 29-kDa species specifically bound to Concanavalin-A, while the 25-kDa species failed to bind to the lectin. Furthermore, the 29-kDa species could be converted to the 25-kDa species by enzymatic deglycosylation. The antisera have also been used to examine the cell- and temporal-specific patterns of expression. The immunoreactive protein species (25 and 29 kDa) were localized primarily to spongiotrophoblast cells present in the junctional zone of the chorioallantoic placenta. Expression was initiated after midgestation and increased during the remaining part of gestation. In summary, PLP-C is a major secretory protein produced by spongiotrophoblast cells during the second half of gestation.

Animals↗
PubMedDate not supplied

Hormonal regulation of prolactin storage in a clonal strain of rat pituitary tumor cells.

GH4C1 cells (GH cells) are a clonal strain of rat pituitary tumor cells which secrete prolactin. GH cells have been used to study hormone secretion, but they store relatively little prolactin compared to normal prolactin-secreting cells. They are not suitable, therefore, for studying some aspects of pituitary function. We have found that the amount of prolactin GH cells store can be regulated. When GH cells were plated at 10(6) cells/well and treated for six days with 180 nM insulin or 1 nM estradiol, there was a 60 percent increase in prolactin storage compared to control cells. Insulin and estradiol in combination acted synergistically to cause a 190 percent increase in prolactin storage. In contrast, they were additive in increasing extracellular prolactin; there was a 40 percent increase in extracellular prolactin after insulin, a 20 percent increase after estradiol, and a 50 percent increase after insulin plus estradiol. The increases in prolactin storage were always greater than the increases in extracellular prolactin. The increases in prolactin storage were dose-dependent and reached maximal levels after four days of treatment with 180 nM insulin plus 1 nM estradiol. Reducing the plating density to 10(3) cells/well increased the response to insulin and estradiol to nineteenfold. Epidermal growth factor (10 nM) acted synergistically with estradiol and insulin in combination to increase prolactin storage 27-fold. The insulin- and estradiol-induced increase in extracellular prolactin was caused by a specific increase in the rate of prolactin synthesis. The fractional increase in prolactin storage above the increase in prolactin production could not be explained by an increase in prolactin synthesis, an increase in intracellular transit time, or a change in the cell-cycle distribution of the population. Hormone storage can, therefore, be regulated independently from other processes which control hormone production. The prolactin stored in response to insulin and estradiol was releasable by potassium depolarization. Following depletion of intracellular prolactin by depolarization, the cells retained their increased capacity for prolactin storage. The ability to increase prolactin storage will make GH cells a more useful system in which to study pituitary function.

Animals↗
PubMed2001

Ectopic production of prolactin by colorectal adenocarcinoma.

PURPOSE: This study assessed the role of prolactin in patients with Dukes B and C colorectal carcinoma. METHODS: Circulating prolactin and carcinoembryonic antigen were assayed using immunoradiometric assay and radioimmunoassay kits, respectively, in preoperative blood (n = 98) and tumor-draining venous blood (n = 34) samples of colorectal carcinoma patients. Immunohistochemical localization of prolactin (n = 98), carcinoembryonic antigen (n = 98), and prolactin receptors (n = 56) was performed. The expression of prolactin messenger ribonucleic acid (n = 50) and prolactin receptor messenger ribonucleic acid (n = 50) was studied by reverse transcriptase polymerase chain reaction. Further, prolactin amplimer was sequenced. RESULTS: Preoperative prolactin and carcinoembryonic antigen levels were significantly higher in patients with colorectal carcinoma than in controls (prolactin, P = 0.001; carcinoembryonic antigen, P = 0.0001). Univariate survival analysis showed that Dukes stage, histologic grade, and circulating prolactin were significant prognostic factors for determining overall survival (Dukes stage, P = 0.00001; histologic grade, P = 0.005; prolactin, P = 0.001). In multivariate analysis, besides Dukes stage, circulating prolactin emerged as the most significant independent prognostic factor influencing overall survival. Preoperative prolactin levels showed excellent significant correlation with response to therapy and progression of disease. A significant tenfold higher mean concentration of prolactin was observed in tumor-draining venous blood than in peripheral blood (P = 0.0001). Diffuse cytoplasmic staining for prolactin was seen in 51 percent (50/98) of the colorectal carcinomas. Prolactin messenger ribonucleic acid expression was seen in 88 percent (44/50) of the colorectal carcinomas. Sequence analysis of the 234-bp prolactin amplimer revealed that the sequence was homologous to exon 5 of pituitary prolactin messenger ribonucleic acid. CONCLUSION: These multiple approaches confirmed that prolactin is produced by colorectal carcinoma cells. Looking at its prognostic value and correlation with disease activity, it may provide new insights into treatment for patients with colorectal carcinoma.

Adenocarcinoma↗
PubMed1991

Endometrial prolactin and implantation.

The role of prolactin in human implantation and human endometrial function is still unclear. Synthesis of prolactin from human endometrium and decidua was first demonstrated in 1977. Prolactin mRNA isolation from term decidua subsequently confirmed expression of the prolactin gene in human endometrium. More recently, a glycosylated form of prolactin has been isolated from both the human pituitary and human endometrium. It appears that predominately glycosylated prolactin is secreted in the late luteal phase of the menstrual cycle, with increasingly greater amounts of non-glycosylated prolactin secreted as pregnancy advances. The biological significance and regulation of prolactin glycosylation is uncertain, although glycosylated ovine prolactin has only 20-33% of the lactogenic activity of ovine prolactin. Pituitary lactotropes, of ectodermal origin, produce pituitary prolactin and are regulated by dopamine, oestradiol and thyrotropin releasing hormone. Decidual cells, of mesodermal origin, are not influenced by these pituitary secretogogues. Progesterone and calcium both appear to stimulate pituitary and decidual prolactin secretion, while arachidonic acid seems to inhibit decidual prolactin release. More recently, insulin like growth factor-1, a polypeptide growth factor implicated in the oestrogen promoted growth reproductive tissues, has been found in high concentration in the pig uterus and has been shown to stimulate the synthesis and secretion of prolactin from human decidua. Prolactin receptors have not been reported on endothelium of blood vessels and no clear evidence exists that endometrial prolactin may modulate the secretion of endothelin, endothelium derived relaxing factor or other potentially important substances controlling menstruation. Prolactin does appear necessary for the normal production of macrophage activating factors, including interferon, and may have a local immunomodulatory role upon human implantation for this reason. Human alpha 2-interferon has sequence homology to ovine trophoblast protein-1 and is found in high concentration in human pregnancy and fetal tissues. There is some evidence that interferon may reduce human endometrial prolactin secretion, but whether endometrial or decidual prolactin is critical to human implantation awaits further study.

Animals↗
PubMed1977

Neuroendocrine control of prolactin in experimental animals.

Hypothalamic regulation of prolactin secretion in animals (mammals) and man appears to be similar, and no significant differences have yet been demonstrated. The hypothalamus contains neurotransmitters and polypeptides that can either inhibit or stimulate prolactin release, although the predominant influence under basal conditions is to inhibit prolactin release. Thus pituitary stalk section or placement of lesions in the basal tuberal region of the hypothalamus results in increased prolactin release and sometimes in initiation of lactation. Among agents in the hypothalamus that can inhibit prolactin release, the most important appear to be an as yet unidentified polypeptide prolactin release inhibiting factor (PIF) and dopamine. There is some evidence that dopamine may account for most, if not all, of the prolactin release inhibiting activity of the hypothalamus. Agents that increase dopamine activity, i.e. L-dopa, monoamine oxidase inhibitors, etc., depress prolactin release. Acetylcholine also can inhibit prolactin release, but it appears to act via the catecholamines. Of the agents in the hypothalamus that stimulate prolactin release, the most important appear to be an as yet uncharacterized polypeptide prolactin releasing factor (PRF), thyrotropin releasing hormone (TRH) and serotonin. TRH is as effective in releasing prolactin as in releasing TSH, but under most physiological states, TSH and prolactin release do not occur together. Serotonin and its precursors, tryptophan and 5-hydroxytryptophan, are powerful releasors of prolactin and have been shown to be involved in some physiological states in which prolactin is released, i.e. during suckling, stress, etc. Other agents in the hypothalamus that can stimulate prolactin release include GABA and some prostaglandins, but these have not yet been shown to be involved in physiological control of prolactin secretion. Exteroceptive stimuli that alter prolactin release act through the CNS and hypothalamus, but some hormones and drugs also can act directly on the pituitary to promote or depress prolactin release.

Acetylcholine↗
PubMed2001

Nuclear translocation of STAT5 and increased expression of Fos related antigens (FRAs) in hypothalamic dopaminergic neurons after prolactin administration.

Ample evidence indicates feedback relationships between pituitary prolactin and hypothalamic dopaminergic neurons. Since the presence of prolactin receptors was earlier demonstrated in hypothalamic dopaminergic neurons, our working hypothesis was that prolactin induced activation of prolactin receptor coupled signaling leads to increased neuronal activity in these neurons. The aim of this study was to correlate prolactin receptor mediated signaling and prolactin induced activation in hypothalamic dopaminergic neurons. We used nuclear translocation of STAT5 as a marker of prolactin receptor induced signaling and expression of Fos related antigens (FRAs) as an indicator of neuronal activation. We performed double label immunocytochemical studies to determine the time course of the presence of FRAs and STAT5 in the nuclei of hypothalamic dopaminergic neurons after ovine prolactin treatment. Exogenous ovine prolactin treatment of ovariectomized rats resulted in an increase in serum ovine prolactin levels and a decrease in endogenous serum prolactin levels, indicating that ovine prolactin activated mechanisms inhibited pituitary prolactin secretion. Indeed, ovine prolactin activated the prolactin receptors in most subpopulations of hypothalamic dopaminergic neurons, resulting in nuclear translocation of STAT5. Also, increased neuronal activity, indicated by expression of FRAs, was observed in the same neuron populations after ovine prolactin treatment. These results suggest that signal transduction mechanisms coupled to prolactin receptors in hypothalamic dopaminergic neurons resemble those observed in other tissues; and nuclear translocation of STAT5 can be used as a marker of prolactin receptor activation in hypothalamic dopaminergic neurons.

Active Transport, Cell Nucleus↗
PubMed1990

Comparisons of glycosylated and nonglycosylated amniotic fluid prolactins in normal second- and third-trimester pregnancies.

Prolactins in glycosylated and nonglycosylated form were isolated from 218 second- and third-trimester amniotic fluid samples by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, electrotransferred to nitrocellulose paper, and probed with anti-human prolactin serum and protein A labeled with iodine 125. The glycosylated and nonglycosylated prolactin bands were exposed by autoradiography. The bands were analyzed by densitometry, and the ratio of glycosylated to total (glycosylated + nonglycosylated) prolactin was calculated (glycosylated/total ratio) and compared with matched prolactin radioimmunoassay measurements. Both radioimmunoassay-measured and nonglycosylated prolactin decreased from the second to the third trimester whereas glycosylated prolactin concentrations remained unchanged. Concomitantly, glycosylated/total prolactin ratios increased significantly (p less than 0.001). The correlation of radioimmunoassay-measured prolactin was closer to nonglycosylated prolactin (r2 = 0.32, p = 0.00001) than to glycosylated prolactin (r2 = 0.02, p = 0.06). We suggest that the proportion of amniotic fluid glycosylated prolactin increases with length of gestation and that glycosylation of prolactin is inversely related to total prolactin secretion. Furthermore, prolactin's immunoreactivity correlated more closely to the nonglycosylated-prolactin variant, suggesting that radioimmunoassay of prolactin poorly recognizes the glycosylated prolactin form.

Amniotic Fluid↗
PubMed1968

Radioimmunoassay for ovine, caprine and bovine prolactin in plasma and tissue extracts.

1. A radioimmunoassay for ovine prolactin is described based on the inhibition of the reaction between (131)I-labelled ovine prolactin and guinea-pig or rabbit antiserum to ovine prolactin. The extent of the reaction after a 4-day incubation period is determined by chromatoelectrophoresis or by adsorption of unchanged (131)I-labelled ovine prolactin on charcoal. The sensitivity is equal to 5.9ng. of prolactin/ml. of plasma with chromatoelectrophoresis, or 0.2ng. of prolactin/ml. of tissue extracts with the charcoal separation. 2. A complete cross-reaction demonstrated between ovine prolactin and caprine pituitary extracts allows the assay to be used to measure caprine prolactin. The partial cross-reactions between ovine prolactin and bovine prolactin and between ovine prolactin and bovine pituitary extract differ, and an alteration in the immunological activity of bovine prolactin during its isolation is suggested. Bovine prolactin in plasma may be measured against a bovine pituitary extract as standard. No cross-reactions were demonstrated with pituitary extracts from a number of other species. The extent of the contamination of ovine and bovine growth hormone preparations by their respective prolactins is shown. 3. Dilutions of ovine and caprine plasma inhibit the reaction between (131)I-labelled ovine prolactin and antiserum with the same characteristics as ovine prolactin. 4. The immunoreactive material in plasma fractionates on Sephadex G-200 and in sucrose density gradients as a single peak similar to that shown by freshly dissolved ovine prolactin. There is no evidence that ovine prolactin is bound to a plasma protein. 5. By suppressing prolactin secretion and assaying serial samples of plasma thereafter it is shown that the immunological activity of the surviving hormone becomes progressively altered with time. It is suggested that this alteration is usually not detected but introduces an element of uncertainty into the quantitative but not the qualitative value of the measurements obtained by reference to standard ovine prolactin.

Adsorption↗
PubMed1995

Role of nitric oxide in control of prolactin release by the adenohypophysis.

Nitric oxide synthase-containing cells were visualized in the anterior pituitary gland by immunocytochemistry. Consequently, we began an evaluation of the possible role of NO in the control of anterior pituitary function. Prolactin is normally under inhibitory hypothalamic control, and in vitro the gland secretes large quantities of the hormone. When hemipituitaries were incubated for 30 min in the presence of sodium nitroprusside, a releaser of NO, prolactin release was inhibited. This suppression was completely blocked by the scavenger of NO, hemoglobin. Analogs of arginine, such as NG-monomethyl-L-arginine (NMMA, where NG is the terminal guanidino nitrogen) and nitroarginine methyl ester, inhibit NO synthase. Incubation of hemipituitaries with either of these compounds significantly increased prolactin release. Since in other tissues most of the actions of NO are mediated by activation of soluble guanylate cyclase with the formation of cyclic GMP, we evaluated the effects of cyclic GMP on prolactin release. Cyclic GMP (10 mM) produced an approximately 40% reduction in prolactin release. Prolactin release in vivo and in vitro can be stimulated by several peptides, which include vasoactive intestinal polypeptide and substance P. Consequently, we evaluated the possible role of NO in these stimulations by incubating the glands in the presence of either of these peptides alone or in combination with NMMA. In the case of vasoactive intestinal polypeptide, the significant stimulation of prolactin release was augmented by NMMA to give an additive effect. In the case of substance P, there was a smaller but significant release of prolactin that was not significantly augmented by NMMA. We conclude that NO has little effect on the stimulatory action of these two peptides on prolactin release. Dopamine (0.1 microM), an inhibitor of prolactin release, reduced prolactin release, and this inhibitory action was significantly blocked by either hemoglobin (20 micrograms/ml) or NMMA and was completely blocked by 1 mM nitroarginine methyl ester. Atrial natriuretic factor at 1 microM also reduced prolactin release, and its action was completely blocked by NMMA. In contrast to these results with prolactin, luteinizing hormone (LH) was measured in the same medium in which the effect of nitroprusside was tested on prolactin release, there was no effect of nitroprusside, hemoglobin, or the combination of nitroprusside and hemoglobin on luteinizing hormone release. Therefore, in contrast to its inhibitory action on prolactin release NO had no effect on luteinizing hormone release. Immunocytochemical studies by others have shown that NO synthase is present in the folliculostellate cells and also the gonadotrophs of the pituitary gland. We conclude that NO produced by either of these cell types may diffuse to the lactotropes, where it can inhibit prolactin release. NO appears to play little role in the prolactin-releasing action of vasoactive intestinal polypeptide and substance P, but mediates the prolactin-inhibiting activity of dopamine and atrial natriuretic factor.

Amino Acid Oxidoreductases↗
PubMed2006

Reproductive experience increases prolactin responsiveness in the medial preoptic area and arcuate nucleus of female rats.

The experience of pregnancy plus lactation produces long-term enhancements in maternal behavior as well as reduced secretion of prolactin, a key hormone for the initial establishment of maternal care. Given that prolactin acts centrally to induce maternal care as well as regulate its own secretion, we tested whether prolactin receptors in brain regions known to regulate behavioral and neuroendocrine processes were up-regulated and more responsive to prolactin in reproductively experienced females. Diestrous primiparous (8 wk after weaning) and age-matched virgin rats were treated with 250 microg ovine prolactin sc or vehicle and the brains collected 2 h later for measurement of mRNA for genes involved in prolactin signaling. Reproductively experienced rats had lower serum prolactin concentrations, compared with virgin rats, suggesting enhanced prolactin feedback on the arcuate neurons regulating prolactin secretion. In the medial preoptic area and arcuate nucleus (regions involved in regulating maternal behavior and prolactin secretion, respectively), the level of long-form prolactin receptor mRNA was higher in primiparous rats, and prolactin treatment induced a further increase in receptor expression in these animals. In the same regions, suppressors of cytokine signaling-1 and -3 mRNA levels were also markedly increased after prolactin treatment in reproductively experienced but not virgin rats. These results support the idea that reproductive experience increases central prolactin responsiveness. The induction of prolactin receptors and enhanced prolactin responsiveness as a result of pregnancy and lactation may help account for the retention of maternal behavior and shifts in prolactin secretion in reproductively experienced females.

Animals↗
PubMed1997

Natural and photoperiodically induced changes in plasma prolactin levels in male great tits.

Plasma levels of prolactin showed a pronounced annual cycle in free-living male great tits (Parus major). During the period from August to April, levels were very low. Prolactin levels started to increase in mid-April, and maximal levels were reached in June. By mid-July prolactin levels had decreased to near basal levels. The exact breeding stage was known for all males captured during the breeding period, and prolactin levels increased continuously from the period of territorial defense to the nestling period. Males were exposed to different light regimes at three different times of the year (late August, late November, and early March). Males exposed to 14L:10D (14 h light:10 h darkness) and 20L:4D showed pronounced prolactin cycles at all times of the year, but the patterns differed markedly with the season. In November the 20L:4D and the 14L:10D prolactin patterns differed markedly from each other. In the 20L:4D group prolactin levels started to increase before testes had reached maximal size, whereas in the 14L:10D group prolactin levels did not start to increase until testes were almost completely regressed. In early March the prolactin pattern of change over time was the same for great tits kept on 20L:4D and 14L:10D. In both cases prolactin levels increased during the testicular growth period, and prolactin levels were maximal during the period of spermatogenesis. Prolactin levels did not change over time in males kept on 8L:16D in August and November. Males exposed to short days in early March showed a significant increase in prolactin levels about 3 weeks after the onset of the experiment. Plasma levels of prolactin in males castrated in late November and exposed to a 20L:4D light regime did not differ from those in intact males. In castrated males given a testosterone implant prolactin levels immediately increased to significantly higher levels than those observed in intact or castrated males. Prolactin levels remained significantly higher in the testosterone implanted males for about a month. In one group of castrated birds the testosterone implant was removed 13 days after the onset of the experiment. This removal resulted in a significant decrease in circulating levels of prolactin.

Animals↗
PubMed2006

Increasing ornithine decarboxylase activity is another way of prolactin preventing methotrexate-induced apoptosis: crosstalk between ODC and BCL-2.

Prolactin has more than 300 separate functions including affecting mammary growth, differentiation, secretion and anti-apoptosis. In the previous studies, prolactin induced Bcl-2 expression to prevent apoptosis and also provoked the activity of ornithine decarboxylase (ODC). Our previous data showed that ODC overexpression upregulates Bcl-2 and prevents tumor necrosis factor alpha (TNF-alpha)- and methotrexate (MTX)-induced apoptosis. Here, we further investigate whether prolactin prevents MTX-induced apoptosis through inducing ODC activity and the relationship between ODC and Bcl-2 upon prolactin stimulation. Prolactin prevented MTX-induced apoptosis in a dose-dependent manner in HL-60 cells. Following prolactin stimulation, ODC enzyme activity also shows an increase in a dose-dependent manner, expressing its maximum level at 3 h, and rapidly declining thereafter. Prolactin-induced ODC activity is completely blocked by a protein kinase C delta (PKCdelta) inhibitor, rottlerin. However, there are no changes in the expressions of ODC mRNA and protein level after prolactin stimulus. It indicates that prolactin may induce ODC activity through the PCKdelta pathway. Besides, Bcl-2 expresses within 1 h of prolactin treatment and this initiating effect of prolactin is not inhibited by alpha-difluoromethylornithine (DFMO). However, Bcl-2 is further enhanced following prolactin stimulation for 4 h and this enhancement is blocked by DFMO. Bcl-2 has no effect on ODC activity and protein levels, but ODC upregulates Bcl-2, which is inhibited by DFMO. Overall, there are two different forms of prolactin effect, it induces Bcl-2 primarily, and following this it stimulates ODC activity. Consequently induced ODC activity further enhances the expression of Bcl-2. The anti-apoptotic effect of prolactin is diminished by DFMO and recovered by putrescine. Obviously, ODC activity is one basis for the anti-apoptotic mechanisms of prolactin. A Bcl-2 inhibitor, HA14-1, together with DFMO, completely blocks the anti-apoptotic effects of prolactin. These results suggest that increasing ODC activity is another way of prolactin preventing MTX-induced apoptosis and that this induction of ODC activity enhances the expression of Bcl-2 strongly enough to bring about the anti-apoptotic function.

Apoptosis↗
PubMed1999

Participation of the opioid system in the regulation of prolactin secretion in androgenized rats: effect of ovarian steroids.

We examined the role of the opioid system on the regulation of prolactin secretion in neonatally androgenized rats and evaluated the participation of ovarian steroids in this regulation. Androgenized rats exhibited an increase of prolactin secretion with higher serum circulating levels in the afternoon (1800) than in the morning (1000). The administration of the opioid antagonist naloxone (2 mg/kg, 30 min before decapitation) reduced serum prolactin levels in both groups. To identify the opioid receptor subtypes involved in this regulation, opioid agonists were administered i.c.v. 15 min before the decapitation (1000). The mu-opioid receptor agonist DAMGO ([D-Ala2, NMe-Phe4, Gly5-ol]-enkephalin) caused a significant increase in serum prolactin concentration. The selective kappa-opioid receptor agonist U-50, 488H (trans-(+/-)-3,4-dichloro-N-[2(1-pyrrolidinyl)-cyclohexyl]-benzene acetamide methane sulfonate salt) induced a small but significant increase in serum prolactin levels but no effect was observed after administration of the delta-opioid agonist DPDPE ([D-Pen2, D-Pen5]-enkephalin). The role of oestradiol and the opioid system in the continuous secretion of prolactin was also study. Chronic gonadectomy (3-4 weeks) reduced serum prolactin concentrations measured at 1000 but the administration of naloxone had no effect. Three days of oestrogen treatment (2 microg/rat in oil) restored serum prolactin levels compared with ovariectomized animals and this effect was abolished by naloxone treatment. Interestingly, acute ovariectomy or administration of tamoxifen to intact androgenized rats did not prevent the continuous secretion of prolactin observed in these animals and naloxone treatment reduced serum prolactin levels in both groups of rats. We also examine the participation of adrenal progesterone and the endogenous opioid peptides on the regulation of prolactin levels in androgenized rats. After adrenalectomy, no changes in serum prolactin levels (1000) were observed compared with the control animal and naloxone treatment significantly reduced circulating prolactin levels. Progesterone treatment to intact androgenized rats significantly increased prolactin levels and the administration of naloxone blocked the stimulatory effect of the steroid. These results suggest that the opioid system play a role in the regulation of prolactin secretion in androgenized rats modulated by the persistence of oestrogen action. Moreover, the presence or absence of progesterone did not modify the regulation of prolactin secretion by the opioids. The mu- and kappa-opioid receptor subtypes are the ones involved in the modulation of pituitary prolactin secretion.

Androgens↗
PubMed1986

Hypothalamic prolactin: characterization by radioimmunoassay and bioassay and response to hypophysectomy and restraint stress.

Prompted by immunohistochemical reports of prolactin-like immunoreactivity in cell bodies within the rat hypothalamus, a study was undertaken to quantitate the immunologic and biologic activity of this material. Hypothalamic concentrations of prolactin-like immunoreactivity averaged 402 +/- 23 pg/mg of protein (n = 30). 97% recovery of rat prolactin standards added to homogenates of hypothalamus insured that neuronal tissue, as prepared for these studies, did not interfere with the radioimmunoassay of rat prolactin. Examination of the elution profile from Sephadex G-75 columns of the prolactin-like immunoreactivity in hypothalamic extracts showed that the majority of hypothalamic prolactin-like substance was of a larger molecular size than pituitary prolactin. While increasing amounts of brain extract progressively displaced more I125 prolactin from antibody-binding sites, the displacement curve produced by adding hypothalamic extract was not parallel to that produced by the addition of increasing amounts of anterior pituitary prolactin standards of rat origin. Hypothalamic extracts from hypophysectomized animals, analyzed for biologic activity in the Nb2 lymphoma cell assay, revealed prolactin-like bioactivity, but the bioactivity/immunoactivity (B/I) ratios for hypothalamic extracts were significantly lower than the B/I ratios for pituitary prolactin (0.71 +/- 0.04 for pituitary, vs. 0.19 +/- 0.06 in the hypothalamus; p less than 0.001). Hypophysectomy, which led to the expected fall in serum prolactin to undetectable levels, and restraint stress, which resulted in a statistically significant 4-fold rise in serum prolactin, caused no change in prolactin concentrations in the hypothalamus, indicating that brain prolactin-like substance is regulated independently of pituitary prolactin and circulating serum prolactin levels.

Animals↗
PubMed2001

The actions of prolactin in the brain during pregnancy and lactation.

The vital role played by prolactin during pregnancy and lactation is emphasized by the physiological adaptations that occur in the mother to maintain a prolonged state of hyperprolactinemia. In many species the placenta provides a source of lactogenic hormones in the circulation, ensuring the continued presence of a hormone capable of activating the prolactin receptor throughout pregnancy. In addition, the tuberoinfundibular dopamine neurons, which normally maintain a tonic inhibitory influence over prolactin secretion, show a reduced ability to respond to prolactin during late pregnancy and lactation, allowing high levels of prolactin to be maintained unopposed by a regulatory feedback mechanisms. There is clear evidence that systemic prolactin gains access to the cerebrospinal fluid, from where it can diffuse to numerous brain regions. Prolactin receptors are expressed in several hypothalamic nuclei, including the medial preoptic and arcuate nuclei, and we have observed marked increases in expression of prolactin receptors in these nuclei during lactation. Moreover, a number of hypothalamic nuclei, including the paraventricular, supraoptic and ventromedial nuclei, in which prolactin receptors were not detected in diestrous rats, were found to express significant amounts of prolactin receptor during lactation. These observations have important implications for the variety of documented actions of prolactin on the brain. Prolactin has been reported to influence numerous brain functions, including maternal behavior, feeding and appetite, oxytocin secretion, and ACTH secretion in response to stress. In light of the high circulating levels of prolactin during pregnancy and lactation and the increased expression of prolactin receptors in the hypothalamus, many of these effects of prolactin may be enhanced or exaggerated during lactation. Hence, prolactin may be a key player in the coordination of neuroendocrine and behavioral adaptations of the maternal brain.

Animals↗
PubMed1999

Effects of TGF-beta1 on prolactin synthesis and secretion: an in-vitro study.

The hypothalamus exerts a predominantly inhibitory influence on prolactin secretion through dopamine. In addition, the expression of anterior pituitary hormone-gene products are regulated by intrapituitary growth factors. In particular, TGF-beta1 produced in the pituitary regulates lactotroph cell proliferation and prolactin gene-expression. This study characterized the regulation of in-vitro prolactin synthesis and secretion by TGF-beta1 using rat anterior pituitary cells in monolayer culture. Furthermore, we studied the interaction of TGF-beta1 with other signals involved in the neuroregulation of prolactin secretion, such as dopamine and TRH, as well as the importance of different signal transduction pathways in this response. TGF-beta1 inhibited prolactin secretion in a time- and concentration-dependent manner, with half-maximal inhibition occurring at the range of 15-30 pM. The inhibitory effect was observed after 4 h, being maximal after 4 days of exposure of the cells to the peptide. This inhibitory effect was mimicked by TGF-beta2 but not by inhibin, and was not influenced by oestrogens, being similar in male, normal female or oestradiol-treated rats. Prolonged pretreatment of the cells with TGF-beta1(4 days) did not modify GH or TSH secretion nor dopamine-induced inhibition of prolactin secretion, and blunted prolactin responses to TRH, Forskolin, But2-cAMP and to the calcium ionophore A23187. The effect observed after long-term treatment (24 h to 4 days) is essentially caused by a decrease in prolactin synthesis, since TGF-beta1 inhibited prolactin mRNA levels and de novo prolactin protein synthesis. However, in the short term (up to 12 h) TGF-beta1 inhibition of prolactin secretion was associated with an increase in intracellular prolactin content, dissecting a dual mechanism of action of TGF-beta1. The short-term TGF-beta1 effect did not modify Erk-2 phosphorylation, basal or TRH-induced increase in intracellular calcium concentration, but blunted basal and forskolin stimulated cAMP levels. But2-cAMP replacement did not revert the inhibition of prolactin secretion. However, pertussis toxin was able to recover a large percentage of TGF-beta1-induced inhibition of prolactin secretion. This study indicates that TGF-beta1 plays a crucial role as a modulator of lactotroph function, inhibiting prolactin biosynthesis after long-term treatment, as well as, after short-term exposure prolactin secretion at the level of the secretory process, through a mechanism pertussis toxin sensitive but independent of Erk-2 phosphorylation, calcium concentrations or intracellular cAMP.

Animals↗
PubMed1992

Seasonal prolactin secretion and its role in seasonal reproduction: a review.

The majority of seasonally breeding mammals show a seasonal pattern of prolactin secretion with peak concentrations in spring or summer and a nadir in autumn or winter. Photoperiod influences prolactin secretion via its effects on the secretion of the pineal hormone melatonin. Preliminary evidence suggests that the effects of melatonin on both prolactin and gonadotrophin secretion are via a common target area, possibly within the anterior hypothalamus, and that differences in response to photoperiod may be due to differences in the processing and/or interpretation of the melatonin signal. In contrast to seasonal gonadotrophin secretion, the seasonal changes in prolactin are not due to changes in the sensitivity of a feedback loop and so must be due to direct effects on the hypothalamic pathways that control prolactin secretion. Little else can be said with confidence about the neuroendocrine mechanisms that lead to the seasonal changes in prolactin secretion. Dopamine and noradrenaline turnover in the arcuate nucleus and median eminence decrease under short daylength. If catecholamine turnover in these structures is positively correlated with catecholamine concentrations in the long or short hypophysial portal vessels, it is unlikely that the decrease in prolactin concentration in winter is due to the effects of increased concentrations of dopamine or noradrenaline in the portal vessels. There is, however, evidence for increased pituitary sensitivity to dopamine under short daylength, so increased dopamine concentrations may not be required for suppression of prolactin secretion at this time. In addition to the diminished secretion of prolactin under short daylength, rate of prolactin synthesis and pituitary content of prolactin also decline although the mechanisms that regulate these changes are poorly understood. Although all seasonal breeders show a seasonal change in prolactin secretion, there are continuously breeding species in which prolactin secretion is also under photoperiodic control. It is likely therefore that a seasonal pattern of prolactin secretion is only evidence of neuroendocrine sensitivity to changing photoperiod. Depending upon the species, this sensitivity to the seasonal changes in daylength may or may not be accompanied by seasonal changes in a biological endpoint such as seasonal reproduction or indeed other adaptations. Whether the seasonal change in prolactin secretion is an endocrine mediator of such adaptations remains in contention. Certainly in some species this signal does have a role in reproduction. For example, in species with an obligate seasonal embryonic diapause, the seasonal increase in prolactin can act as a luteotrophin (mink and western spotted skunk) or luteostatin (Bennett's and tammar wallabies.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗