Inhibition Of Prolactin Secretion Research Articles

Effect of prolactin concentration during the dry period on the subsequent milk production of dairy cows

Shortening the dry period has a negative impact on milk production of the following lactation. One possible explanation is that a period of low prolactin (PRL) concentration is necessary to restore mammary gland milk production capacity. Therefore, the objective of this study was to determine the effect of lowering blood PRL level on subsequent lactation milk production. In this experiment, quinagolide was used to inhibit PRL secretion during the dry period. Thirty Holstein cows were randomly assigned one of 3 dry period managements: a conventional (60 d) dry period (CD) and 2 short (35 d) dry period treatments (SD). Short dry period cows received either water (SDwater) or quinagolide (2 mg, SDquin) injections twice daily from dry-off until 14 d before calving. Cows were followed during the first 20 wks of the subsequent lactation. When CD cows were dry but SD cows were lactating, concentration of PRL was lower in the CD cows than in the SD cows. During the injection period, PRL of SDquin cows was lower than that of the other treatments and was greater in the blood of SDwater than in that of CD cows. After the injection period until calving, no difference in PRL concentration was observed between treatments. After calving, PRL concentration of the SDquin cows was greater than those of CD and SDwater cows. During the first 20 wks of lactation, energy corrected milk (ECM) was lower in SDwater cows than in CD and SDquin cows. The ECM of the latter groups were not different. During the same period, mammary expression of genes related to milk synthesis, pro-apoptotic genes, as well as the expression of the short and long isoforms of the PRLR genes were not affected; however, the expression of SOCS3 gene tended to be lower for the SDquin than the SDwater cows. Lowering the PRL level during short dry period restored milk production to the level normally observed after a conventional dry period, which suggests that higher PRL levels during short dry period are the cause of the lower milk production after a short dry period. Ultimately, strategies to lower blood PRL level may help the adoption of short dry period.

Cardiomyocyte Notch1 signaling is essential for protection of the maternal heart from peripartum stress

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft Background Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without known cardiovascular disease and is characterized by a sudden onset of heart failure (HF) before, under or after delivery. Previous studies suggest impaired endothelial to cardiomyocyte crosstalk as a major pathomechanism of the disease. Purpose Analyses of the role of Notch1 signaling for the endothelial-cardiomyocyte crosstalk in PPCM. Methods and results Serum from PPCM patients with acute HF reduced Notch1 expression in induced pluripotent stem cell derived cardiomyocytes (-20%, P<0.05) compared to serum from postpartum-matched healthy controls (PP-Ctrl). Beside miRNA-146a previously described to be up-regulated in PPCM plasma (6.8-fold, P<0.01), additional miRNAs targeting Notch1 signaling (miR-30a-3p, miR-34a, miR-200b-3p, miR-200c-3p, miR-429-3p, miR-449a) were up-regulated in PPCM plasma. Overexpression of these miRNAs in cardiomyocytes (CM) reduces Notch1 protein levels. Mice with a CM-restricted knockout of Notch1 (N1-KO) are born at the expected Mendelian ratio and nulli pari (NP) N1-KO female mice do not show a distinct cardiac phenotype at the age of 3 to 4 months compared to WT female mice (%FS WT: 41±5 vs N1-KO: 37±6; n= 9-12). However, they develop mild HF at the age of 6 months (%FS WT: 44±4 vs N1-KO: 31±8; n=11-14; P<0.01). Mated N1-KO females displayed normal cardiac function and LV dimensions in the last week of the first pregnancy. After 3 pregnancies and nursing periods, N1-KO developed severe HF (%FS WT PP: 30±5 vs N1-KO PP: 16±5; n=8-12; P<0.01), and show enhanced mortality (P<0.01). N1-KO-NP and N1-KO-PP displayed significant increase in the cardiac expression of the stress markers ANP and BNP compared to respective WT-NP and WT-PP. RNA-Seq analysis of N1-KO-PP revealed 1380 transcripts (adj. P<0.01) differently regulated genes, among them down-regulation of ErbB4, a known driver in PPCM onset. SiRNA-mediated knockdown of Notch1 in CM were associated with a decrease in ErbB4 protein expression. Treatment with bromocriptin (BR) was not able to improve survival and to rescue cardiac function and LV dimensions in postpartum N1-KO females (WT: 37±4, N1-KO: 23±10; n=7-8). Moreover, RNA-Seq analysis revealed that BR had no effect on the dysregulated cardiac mRNA. In conclusion, the pathophysiology of PPCM is associated with reduced cardiac Notch1 expression, which results in part from 16-kDa-prolactin mediated upregulation of miRNAs targeting Notch1. The reduced cardiac Notch1 expression contributes to PPCM as indicated with severe postpartum HF and high mortality in N1-KO mice. Inhibition of prolactin secretion with BR failed to rescue the development of PPCM in N1-KO mice suggesting that deregulated Notch1 is downstream of the 16-kDa prolactin-miRNA pathophysiology.

Effects of Oral Consumption of Nicotiana Tabacum During Pregnancy on the Liver and Prolactin Levels of Adult Female Wistar Rats

Introduction: Tobacco (Nicotiana tabacum) is a globally consumed plant that contains harmful alkaloids such as nicotine. Aim: To study the effects of tobacco consumption during pregnancy on the liver and prolactin levels of adult female Wistar rats. Materials and Methods: The research was done using 21 female Wistar rats which were randomly and evenly separated into groups I, II and III. Pregnant rats in groups II (GII) and III(GIII) received 0.32 g/kg and 0.64 g/kg body weight of tobacco respectively with the use of an oral gavage while pregnant rats in the control group (GI) did not receive the stock solution. On the 23rd day, blood samples and the livers were collected for examination. Blood samples were collected from the mother rats forthe estimation of Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), and total bilirubin levels. The liverswere stained with Hematoxylin and Eosin stains to examine the histological architecture. Results: Liver enzyme assays on the mother rats showed that AST for GII (54.67±3.06 iu/L) and GIII(55.00±7.02 iu/L) were not significantly different (p>0.05) from GI(56.00±0.00 iu/L) using Tukey post hoc test. ALT for GII (41.67±3.51 iu/L) and GIII (47.00±2.58 iu/L) were also not significantly different (p>0.05) from GI (45.00±1.41 iu/L). The total bilirubin value for GII (0.87±0.29 mg/dL) was not significantly different (p>0.05) from GI (0.85±0.07 mg/dL), but total bilirubin for GIII (1.88±0.22 mg/dL) was significantly different(p<0.05) to that of GI. There was a significant decrease(p<0.05) in prolactin levels of mother rats in GII (1.75±0.35 ng/ml) and GIII (1.50±0.71 ng/ml) when compared to GI (11.15±0.35 ng/ml). Histological findings showed that the liver of mother rats in GII and GIII were damaged. Conclusion: The consumption of tobacco (Nicotiana tabacum) by female Wistar rats during pregnancy inhibits prolactin secretion and severely alters theliver histological architecture.

Microglia depletion prevents lactation by inhibition of prolactin secretion

Microglial cells were eliminated from the brain with sustained 3-4weeks long inhibition of colony stimulating factor 1 receptor by Pexidartinib 3397 (PLX3397). The prepartum treated mice mothers did not feed their pups after parturition. The pups of mothers treated orally only in the postpartum period starting immediately after parturition showed reduced body weight by 15.5± 0.22 postnatal days as the treatment progressed without the mothers showing altered caring behaviors. The apparent weight gain of foster pups during a suckling bout was reduced in mother mice fed by PLX3397-containing diet and also in rat dams following sustained intracerebroventricular infusion of PLX3397 in a separate experiment suggesting that lactation was affected by the reduced number of microglia. Prolactin secretion and signaling were markedly reduced in PLX3397-treated mothers. The results suggest that microglial cells are required for prolactin secretion and lactation whereas maternal motivation may not be directly affected by microglia.

Effect of High-Dose Cabergoline Therapy for Hyperprolactinemic Infertility among Bangladeshi Women

Background: Cabergoline is effective in the treatment of hyperprolactinemic hypogonadism. It is a highly effective and long-acting inhibitor of prolactin secretion. The rate of cabergoline-induced pregnancy in women with prolactinoma, is unknown. Objective: The aim of present study is to evaluate the efficacy and safety of high-dose cabergoline therapy for hyperprolactinemic infertility among Bangladeshi women. Method: This descriptive cross- sectional study was conducted among 50 patients from January, 2020 to January, 2022 in at The Medinova Diagnostic Centre, Sylhet, Bangladesh. Results: In our study, maximum (14) patients belong to the age group of 19 to 23 years, and minimum number of patients (4) was between 39 to 43 years. Maximum (52%) patients had the primary infertility and 48% had secondary infertility. The mean values of thyroid stimulating hormone (TSH), Follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin PRL is 3.93±6.58, 10.96±13.58, 9.83±6.8, and 12.46±14.39 respectively and these were significant. 12% patients had PCO and 88% patients were normal in our study. 78% semens were normal, 4% semen showed Azzospermia, 14% semens showed Oligo Astheno Spine and 4% semens showed Astheno spine. Conclusion: In infertile women with prolactinoma, cabergoline can achieve a high pregnancy rate with uneventful outcomes. The findings demonstrated that cabergoline can be used safely to improve menstrual cycles in hyperprolactinemia.

A CASE OF RECURRENT HIVES WITH LACTATION

<h3>Introduction</h3> Development of hives due to lactation is a rare phenomenon seen in the postpartum period. Lactation is influenced by oxytocin and prolactin release, which stimulates lactogenesis, and initiates milk secretion. We describe a rare case of postpartum hives that improved with the use of bromocriptine. <h3>Case</h3> A 33-year-old female presented to clinic with recurrent hives postpartum. Three years prior to presentation she delivered her first child via scheduled cesarean section. After four days of colostrum feeding, she began breastfeeding, but developed diffuse hives within 20 minutes. Although initially resolving with diphenyhradmine, she had recurrent flare of hives every 2-3 hours, resulting in two hospitalizations and intravenous diphenhydramine for persistent hives. Her hives disappeared on postpartum day nine. She delivered her second child via caesarean section. She developed severe, diffuse hives on the fourth day of hospitalization at the time of lactogenesis, refractory to intravenous diphenhydramine, H2-antagonists and methylprednisolone. She was started on bromocriptine with improvement in her hives within hours of administration. <h3>Discussion</h3> Hives with breastfeeding represents a unique phenomenon that can be debilitating postpartum. There are few case reports detailing lactation anaphylaxis, an IgE-independent reaction related to a prolactin surge at time of let-down. Similarly, our patient presents with two recurrent episodes of hives at the time of lactation initiation. This theory is supported by her rapid improvement with administration of bromocriptine, a dopamine antagonist that suppresses prolactin secretion. Early recognition of prolactin-induced hives could allow for intervention prior to delivery with antihistamines, glucocorticoids, and bromocriptine to provide future guidance with subsequent deliveries.

Cabergoline treatment promotes myocardial recovery in peripartum cardiomyopathy.

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 (16kDa 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. Postpartum (PP) female PPCM-prone mice with a cardiomyocyte restricted STAT3-deficiency (αMHC-Cretg/+ ; Stat3fl/fl ; CKO) were treated over two consecutive nursing periods with cabergoline (CKO Cab, 0.5mg/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 (1mg per week for 2weeks, followed by 0.5mg per week for another 6weeks) due to a temporary unavailability of bromocriptine. All PPCM patients initially presented with a severely reduced LV ejection fraction (LVEF: 26±2%). However, at 6months of follow-up, LV function (LVEF: 56±2%) fully recovered in all three PPCM patients, and no adverse events were detected. 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.

Prolactin Action Is Necessary for Parental Behavior in Male Mice.

Parental care is critical for successful reproduction in mammals. Recent work has implicated the hormone prolactin in regulating male parental behavior, similar to its established role in females. Male laboratory mice show a mating-induced suppression of infanticide (normally observed in virgins) and onset of paternal behavior 2 weeks after mating. Using this model, we sought to investigate how prolactin acts in the forebrain to regulate paternal behavior. First, using c-fos immunoreactivity in prolactin receptor (Prlr) Prlr-IRES-Cre-tdtomato reporter mouse sires, we show that the circuitry activated during paternal interactions contains prolactin-responsive neurons in multiple sites, including the medial preoptic nucleus, bed nucleus of the stria terminalis, and medial amygdala. Next, we deleted Prlr from three prominent cell types found in these regions: glutamatergic, GABAergic, and CaMKIIα. Prlr deletion from CaMKIIα, but not glutamatergic or GABAergic cells, had a profound effect on paternal behavior as none of these KO males completed the pup-retrieval task. Prolactin was increased during mating, but not in response to pups, suggesting that the mating-induced secretion of prolactin is important for establishing the switch from infanticidal to paternal behavior. Pharmacological blockade of prolactin secretion at mating, however, had no effect on paternal behavior. In contrast, suppressing prolactin secretion at the time of pup exposure resulted in failure to retrieve pups, with exogenous prolactin administration rescuing this behavior. Together, our data show that paternal behavior in sires is dependent on basal levels of circulating prolactin acting at the time of interaction with pups, mediated through Prlr on CaMKIIα-expressing neurons.SIGNIFICANCE STATEMENT Parental care is critical for offspring survival. Compared with maternal care, however, the neurobiology of paternal care is less well understood. Here we show that the hormone prolactin, which is most well known for its female-specific role in lactation, has a role in the male brain to promote paternal behavior. In the absence of prolactin signaling specifically during interactions with pups, father mice fail to show normal retrieval behavior of pups. These data demonstrate that prolactin has a similar action in both males and females to promote parental care.

Sex-specific Regulation of Prolactin Secretion by Pituitary Bradykinin Receptors.

Sex differences in the control of prolactin secretion are well documented. Sex-related differences in intrapituitary factors regulating lactotroph function have recently attracted attention. Sex differences in prolactinoma development are well documented in clinic, prolactinomas being more frequent in women but more aggressive in men, for poorly understood reasons. Kallikrein, the enzyme releasing kinins has been found in the pituitary, but there is no information on pituitary kinin receptors and their function. In the present work, we characterized pituitary bradykinin receptors (BRs) at the messenger RNA and protein levels in 2 mouse models of prolactinoma, Drd2 receptor gene inactivation and hCGβ gene overexpression, in both males and females, wild type or genomically altered. BR B2 (B2R) accounted for 97% or more of total pituitary BRs in both models, regardless of genotype, and was present in lactotrophs, somatotrophs, and gonadotrophs. Male pituitaries displayed higher level of B2R than females, regardless of genotype. Pituitary B2R gene expression was downregulated by estrogen in both males and females but only in females by dopamine. Activation of B1R or B2R by selective pharmacological agonists induced prolactin release in male pituitaries but inhibited prolactin secretion in female pituitaries. Increased B2R content was observed in pituitaries of mutated animals developing prolactinomas, compared to their respective wild-type controls. The present study documents a novel sex-related difference in the control of prolactin secretion and suggests that kinins are involved, through B2R activation, in lactotroph function and prolactinoma development.

Hypophysial angiogenesis decodes annual time and underlies physiological adaptation to seasonal changes in the environment.

Adaptation to annual changes in the environment is controlled by hypophysial hormones. In temperate zones, photoperiod is the primary external cue that regulates annual biological cycles and is translated by the pattern of melatonin secretion acting primarily in the hypophysial pars tuberalis. Angiogenic mechanisms within this tissue contribute to decode the melatonin signal through alternative splicing of the vascular endothelial growth factor A (VEGF-A) gene in both the pars tuberalis and the capillary loops of the infundibulum. The resulting melatonin-evoked differential productions of VEGF-A isoforms will induce seasonal remodeling of the vascular connection between the hypothalamus and hypophysis, and act as paracrine messengers in the pars distalis to generate the required seasonal endocrine response. Specifically, the long melatonin signal in winter upregulates antiangiogenic VEGF-A isoforms, which will reduce the number of vascular loops and the density of VEGF receptors in endocrine and folliculo-stellate (FS) cells, inhibit prolactin secretion, and stimulate FSH. In contrast, the short melatonin signal in summer upregulates proangiogenic VEGF-A isoforms that will increase the number of vascular loops and the density of VEGF receptors in endocrine and FS cells, stimulate prolactin secretion, and suppress FSH. A similar system has been identified in long day seasonal breeders, revealing that this is a conserved mechanism of adaptation across species. Thus, an angiogenesis-based, intrahypophysial system for annual time measurement controls local microvascular plasticity and conveys the photoperiodic signal readout from the melatonin sensitive pars tuberalis to the endocrine cells of the pars distalis to regulate seasonal adaptation to the environment.

Prolactin mediates behavioural rejection responses to avian brood parasitism.

Adaptations resulting from co-evolutionary interactions between avian brood parasites and their hosts have been extensively studied, yet the physiological mechanisms underlying antiparasitic host defences remain little known. Prolactin, one of the main hormones involved in the regulation of avian parental behaviour, might play a key role in the orchestration of the host responses to avian brood parasitism. Given the positive association between prolactin and parental behaviour during incubation, decreasing prolactin levels are expected to facilitate egg-rejection decisions. We tested this prediction by implanting Eurasian blackbird (Turdus merula) females with an inhibitor of prolactin secretion, bromocriptine mesylate, to experimentally decrease their plasma prolactin levels. Bromocriptine mesylate-implanted individuals ejected mimetic model eggs at higher rates, and showed shorter latency to egg ejection, than placebo-treated birds. To our knowledge, this is the first experimental evidence that behavioural host defences against avian brood parasitism are mediated by prolactin.

Ovulation Induction in Patients with Polycystic Ovarian Syndrome (PCOS) &amp; Hyperprolactinemia (HPRL): Efficacy of Letrozole (LE) Combined with Cabergoline (CE) in Comparison to (LE) Alone

Objectives: (PCOS) is the most common cause of anovulatory infertility, with majority of patients having mild (HPRL). (CE), a dopamine receptor agonist, inhibits prolactin secretion, leading to better ovulatory response. (LE), an aromatase inhibitor, without adverse effects on endometrium &amp; induces fewer mature follicles with less risk of OHSS. Our aim was to investigate effects of combined (LE) &amp; (CE) in comparison to (LE) alone on ovulation &amp; clinical pregnancy rates in (PCOS) patients with (HPRL). Patients &amp; Methods: 180 women with (PCOS) and of 22-38 years old, were enrolled in a hospital based clinical trial. Patients randomly allocated into 2 groups, (A&amp;B). All with a serum prolactin &gt; 32 ng/ml. Patients in (A): (92) were given (LE), 5mg for 5days: (3 – 7 of the cycle)/3 cycles and (CE), 0.5mg weekly for 12 weeks. Those in (B): (88) received only (LE), same dose &amp; duration as in (A). All patients were matched for their age and BMI. Exclusion criteria: other causes of (HPRL). Outcome measure: ovulation rate &amp; detection of both chemical &amp; clinical pregnancies by βhCG and ultrasound of fetal cardiac activity, 2-4 weeks after missed period. Follow-up for 6 months. Data analysis by using SPSS version for windows, P-value significant if (&lt; 0.05). Results: 3 patients from (A) &amp; 5 from (B) had drug side effects and were excluded. None of patients were lost during the follow-up period. In (A), difference between mean serum prolactin level before &amp; after treatment was statistically significant (P&lt;0.001): 48.3±4.2ng/ml and 8.1±5.2ng/ml, respectively. No significant decrease of prolactin level in (B) (P &gt;0.05). After treatment, BMI in (A) 24.1± 3.2, &amp; 24.2 ± 3.6 in (B) (P=0.567). (56.2%) of women in (A) became regularly menstruating but only (30.1%) in (B) (P&lt; 0.05). Ovulation rate was higher in (A) (50.6%) in comparison to (B) (26.5%), (P&lt;0.05). Clinical pregnancy rate in (A) (41.6%) and (21.6%) in (B) (P&lt;0.05). Neither twin pregnancy, nor OHSS were recorded in both groups. Conclusions: The combination of (LE) &amp; (CE) is superior to (LE) alone in management of anovulatory patients with (PCOS) and should be used as the first-line treatment for them

Ovulation Induction in Patients with Polycystic Ovarian Syndrome (PCOS) &amp; Hyperprolactinemia (HPRL): Efficacy of Letrozole (LE) Combined with Cabergoline (CE) in Comparison to (LE) Alone

Objectives: (PCOS) is the most common cause of anovulatory infertility, with majority of patients having mild (HPRL). (CE), a dopamine receptor agonist, inhibits prolactin secretion, leading to better ovulatory response. (LE), an aromatase inhibitor, without adverse effects on endometrium &amp; induces fewer mature follicles with less risk of OHSS. Our aim was to investigate effects of combined (LE) &amp; (CE) in comparison to (LE) alone on ovulation &amp; clinical pregnancy rates in (PCOS) patients with (HPRL). Patients &amp; Methods: 180 women with (PCOS) and of 22-38 years old, were enrolled in a hospital based clinical trial. Patients randomly allocated into 2 groups, (A&amp;B). All with a serum prolactin &gt; 32 ng/ml. Patients in (A): (92) were given (LE), 5mg for 5days: (3 – 7 of the cycle)/3 cycles and (CE), 0.5mg weekly for 12 weeks. Those in (B): (88) received only (LE), same dose &amp; duration as in (A). All patients were matched for their age and BMI. Exclusion criteria: other causes of (HPRL). Outcome measure: ovulation rate &amp; detection of both chemical &amp; clinical pregnancies by βhCG and ultrasound of fetal cardiac activity, 2-4 weeks after missed period. Follow-up for 6 months. Data analysis by using SPSS version for windows, P-value significant if (&lt; 0.05). Results: 3 patients from (A) &amp; 5 from (B) had drug side effects and were excluded. None of patients were lost during the follow-up period. In (A), difference between mean serum prolactin level before &amp; after treatment was statistically significant (P&lt;0.001): 48.3±4.2ng/ml and 8.1±5.2ng/ml, respectively. No significant decrease of prolactin level in (B) (P &gt;0.05). After treatment, BMI in (A) 24.1± 3.2, &amp; 24.2 ± 3.6 in (B) (P=0.567). (56.2%) of women in (A) became regularly menstruating but only (30.1%) in (B) (P&lt; 0.05). Ovulation rate was higher in (A) (50.6%) in comparison to (B) (26.5%), (P&lt;0.05). Clinical pregnancy rate in (A) (41.6%) and (21.6%) in (B) (P&lt;0.05). Neither twin pregnancy, nor OHSS were recorded in both groups. Conclusions: The combination of (LE) &amp; (CE) is superior to (LE) alone in management of anovulatory patients with (PCOS) and should be used as the first-line treatment for them.

The sodium leak channel NALCN regulates cell excitability of pituitary endocrine cells.

Anterior pituitary endocrine cells that release hormones such as growth hormone and prolactin are excitable and fire action potentials. In these cells, several studies previously showed that extracellular sodium (Na+ ) removal resulted in a negative shift of the resting membrane potential (RMP) and a subsequent inhibition of the spontaneous firing of action potentials, suggesting the contribution of a Na+ background conductance. Here, we show that the Na+ leak channel NALCN conducts a Ca2+ - Gd3+ -sensitive and TTX-resistant Na+ background conductance in the GH3 cell line, a cell model of pituitary endocrine cells. NALCN knockdown hyperpolarized the RMP, altered GH3 cell electrical properties and inhibited prolactin secretion. Conversely, the overexpression of NALCN depolarized the RMP, also reshaping the electrical properties of GH3 cells. Overall, our results indicate that NALCN is functional in GH3 cells and involved in endocrine cell excitability as well as in hormone secretion. Indeed, the GH3 cell line suitably models native pituitary cells that display a similar Na+ background conductance and appears as a proper cellular model to study the role of NALCN in cellular excitability.

Galactorrhea as a side effect of antidepressant drugs. A case report

IntroductionGalactorrhea wiht antidepressants SSRIs or SNRI is a rarely adverse effect. Some authors believe that the risk of galactorrhea in women who use SSRIs is 8 times higher than in patients treated with other types of drugs. Serotonin is believed to be a potent physiological stimulator of prolactin release.Prolactin stimulates the growth of the mammary glands and the galactorrhea. The SSRIs would activate the serotonergic pathways, these in turn would stimulate the release of prolactin directly in the pituitary and in the hypothalamus, inhibiting the release of dopamine and increasing the release of stimulating factors. The main inhibitor of prolactin secretion is dopamine.ObjectivesThe objective is to reveal this rare complication through the report of a clinical caseMethodsA 45-year-old woman with a diagnosis of mixed anxiety-depressive disorder. Treatment with 20 mg of escitalopram was started, with a good therapeutic response, but with breast pain and swelling. She was switched to duloxetine 60 mg, with a good response and adequate tolerance. At 6 months of treatment, she begins to present breast pain and yellow-green breast discharge, with elevated prolactin levels and normal cranial MRI.ResultsShe was diagnosed with functional hyperprolactinemia, and treatment with vortioxetine was started. Finally, the Prolactin levels normalize.ConclusionsGalactorrhea is a very rare and annoying side effect that can lead to discontinuation of treatment and requires a change in the therapeutic strategy.DisclosureNo significant relationships.

Total barley maiya alkaloids inhibit prolactin secretion by acting on dopamine D2 receptor and protein kinase A targets

Ethnopharmacological relevance: Barley maiya from gramineous plants (Hordeum vulgare L.) is obtained from ripe fruits through germination and drying. It is often used to treat diseases associated with high prolactin levels. Objective: To investigate the anti-hyperprolactinemia (anti-HPRL) mechanisms of total barley maiya alkaloids (TBMA) and hordenine. Methods: This experiment included 9 groups: Normal group, TBMA group, hordenine group, TBMA + haloperidol group, TBMA + forskolin group, TBMA + 8-bromo-cAMP group, hordenine + haloperidol group, hordenine + forskolin group, and hordenine + 8-bromo-cAMP group. The prolactin (PRL) concentration in the supernatant and the total cAMP concentration in the cells were detected by ELISA. The expression levels of PRL, dopamine D2 receptor (DRD2) and cAMP/PKA/CREB protein were measured by Western Blot. Results: In the TBMA group and the hordenine group, the PRL level in MMQ cells was significantly decreased, but in GH3 cells there was no change. DRD2 expression level was markedly increased, cAMP concentration was decreased, and the activity of PKA and CREB declined in MMQ cells. Compared with the TBMA group, there was a significant decrease of DRD2 expression level, a remarkable increase of PRL secretion and an increase of cAMP/PKA/CREB expression in MMQ cells within the TBMA + haloperidol group. Compared with the forskolin group, there was no significant change in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the TBMA + forskolin group. There was a decrease in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the TBMA + 8-bromo-cAMP group compared with the 8-bromo-cAMP group. Compared with the hordenine group, DRD2 expression level was significantly decreased, PRL secretion was markedly increased, and cAMP/PKA/CREB expression level was increased in MMQ cells within the hordenine + haloperidol group. There was no significant change in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the hordenine + forskolin group compared with the forskolin group and within the hordenine + 8-bromo-cAMP group compared with the 8-bromo-cAMP group. Conclusion: TBMA and hordenine can both play an anti-HPRL role via DRD2, and TBMA can also act on PKA targets to exert its anti-HPRL effect. TBMA and hordenine may be potential treatment strategies for HPRL.

Lomens-P0 (mixed extracts of Hordeum vulgare and Chrysanthemum zawadskii) regulate the expression of factors affecting premenstrual syndrome symptoms.

BACKGROUND/OBJECTIVESPremenstrual syndrome (PMS) is a disorder characterized by repeated emotional, behavioral, and physical symptoms before menstruation, and the exact cause and mechanism are uncertain. Hyperprolactinemia interferes with the normal production of estrogen and progesterone, leading to PMS symptoms. Thus, we judged that the inhibition of prolactin hypersecretion could mitigate PMS symptoms.MATERIALS/METHODS Hordeum vulgare L. extract (HVE), Chrysanthemum zawadskii var. latilobum extract (CZE), and Lomens-P0 the mixture of these extracts were tested in subsequent experiments. The effect of extracts on prolactin secretion at the in vitro level was measured in GH3 cells. Nitric oxide and pro-inflammatory mediator expression were measured in RAW 264.7 cells to confirm the anti-inflammatory effect. Also, the hyperprolactinemic Institute for Cancer Research (ICR) mice model was used to measure extract effects on prolactin and hormone secretion and uterine inflammation.RESULTSAnti-inflammatory effects of and prolactin secretion suppress by HVE and CZE were confirmed through in vitro experiments (P < 0.05). Treatment with Lomens-P0 inhibited prolactin secretion (P < 0.05) and restored normal sex hormone secretion in the hyperprolactinemia mice model. In addition, extracts significantly inhibited the expression of pro-inflammatory biomarkers, including interleukin-1β, and -6, tumor necrosis factor-α, inducible nitric oxide synthase, and cyclooxygenase-2 (P < 0.01). We used high-performance liquid chromatography analyses to identify tricin and chlorogenic acid as the respective components of HVE and CZE that inhibit prolactin secretion. The Lomens-P0, which includes tricin and chlorogenic acid, is expected to be effective in improving PMS symptoms in the human body.CONCLUSIONSThe Lomens-P0 suppressed the prolactin secretion in hyperprolactinemia mice, normalized the sex hormone imbalance, and significantly suppressed the expression of inflammatory markers in uterine tissue. This study suggests that Lomens-P0 may have the potential to prevent or remedy materials to PMS symptoms.

The prolactine hypothesis for peripartum cardiomyopathy: has it found its feet for good?

Abstract Background Peripartum cardiomyopathy (PPCM) is a rare but serious condition that affects childbearing women. Dopamine agonists (DAs) may represent a specific therapy, potentially facilitating left ventricular recovery, through inhibition of prolactin secretion. However, their therapeutic value in this setting has not been fully demonstrated. Purpose To perform a meta-analysis aimed at evaluating the extent to which DAs are able to interfere with the natural history of PPCM. Methods We systematically searched MEDLINE, Embase, Web of Science, Cochrane Library, Google Scholar, Scopus and DARE for both randomized controlled trials (RCTs) and observational studies addressing the impact of DAs on main outcomes of PPCM patients, published up until February 1, 2020. Endpoints were those of mortality, recovery from heart failure and, likewise, the degree to which left ventricular ejection fraction (LVEF) was restored. All analyses were conducted under a DA plus optimized medical therapy (OMT) vs. OMT alone design, while results were pooled using traditional meta-analytic techniques, under a random-effects model. Odds ratios (ORs) were computed for the first two outcomes, whereas mean difference (MD) was calculated to quantify LVEF restoration. Results 2 RCTs, 2 prospective cohort, 1 prospective case-control and 2 retrospective cohort studies, encompassing 452 patients, were regarded as eligible for quantitative evaluation. 180 patients were allocated to the DA arm, which was mostly represented by bromocriptine; in fact, only 1 study, including 24 patients, specified cabergolin utilization. Overall, 5 papers including 295 patients reported 42 deaths, whereas 5 papers comprising 305 patients detailed 220 heart failure recoveries, thus unveiling that LVEF restoration was the norm. The addition of a DA to OMT provided no signal of a survival benefit (OR 0.71, 95% CI 0.27–1.87, p=0.49, i2=27%). On the other hand, the incorporation of a DA into the therapeutic regimen narrowly missed significance for the heart failure recovery endpoint (OR 2.68, 95% CI 0.98–7.31, p=0.05, i2=56%). Furthermore, DAs were demonstrated to incrementally improve LVEF by 15% (MD 15.00, 95% CI 10.24–19.76, p&amp;lt;0.00001, i2=77%). Adverse events, including thromboembolic ones, were rare, though adjunct anticoagulation was broadly reported. Conclusion In PPCM patients, the addition of a DA to OMT seems to be both effective at incrementally improving LVEF and safe, even though not reaching survival benefit status. These findings appear to corroborate the so-called prolactin hypothesis for PPCM pathophysiology. Funding Acknowledgement Type of funding source: None

Профілактика та корекція дисгормональних порушень репродуктивної системи у сучасних умовах хронічного стресу

The objective: to determine the optimal prophylactic and therapeutic drug to support and restore the biphasic menstrual cycle against the background of the influence of chronic stress. Materials and methods. A comparative study of the effectiveness of the use of preparations of dry extract of common rod (Vitex Agnus castus ) BNO 1095 and various vitamin complexes with a sedative effect, which contain vitamins of group B, magnesium, folic acid, herbal preparations of valerian, pasiflora, was carried out. The hormonal profile and psychoemotional state in women with dyshormonal disorders in modern conditions were studied. Results. The clinical efficacy and feasibility of using the drug Vitex Agnus castus in women with dyshormonal disorders in conditions of psychoemotional disadaptation due to the harmonizing effect on the concentration of female sex hormones, normalizing the ratio of gonadotropic hormones, eliminating the estradiol / progesterone imbalance against the background of a decrease in prolactin level has been proven. Conclusion. The presented results of the study prove the effectiveness of the use of the phytopreparation Vitex Agnus castus in women with dyshormonal disorders under conditions of chronic stress due to its dopaminergic effect on psychoemotional status as a result of elimination of latent stress-induced hyperprolactinemia, comparable to the effect of synthetic inhibitors of prolactin secretion. In addition, the drug Vitex Agnus castus can be prescribed to prevent the occurrence of phase inconsistency in the secretion of gonadotropic hormones due to the activation of stress-limiting systems and local neuroendocrine modulators, which helps to reduce stress stress. Keywords: dyshormonal disorders, chronic stress, maladjustment.

Morphological plasticity of the tuberoinfundibular dopaminergic neurones in the rat during the oestrous cycle and lactation

The hypothalamic tuberoinfundibular dopaminergic (TIDA) neurones are critical with respect to regulating prolactin secretion from the anterior pituitary. Under most physiological conditions, they are stimulated by prolactin to release dopamine into the median eminence which subsequently suppresses further prolactin secretion from the lactotrophs. During lactation, the TIDA neurones are known to undergo both electrophysiological and neurochemical changes that alleviate this negative-feedback, thus allowing circulating prolactin levels to rise. The present study aimed to determine whether TIDA neurone morphology, most notably spine density, is also modified during lactation. This was achieved by stereotaxically injecting the arcuate nucleus of female, tyrosine hydroxylase-promoter driven Cre-recombinase transgenic rats with Cre-dependent adeno-associated virus-expressing Brainbow. This resulted in the highly specifici transfection of between 10% and 30% of the TIDA neurones, thus allowing the morphologies on multiple individual neurones to be examined in a single hypothalamic slice. The transfected neurones exhibited a range of complex forms, including a diversity of soma and location of axonal origin. Neuronal spine counting showed that the density of somatic, but not dendritic, spines was significantly higher during lactation than at any other reproductive stage. There was also a significant fall in somatic spine density across the oestrous cycle from dioestrus to oestrus. Although the functional characteristics of the additional somatic spines have not been determined, if, as might be expected, they represent an increased excitatory input to the TIDA neurones, this could have important physiological implications by perhaps supporting altered neurotransmitter release at their neuroendocrine terminals. Enhanced excitatory input may, for example, favour the release of the opioid peptide enkephalin rather than dopamine, which is potentially significant because the expression of the peptide is known to increase in the TIDA neurones during lactation and, in contrast to dopamine, it stimulates rather than inhibits prolactin secretion from the pituitary.