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Neuroendocrinology 2013The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated... (Review)
Review
The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated in this regulation and lately, prolactin (PRL) has been included into that list. However, since PRL is secreted by anterior pituitary lactotropes, the actual outcome of its autocrine/paracrine actions on pituitary cells has remained difficult to assess. The availability of the pure PRL receptor antagonist Del1-9-G129R-hPRL has been helpful to circumvent this problem. While PRL has been traditionally associated with increased cell proliferation, recent studies revealed that this hormone actually induces apoptosis and decreases proliferation of anterior pituitary cells, by mechanisms involving the PRL receptor. The aim of this short review is to overview our current understanding of the regulation of pituitary homeostasis by PRL. Moreover, studies involving Del1-9-G129R-hPRL have helped anticipate to what extent future treatments involving PRL receptor inhibitors may interfere with processes regulated by PRL at the central level.
Topics: Animals; Homeostasis; Humans; Pituitary Gland; Prolactin; Protein Binding; Receptors, Prolactin; Signal Transduction
PubMed: 23969780
DOI: 10.1159/000354701 -
Proceedings of the National Academy of... Jan 1984A modification of prolactin, in which the asparagine at position 31 carries a carbohydrate unit, was isolated from ovine pituitary glands. Sequence and amino acid...
A modification of prolactin, in which the asparagine at position 31 carries a carbohydrate unit, was isolated from ovine pituitary glands. Sequence and amino acid analyses identified the point of linkage of the carbohydrate. Glucosamine was found in acid hydrolysates, an indication that the carbohydrate is attached through N-acetylglucosamine. The glycosylated prolactin binds to concanavalin A and lentil lectin and is eluted with methyl alpha-D-mannopyranoside. During gel electrophoresis in sodium dodecyl sulfate, the glycosylated hormone migrates as a Mr 25,000 protein; prolactin has a Mr of 23,000. The modified prolactin had a potency of 20 international units/mg, approximately equal to 60% the potency of a reference prolactin preparation when measured by the pigeon crop sac assay. In a radioimmunoassay, the glycosylated form had only 34% the immunoreactivity of ovine prolactin.
Topics: Amino Acid Sequence; Animals; Disulfides; Glycoproteins; Molecular Weight; Prolactin; Sheep
PubMed: 6582495
DOI: 10.1073/pnas.81.2.385 -
Journal of Physiology and Pharmacology... Oct 2012Prolactin (PRL) is a hormone mainly secreted by the anterior pituitary. Recent studies have shown that it may also be produced by many extrapituitary cells. The PRL gene... (Review)
Review
Prolactin (PRL) is a hormone mainly secreted by the anterior pituitary. Recent studies have shown that it may also be produced by many extrapituitary cells. The PRL gene expression is controlled by two independent promoter regions, which may be differentially regulated in the pituitary and extrapituitary organs. Proteolytic modifications of PRL generate variants of the hormone. A16 kDa PRL fragment, acting through a specific receptor, has both an antiangiogenic activity as well as an inhibitory effect on tumor growth. Stimulation of the PRL receptor involves many signal transduction pathways, for example JAK2/STAT, MAPK, c-src and Fyn kinase cascade, and these pathways may vary in different tissues. PRL synthesis and secretion is mainly regulated by the inhibitory influence of dopamine but other hormones are also involved in these mechanisms. The essential biological action of PRL is the stimulation of lactogenesis and galactopoesis. Apart from its classical functions, PRL affects other aspects of human body function including osmoregulation, metabolism and regulation of the immune and the central nervous system. Hyperprolactinemia is a common syndrome affecting both men and women. It is manifested by the presence of galactorrhoea and through the symptoms of hypogonadotrophic hypogonadism. Following on from the fact that PRL has so many pleiotropic tissue specific effects it is not surprising to learn that hyperprolactinaemia is a systemic condition which may predispose to numerous cardiovascular and immune-mediated reactions. The exact effects of PRL on both immune and cardiovascular systems are being currently unraveled and may lead to the introduction of novel therapeutic approaches in the future.
Topics: Animals; Cardiovascular Physiological Phenomena; Central Nervous System; Humans; Hyperprolactinemia; Immune System; Prolactin; Receptors, Prolactin
PubMed: 23211297
DOI: No ID Found -
The Journal of Clinical Endocrinology... Jul 2021Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a 2-generation family with 3 women experiencing...
CONTEXT
Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a 2-generation family with 3 women experiencing alactogenesis.
OBJECTIVE
We hypothesized a heterozygous genetic mutation.
METHODS
This was a family-based study. Two generations of women (proband, sister, and niece) with puerperal alactogenesis and one control were studied. Prolactin levels in the 3 women ranged from 0.618 to 1.4 ng/mL (range, 2.8-29.2 ng/mL). All the women had regular menstrual cycles during their reproductive years. The niece required fertility treatment to become pregnant and the proband and sister underwent menopause before age 45 years. Prolactin gene (PRL) exons 1 to 5 were sequenced. We sought a heterozygous, deleterious gene variant with functional consequences.
RESULTS
We identified a heterozygous mutation (c.658C > T) changing CGA to TGA (p.Arg220Ter) in exon 5 of the prolactin gene. Transfection of PRL containing the stop gain mutation resulted in similar intracellular prolactin levels compared to PRL wild type, but little detectable immunoactive or bioactive prolactin in conditioned medium. Prolactin secretion was also impaired by a PRL stop gain mutation deleting both of the terminal cysteine amino acids (c.652A > T; p.Lys218Ter).
CONCLUSION
This is the first report of a PRL mutation causing familial prolactin deficiency and alactogenesis. The loss of the terminal cysteine resulted in failure of prolactin secretion. Secretion was not rescued by deleting the penultimate cysteine, with which it forms a disulfide bond. These data suggest that the PRL C terminal is critical for protein secretion.
Topics: Adult; Aged; Female; Genetic Diseases, Inborn; Humans; Lactation; Lactation Disorders; Menarche; Pedigree; Prolactin
PubMed: 33770166
DOI: 10.1210/clinem/dgab201 -
ESC Heart Failure Feb 2023Peripartum cardiomyopathy (PPCM) is a rare heart disease, occurring in previously heart-healthy women during the last month of pregnancy or the first months after...
AIMS
Peripartum cardiomyopathy (PPCM) is a rare heart disease, occurring in previously heart-healthy women during the last month of pregnancy or the first months after delivery due to left ventricular (LV) systolic dysfunction. A common pathomechanistic pathway of PPCM includes increased oxidative stress and the subsequent generation of a cleaved prolactin fragment (16 kDa PRL), which promotes the onset of heart failure (HF) in a microRNA (miR)-146a-dependent manner. Inhibition of prolactin secretion with the dopamine D2 receptor (D2R) agonist bromocriptine combined with standard HF therapy supports cardiac recovery. This study examined whether treatment with the more selective D2R agonist cabergoline prevents HF development in an experimental PPCM mouse model and might be used as an alternative treatment regime for PPCM.
METHODS AND RESULTS
Postpartum (PP) female PPCM-prone mice with a cardiomyocyte restricted STAT3-deficiency (αMHC-Cre ; Stat3 ; CKO) were treated over two consecutive nursing periods with cabergoline (CKO Cab, 0.5 mg/kg/day) and were compared with bromocriptine treated CKO (CKO Br) and postpartum-matched WT and CKO mice. Cabergoline treatment in CKO PP mice preserved cardiac function [fractional shortening (FS): CKO Cab: 34.5 ± 9.4% vs. CKO: 22.1 ± 9%, P < 0.05] and prevented the development of cardiac hypertrophy, fibrosis, and inflammation as effective as bromocriptine therapy (FS: CKO Br: 33.4 ± 5.6%). The myocardial up-regulation of the PPCM biomarkers plasminogen inhibitor activator 1 (PAI-1) and miR-146a were prevented by both cabergoline and bromocriptine therapy. A small cohort of three PPCM patients from the German PPCM Registry was treated with cabergoline (1 mg per week for 2 weeks, followed by 0.5 mg per week for another 6 weeks) due to a temporary unavailability of bromocriptine. All PPCM patients initially presented with a severely reduced LV ejection fraction (LVEF: 26 ± 2%). However, at 6 months of follow-up, LV function (LVEF: 56 ± 2%) fully recovered in all three PPCM patients, and no adverse events were detected.
CONCLUSIONS
In the experimental PPCM mouse model, the selective D2R agonist cabergoline prevents the onset of postpartum HF similar to bromocriptine. In PPCM patients, cabergoline treatment was safe and effective as all patients fully recovered. Cabergoline might serve as a promising alternative to bromocriptine. However, these findings are based on experimental data and a small case series and thus have to be interpreted with caution and should be validated in a larger clinical trial.
Topics: Pregnancy; Female; Mice; Animals; Bromocriptine; Cabergoline; Peripartum Period; Prolactin; Cardiomyopathies; Heart Failure; Myocytes, Cardiac; Dopamine Agonists; Ventricular Dysfunction, Left; MicroRNAs
PubMed: 36300679
DOI: 10.1002/ehf2.14210 -
Fertility and Sterility Mar 1988Thirty-two patients with ovarian hyperstimulation were randomized to receive bromocriptine or placebo from cycle day 5 onward. Bromocriptine decreased serum and... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Thirty-two patients with ovarian hyperstimulation were randomized to receive bromocriptine or placebo from cycle day 5 onward. Bromocriptine decreased serum and follicular fluid prolactin (PRL), accelerated ovarian follicle growth, increased serum and follicular fluid estradiol, lowered luteal phase progesterone, and shortened the luteal phase length of the cycle. The maximal luteal phase estradiol and progesterone concentrations correlated with each other in the placebo group, but not in the bromocriptine group. These findings indicate that hypoprolactinemia interferes with ovarian function. The unchanged concentrations of gonadotropic hormones and pattern of luteinizing hormone pulsation during bromocriptine suggest direct ovarian effects of hypoprolactinemia. Because PRL suppression enhanced follicular responses and inhibited corpus luteum formation and function, the follicular and corpus luteum actions of PRL may be different.
Topics: Adult; Bromocriptine; Female; Humans; Menstrual Cycle; Ovarian Follicle; Ovary; Prolactin
PubMed: 3342895
DOI: No ID Found -
Cells Feb 2021Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is...
Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is known to rescue immature B cells from B cell receptor engagement-induced apoptosis in lupus-prone mice. The objective of this study was to characterize in vitro prolactin signaling in immature B cells, using sorting, PCR array, RT-PCR, flow cytometry, and chromatin immunoprecipitation. We found that all B cell maturation stages in bone marrow express the prolactin receptor long isoform, in both wild-type and MRL/lpr mice, but its expression increased only in the immature B cells of the latter, particularly at the onset of lupus. In these cells, activation of the prolactin receptor promoted STAT3 phosphorylation and upregulation of the antiapoptotic Bcl2a1a, Bcl2l2, and Birc5 genes. STAT3 binding to the promoter region of these genes was confirmed through chromatin immunoprecipitation. Furthermore, inhibitors of prolactin signaling and STAT3 activation abolished the prolactin rescue of self-engaged MRL/lpr immature B cells. These results support a mechanism in which prolactin participates in the emergence of lupus through the rescue of self-reactive immature B cell clones from central tolerance clonal deletion through the activation of STAT3 and transcriptional regulation of a complex network of genes related to apoptosis resistance.
Topics: Animals; Apoptosis; Mice; Mice, Inbred MRL lpr; Prolactin; STAT3 Transcription Factor
PubMed: 33557010
DOI: 10.3390/cells10020316 -
Biophysical Journal Apr 2022Metal binding by members of the growth hormone (GH) family of hematopoietic cytokines has been a subject of considerable interest. However, beyond appreciation of its...
Metal binding by members of the growth hormone (GH) family of hematopoietic cytokines has been a subject of considerable interest. However, beyond appreciation of its role in reversible packing of GH proteins in secretory granules, the molecular mechanisms of metal binding and granule formation remain poorly understood. Here, we investigate metal binding by a GH family member prolactin (PRL) using paramagnetic metal titration and chelation experiments. Cu-mediated paramagnetic relaxation enhancement measurements identified two partial metal-binding sites on the opposite faces of PRL composed of residues H30/H180 and E93/H97, respectively. Coordination of metal ions by these two sites causes formation of inter-molecular bridges between the PRL protomers and enables formation of reversible higher aggregates. These findings in vitro suggest a model for reversible packaging of PRL in secretory granules. The proposed mechanism of metal-promoted PRL aggregation lends insight and support to the previously suggested role of metal coordination in secretory granule formation by GH proteins.
Topics: Binding Sites; Cytoplasmic Granules; Growth Hormone; Prolactin; Proteins
PubMed: 35192840
DOI: 10.1016/j.bpj.2022.02.024 -
British Medical Journal Apr 1974Rat hearts with coronary circulations perfused by the Langendorff technique were studied. Recordings were made of the electrical and mechanical activity. Once the rate...
Rat hearts with coronary circulations perfused by the Langendorff technique were studied. Recordings were made of the electrical and mechanical activity. Once the rate and rhythm of each heart and stabilized it was perfused with Ringer-Locke solution for 90 minutes; frusemide (40 mug/ml) was added to the perfusate during the last 30 minutes of this period. Eighteen experiments were performed-six controls, six in which prolactin at a concentration of 50 ng/ml was added to the perfusate for the whole 90 minutes, and six in which a prolactin concentration of 200 ng/ml was used.With the controls heart rate and rhythm remained steady, but there was a slow decline in amplitude of the contraction. With a prolactin concentration of 50 ng/ml the heart rate rose to about 40% above control during the first hour and after an initial sharp increase the contraction amplitude declined more rapidly than in the controls. The prolactin concentration of 200 ng/ml produced a decline of about 25% in heart rate over the first hour and amplitude behaved much as in the controls. Frusemide had no clear effect on the rate of beating of the controls, but it tended to reverse both the acceleration produced by 50 ng/ml prolactin and the slowing produced by the higher dose. Both the doses of prolactin consistently caused disturbances of rhythm. These effects occur at concentration of prolactin found in human plasma in various pathophysiological conditions.
Topics: Animals; Arrhythmias, Cardiac; Electrocardiography; Electrophysiology; Furosemide; Heart; Heart Rate; In Vitro Techniques; Perfusion; Prolactin; Rats
PubMed: 4821039
DOI: 10.1136/bmj.2.5909.27 -
Postgraduate Medical Journal Apr 1975Prolactin in man appears to form an essential part of the complex of hormones necessary for milk secretion and lactation. Levels of prolactin during pregnancy gradually...
Prolactin in man appears to form an essential part of the complex of hormones necessary for milk secretion and lactation. Levels of prolactin during pregnancy gradually increase towards term, and remain elevated for up to 6 weeks post partum. The lactogenic effects of prolactin appear to be blocked at the mammary gland by the elevated levels of fetoplacental steroids secreted during pregnancy. The immediate decline in steroid levels at delivery removes this block to prolactin and milk secretion ensues. The amenorrhoea associated with both puerperal lactation and galactorrhoea appears to reflect failure of cyclical discharge of gonadotrophins and anovulation. This appears to be due to peripheral inhibition of steroidogenesis by the elevated levels of prolactin associated with these situations. No consistent changes in circulating levels of prolactin occur during the menstrual cycle, but changes in prolactin levels within the follicular fluid of the developing ovarian follicle indicate a specific and permissive role of prolactin in steroidogenesis.
Topics: Amenorrhea; Anovulation; Breast; Female; Humans; Lactation; Lactation Disorders; Menstruation; Milk, Human; Ovary; Postpartum Period; Pregnancy; Progesterone; Prolactin
PubMed: 1197152
DOI: 10.1136/pgmj.51.594.231