Inhibition Of Prolactin Release Research Articles

Prolactin Mediates Long-Term, Seasonal Rheostatic Regulation of Body Mass in Female Mammals.

A series of well-described anabolic and catabolic neuropeptides are known to provide short-term, homeostatic control of energy balance. The mechanisms that govern long-term, rheostatic control of regulated changes in energy balance are less well characterized. Using the robust and repeatable seasonal changes in body mass observed in Siberian hamsters, this report examined the role of prolactin in providing long-term rheostatic control of body mass and photoinduced changes in organ mass (ie, kidney, brown adipose tissue, uterine, and spleen). Endogenous circannual interval timing was observed after 4 months in a short photoperiod, indicated by a significant increase in body mass and prolactin mRNA expression in the pituitary gland. There was an inverse relationship between body mass and the expression of somatostatin (Sst) and cocaine- and amphetamine-regulated transcript (Cart). Pharmacological inhibition of prolactin release (via bromocriptine injection), reduced body mass of animals maintained in long photoperiods to winter-short photoperiod levels and was associated with a significant increase in hypothalamic Cart expression. Administration of ovine prolactin significantly increased body mass 24 hours after a single injection and the effect persisted after 3 consecutive daily injections. The data indicate that prolactin has pleiotropic effects on homeostatic sensors of energy balance (ie, Cart) and physiological effectors (ie, kidney, BAT). We propose that prolactin release from the pituitary gland acts as an output signal of the hypothalamic rheostat controller to regulate adaptive changes in body mass.

Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening heart disease, with onset in the last month of pregnancy or in the first months after delivery in previously heart-healthy women. PPCM patients typically present with heart failure due to left ventricular (LV) dysfunction with an LV ejection fraction (EF) < 45 %. In the last years clinical and experimental studies contributed to a better understanding of the pathophysiology and the clinical course of PPCM. In the context of oxidative stress, the nursing hormone prolactin is cleaved into a smaller antiangiogenic and proapoptotic 16k Da form, leading to myocardial dysfunction. In an animal model this can be prevented by treatment with the dopamine agonist bromocriptine, which suppresses prolactin release. This therapeutic approach was confirmed in several clinical studies. Therefore, the current guidelines recommend a treatment consisting of a heart failure treatment according to current guidelines in combination with the dopamine agonist bromocriptine. If the diagnosis is made early and the treatment is started immediately, the prognosis is good compared to other forms of cardiomyopathies, as LV function recovers in most cases.In the acute phase the severity of heart failure differs among PPCM patients. Some patients present with mild forms, whereas some PPCM patients display severely reduced LV function and cardiogenic shock. Especially the latter cases are still challenging, as treatment with β1-adrenergic receptor agonists is associated with progression of heart failure and a worse cardiac outcome. Therefore, patients with cardiogenic shock complicating PPCM should be treated in centers experienced in mechanical circulatory support in combination with bromocriptine treatment.

Prolactin signaling modulates stress-induced behavioral responses in a preclinical mouse model of migraine.

The aim of this study was to determine if prolactin signaling modulates stress-induced behavioral responses in a preclinical migraine model. Migraine is one of the most complex and prevalent disorders. The involvement of sex-selective hormones in migraine pathology is highly likely as migraine is more common in women and its frequency correlates with reproductive stages. Prolactin has been shown to be a worsening factor for migraine. Normally prolactin levels are low; however levels can surge during stress. Dopamine receptor agonists, which suppress pituitary prolactin release, are an effective migraine treatment in a subset of patients. Previously, we showed that administration of prolactin onto the dura mater induces female-specific behavioral responses, suggesting that prolactin may play a sex-specific role in migraine. The effects of prolactin signaling were assessed using a preclinical migraine model we published recently in which behavioral sensitization is induced by repeated stress. Plasma prolactin levels were assessed in naïve and stressed CD-1 mice (n=3-5/group) and transgenic mice with conditional deletion of the Prlr in Nav1.8-positive sensory neurons (Prlr conditional knock-out [CKO]; n=3/group). To assess the contribution of prolactin release during stress, naïve or stressed male and female CD-1 mice were treated with the prolactin release inhibitor bromocriptine (2mg/kg; n=7-12/group) or vehicle for 5days (8-12/group) and tested for facial hypersensitivity following stress. Additionally, the contribution of ovarian hormones in regulating the prolactin-induced responses was assessed in ovariectomized female CD-1 mice (n=6-10/group). Furthermore, the contribution of Prlr activation on Nav1.8-positive sensory neurons was assessed. Naïve or stressed male and female Prlr CKO mice and their control littermates were tested for facial hypersensitivity (n=8-9/group). Immunohistochemistry was used to confirm loss of Prlr in Nav1.8-positive neurons in Prlr CKO mice. The total sample size is n=245; the full analysis sample size is n=221. Stress significantly increased prolactin levels in vehicle-treated female mice (39.70±2.77; p<0.0001). Bromocriptine significantly reduced serum prolactin levels in stressed female mice compared to vehicle-treated mice (-44.85±3.1; p<0.0001). Additionally, no difference was detected between female stressed mice that received bromocriptine compared to naïve mice treated with bromocriptine (-0.70±2.9; p=0.995). Stress also significantly increased serum prolactin levels in male mice, although to a much smaller extent than in females (0.61±0.08; p<0.001). Bromocriptine significantly reduced serum prolactin levels in stressed males compared to those treated with vehicle (-0.49±0.08; p=0.002). Furthermore, bromocriptine attenuated stress-induced behavioral responses in female mice compared to those treated with vehicle (maximum effect observed on day 4 post stress [0.21±0.08; p=0.03]). Bromocriptine did not attenuate stress-induced behavior in males at any timepoint compared to those treated with vehicle. Moreover, loss of ovarian hormones did not affect the ability of bromocriptine to attenuate stress responses compared to vehicle-treated ovariectomy mice that were stressed (maximum effect observed on day 4 post stress [0.29±0.078; p=0.013]). Similar to CD-1 mice, stress increased serum prolactin levels in both Prlr CKO female mice (27.74±9.96; p=0.047) and control littermates (28.68±9.9; p=0.041) compared to their naïve counterparts. There was no significant increase in serum prolactin levels detected in male Prlr CKO mice or control littermates. Finally, conditional deletion of Prlr from Nav1.8-positive sensory neurons led to a female-specific attenuation of stress-induced behavioral responses (maximum effect observed on day 7 post stress [0.32±0.08; p=0.007]) compared to control littermates. These data demonstrate that prolactin plays a female-specific role in stress-induced behavioral responses in this preclinical migraine model through activation of Prlr on sensory neurons. They also support a role for prolactin in migraine mechanisms in females and suggest that modulation of prolactin signaling may be an effective therapeutic strategy in some cases.

Hyperprolactinemia in a male pituitary androgen receptor knockout mouse is associated with female-like lactotroph development.

Circulating prolactin concentration in rodents and humans is sexually dimorphic. Oestrogens are a well-characterised stimulator of prolactin release. Circulating prolactin fluctuates throughout the menstrual/oestrous cycle of females in response to oestrogen levels, but remains continually low in males. We have previously identified androgens as an inhibitor of prolactin release through characterisation of males of a mouse line with a conditional pituitary androgen receptor knockout (PARKO) which have an increase in circulating prolactin, but unchanged lactotroph number. In the present study, we aimed to specify the cell type that androgens act on to repress prolactin release. PARKO, lactotroph-specific, Pit1lineage-specific and neural-specific conditional androgen receptor knockout male mice were investigated using prolactin ELISA, pituitary electron microscopy, immunohistochemistry and qRT-PCR. Lactotroph-specific, Pit1lineage-specific and neural-specific conditional AR knockouts did not duplicate the high circulating prolactin seen in the PARKO line. Using electron microscopy to examine ultrastructure, we showed that pituitary androgen receptor knockout male mice develop lactotrophs that resemble those seen in female mice. Castrated PARKO males have significantly reduced circulating prolactin compared to intact males. When expression of selected oestrogen-regulated anterior pituitary genes was examined, there were no differences in expression level between controls and knockouts. The cell type that androgens act on to repress prolactin release is not the lactotroph, cells in the Pit1-lineage, or the dopaminergic neurons in the hypothalamus. PARKO males develop a female-specific lactotroph ultrastructure that this is likely to contribute to the increase in circulating prolactin. Castrated PARKO males have significantly reduced circulating prolactin compared to intact males, which suggests that removal of both circulating oestrogens and androgens reduces the stimulation of pituitary prolactin release. Further investigation is needed into prolactin regulation by changes in androgen-oestrogen balance, which is involved sexual dimorphism of development and diseases including hyperprolactinemia.

Evaluation of the acute, sub-chronic and chronic oral toxicity, genetic toxicity, and safety of a Lomens-P0.

The online version contains supplementary material available at 10.1007/s43188-021-00090-5.

Use of Bromocriptine for the Treatment of Peripartum Cardiomyopathy: A Meta-Analysis of Randomized Controlled Trials

Peripartum cardiomyopathy is a rare, pregnancy associated cause of left ventricular heart failure in previously healthy women. It remains an important cause of cardiac-related maternal morbidity and mortality worldwide. Half of the patients will recover left ventricular function after 6 months. However, in the remainder of patients who do not recover cardiac function, they will require advanced heart failure therapies. Bromocriptine, a dopamine agonist which inhibits prolactin release, has demonstrated improvement in left ventricular recovery and clinical outcome. We sought to determine the effect of adding Bromocriptine to standard heart failure therapy on the improvement and recovery of left ventricular function and cardiovascular mortality of these patients.

P14 Use of bromocriptine for the treatment of peripartum cardiomyopathy: a meta-analysis of randomized controlled trials

Abstract Background Peripartum cardiomyopathy is a rare, pregnancy associated cause of left ventricular heart failure in previously healthy women. It remains an important cause of cardiac-related maternal morbidity and mortality worldwide. Half of the patients will recover left ventricular function after 6 months. However, in the remainder of patients who do not recover cardiac function, they will require advanced heart failure therapies. Bromocriptine, a dopamine agonist which inhibits prolactin release, has demonstrated improvement in left ventricular recovery and clinical outcome. We sought to determine the effect of adding Bromocriptine to standard heart failure therapy on the improvement and recovery of left ventricular function of these patients. Inclusion Criteria. Studies were included if they satisfied the following criteria:1) Randomized Controlled Trials; 2) Pregnant patients who fulfilled the criteria for diagnosis of peripartum cardiomyopathy and 3) Reported data on improvement in left ventricular ejection fraction and clinical outcomes. Methods Using PUBMED, Clinical Key, Science Direct, Scopus, and Cochrane databases, a search for eligible studies was conducted from June to December 31, 2018. The quality of each study was evaluated using the Cochrane Risk of Bias Tool. The primary outcome of interest is on the effect of Bromocriptine on the improvement of left ventricular function and clinical outcomes among these patients. Review Manager 5.3 was utilized to perform analysis of random effects for continuous outcomes. Results We identified 2 randomized controlled trials of 58 pregnant patients diagnosed with peripartum cardiomyopathy, showing that among those who received Bromocriptine on top of standard heart failure therapy, there is a significant improvement in the left ventricular ejection fraction at 6 months [mean difference 15.14 (95% CI, 6.53 to 23.75) p &amp;lt;0.05] compared to standard heart failure therapy alone. It was also observed that those who received Bromocriptine had better clinical outcomes. Conclusion The addition of Bromocriptine on top of standard heart failure therapy significantly improved the left ventricular ejection fraction of patients with peripartum cardiomyopathy at 6 months post-partum. This novel therapy may be considered to improve the management of these patients.

Use of bromocriptine for the treatment of peripartum cardiomyopathy: A meta-analysis of randomized controlled trials

Background: Peripartum cardiomyopathy is a rare, pregnancy associated cause of left ventricular heart failure in previously healthy women. It remains an important cause of cardiac-related maternal morbidity and mortality worldwide. Half of the patients will recover left ventricular function after 6 months. However, in the remainder of patients who do not recover cardiac function, they will require advanced heart failure therapies. Bromocriptine, a dopamine agonist which inhibits prolactin release, has demonstrated improvement in left ventricular recovery and clinical outcome. We sought to determine the effect of adding Bromocriptine to standard heart failure therapy on the improvement and recovery of left ventricular function and cardiovascular mortality of these patients. Inclusion Criteria: Studies were included if they satisfied the following criteria:1) Randomized Controlled Trials; 2) Pregnant patients who fulfilled the criteria for diagnosis of peripartum cardiomyopathy and 3) Reported data on improvement in left ventricular ejection fraction and clinical outcomes. Methods: Using PUBMED, Clinical Key, Science Direct, Scopus, and Cochrane databases, a search for eligible studies was conducted from June to December 31, 2018. The quality of each study was evaluated using the Cochrane Risk of Bias Tool. The primary outcome of interest is on the effect of Bromocriptine on the improvement of left ventricular function and clinical outcomes among these patients. Review Manager 5.3 was utilized to perform analysis of random effects for continuous outcomes. Results: We identified 2 randomized controlled trials of 116 pregnant patients diagnosed with peripartum cardiomyopathy, showing that among those who received Bromocriptine on top of standard heart failure therapy, there is a significant improvement in the left ventricular ejection fraction at 6 months [mean difference 15.14 (95% CI, 6.53 to 23.75) p

Use of Bromocriptine for the Treatment of Peripartum Cardiomyopathy: A Meta-Analysis of Randomized Controlled Trials

Background Peripartum cardiomyopathy is a rare, pregnancy associated cause of left ventricular heart failure in previously healthy women. It remains an important cause of cardiac-related maternal morbidity and mortality worldwide. Half of the patients will recover left ventricular function after 6 months. However, in the remainder of patients who do not recover cardiac function, they will require advanced heart failure therapies. Bromocriptine, a dopamine agonist which inhibits prolactin release, has demonstrated improvement in left ventricular recovery and clinical outcome. We sought to determine the effect of adding Bromocriptine to standard heart failure therapy on the improvement and recovery of left ventricular function and cardiovascular mortality of these patients. Inclusion Criteria. Studies were included if they satisfied the following criteria:1) Randomized Controlled Trials; 2) Pregnant patients who fulfilled the criteria for diagnosis of peripartum cardiomyopathy and 3) Reported data on improvement in left ventricular ejection fraction and clinical outcomes. Methods. Using PUBMED, Clinical Key, Science Direct, Scopus, and Cochrane databases, a search for eligible studies was conducted from June to December 31, 2018. The quality of each study was evaluated using the Cochrane Risk of Bias Tool. The primary outcome of interest is on the effect of Bromocriptine on the improvement of left ventricular function and clinical outcomes among these patients. Review Manager 5.3 was utilized to perform analysis of random effects for continuous outcomes. Results. We identified 2 randomized controlled trials of 116 pregnant patients diagnosed with peripartum cardiomyopathy, showing that among those who received Bromocriptine on top of standard heart failure therapy, there is a significant improvement in the left ventricular ejection fraction at 6 months [mean difference 15.14 (95% CI, 6.53 to 23.75) p <0.05] compared to standard heart failure therapy alone. It was also observed that those who received Bromocriptine had better clinical outcomes. Conclusion. The addition of Bromocriptine on top of standard heart failure therapy significantly improved the left ventricular ejection fraction of patients with peripartum cardiomyopathy at 6-months post-partum. This novel therapy may be considered to improve the management of these patients.

Neuromedin U suppresses prolactin secretion via dopamine neurons of the arcuate nucleus

Neuromedin U (NMU) has a precursor that contains one additional peptide consisting of 33 or 36 amino acid residues. Recently, we identified this second peptide from rat brain and designated it neuromedin U precursor-related peptide (NURP), showing it to stimulate prolactin release from the pituitary when injected via the intracerebroventricular (icv) route. Here, we examined whether NMU, like NURP, also stimulates prolactin release. Unlike NURP, icv injection of NMU significantly decreased the secretion of prolactin from the pituitary. This suppression of prolactin release by NMU was observed in hyper-prolactin states such as lactation, stress, pseudopregnancy, domperidone (dopamine antagonist) administration, and icv injection of NURP. Immunohistochemical analysis revealed that icv injection of NMU induced cFos expression in dopaminergic neurons of the arcuate nucleus, but not the substantia nigra. Mice with double knockout of NMU and neuromedin S (NMS), the latter also binding to NMU receptors, showed a significant increase of the plasma prolactin level after domperidone treatment relative to wild-type mice. These results suggest that NMU and NURP may play important reciprocal roles in physiological prolactin secretion.

Androgen and prolactin manipulation induces changes in aggressive and nurturing behavior in a fish with male parental care

Parental care can include two general types of behavior: (1) aggressive behavior, which is used to defend offspring from predators; and (2) nurturing behavior, which is used to provide offspring with environmental conditions or resources necessary for survival. Many studies have implicated androgens in promoting aggressive behavior and prolactin in promoting nurturing behavior. We experimentally manipulated these hormones to investigate their effects on parental care behavior in bluegill (Lepomis macrochirus). Parental males, which provide sole care to the developing eggs and larvae, received an implant with an androgen (11-ketotestosterone [11-KT]), an androgen antagonist (flutamide), prolactin, a prolactin-release inhibitor (bromocriptine), or castor oil (placebo). We found that 11-KT implants led to a significant increase in the frequency of aggressive behavior directed towards a simulated brood predator, and were associated with a nearly significant decrease in the frequency of nurturing behavior directed towards the developing eggs. In contrast, prolactin implants were associated with a significant increase in the frequency of nurturing behavior, but also reduced the frequency of aggressive behavior directed towards the simulated brood predator. These results suggest a hormone-mediated mechanistic trade-off between nurturing and aggressive behavior, whereby parental males are unable to be both highly nurturing and highly aggressive.

GH3 and RC-4BC cell lines are not suitable as in vitro models to study prolactin modulation and AHR responsiveness in rat pituitary

Some environmental contaminants and pharmaceuticals increase the incidence of uterine tumors in toxicological studies with rats. These tumors can result from a hormonal imbalance due to rat-specific disrupted pituitary prolactin regulation, and are therefore of questionable relevance for humans. In this study we compared in vitro prolactin regulation in rat primary pituitary cells to that in pituitary cell lines, GH3 and RC-4BC. Moreover, we assessed the potential effects of aryl hydrocarbon receptor (AHR) activation on prolactin regulation by using two different AHR agonists, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and DELAQ, the N-deethylated minor metabolite of the pharmaceutical laquinimod.In rat primary pituitary cells, known prolactin stimulant thyrotropin-releasing hormone (TRH) marginally increased prolactin secretion (1.2-fold) and gene expression (1.3-fold). In contrast, synthetic dopamine receptor agonist quinpirole, a known inhibitor of prolactin release, significantly inhibited prolactin secretion (2.6-fold) and gene expression (3.6-fold). In GH3 cells, TRH strongly increased prolactin secretion (6.8-fold) and gene expression (30.8-fold), whereas quinpirole did not affect prolactin secretion nor gene expression. In RC-4BC cells, both TRH and quinpirole did not modulate prolactin secretion nor gene expression. Prolactin secretion and gene expression did not significantly change upon exposure to TCDD or DELAQ. However, DELAQ, but not TCDD, attenuated quinpirole-inhibited prolactin gene expression by 51% in primary pituitary cells.This study shows that pituitary prolactin regulation in rat primary pituitary cells in vitro is distinctly different from rat pituitary cell lines GH3 and RC-4BC. Therefore, effects on pituitary prolactin regulation in vitro should best be performed using rat primary pituitary cells. Additionally, AHR ligands may interact with rat pituitary prolactin regulation, but this appears to depend on the ligand and constitutive prolactin secretion. However, interpretation of the in vitro results with respect to occurrence of uterine tumors in rats should take the complex regulation of prolactin release in the pituitary into account as well as the in vivo hypothalamus-pituitary-gonadal (HPG) axis and its feedback loops.

Myostatin regulates pituitary development and hepatic IGF1.

Circulating myostatin-attenuating agents are being developed to treat muscle-wasting disease despite their potential to produce serious off-target effects, as myostatin/activin receptors are widely distributed among many nonmuscle tissues. Our studies suggest that the myokine not only inhibits striated muscle growth but also regulates pituitary development and growth hormone (GH) action in the liver. Using a novel myostatin-null label-retaining model (Jekyll mice), we determined that the heterogeneous pool of pituitary stem, transit-amplifying, and progenitor cells in Jekyll mice depletes more rapidly after birth than the pool in wild-type mice. This correlated with increased levels of GH, prolactin, and the cells that secrete these hormones, somatotropes and lactotropes, respectively, in Jekyll pituitaries. Recombinant myostatin also stimulated GH release and gene expression in pituitary cell cultures although inhibiting prolactin release. In primary hepatocytes, recombinant myostatin blocked GH-stimulated expression of two key mediators of growth, insulin-like growth factor (IGF)1 and the acid labile subunit and increased expression of an inhibitor, IGF-binding protein-1. The significance of these findings was demonstrated by smaller muscle fiber size in a model lacking myostatin and liver IGF1 expression (LID-o-Mighty mice) compared with that in myostatin-null (Mighty) mice. These data together suggest that myostatin may regulate pituitary development and function and that its inhibitory actions in muscle may be partly mediated by attenuating GH action in the liver. They also suggest that circulating pharmacological inhibitors of myostatin could produce unintended consequences in these and possibly other tissues.

Peripartum Cardiomyopathy: a Review for the Clinician.

This review summarizes the pathophysiology, diagnosis, and treatment of peripartum cardiomyopathy (PPCM), with a focus on recent discoveries of clinical relevance. An increase in oxidative stress and anti-angiogenic activity play key roles in the pathophysiology of peripartum cardiomyopathy. Therapies that target this dysregulation may have a future role in treatment. Suppression of prolactin release using bromocriptine, a dopamine-receptor antagonist, has been associated with more favorable outcomes in small studies but more research is needed. Similarly, VEGF agonists may prove to be a novel therapy by upregulating angiogenesis. Peripartum cardimyopathy typically presents in the third trimester or in first few months postpartum. Both genetic and clinical risk factors for PPCM have been identified. Women with PPCM should be managed by a multidisciplinary team with experience in high risk pregnancy and the treatment of heart failure. These women benefit from the use of standard treatments for heart failure therapy with the exception of avoiding ACE inhibitors and ARBs while pregnant. While the rate of recovery of ventricular function in PPCM is higher than in other forms of dilated cardiomyopathy, mechanical circulatory support and/or cardiac transplantation are required in some cases.

Bromocriptine treatment in patients with peripartum cardiomyopathy and right ventricular dysfunction

BackgroundRight ventricular (RV) dysfunction predicts adverse outcome in peripartum cardiomyopathy (PPCM). We recently demonstrated beneficial effects associated with the prolactin release inhibitor bromocriptine at different doses when added to standard heart failure therapy in PPCM. Here, we evaluated for the first time the therapeutic potential of bromocriptine particularly in PPCM patients with RV involvement.MethodsIn this study, 40 patients with PPCM were included, of whom 24 patients had reduced RV ejection fraction (RVEF < 45%). We examined the effect of short-term (1W: bromocriptine, 2.5 mg, 7 days, n = 10) compared with long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for another 6 weeks, n = 14) in addition to guideline-based heart failure therapy in patients with an initial RVEF < 45% on the following outcomes: (1) change from baseline (Δ delta) in RVEF, (2) change from baseline in left ventricular EF (LVEF), and (3) rate of patients with full LV recovery (LVEF ≥ 50%) and (4) rate of patients with full RV recovery (RVEF ≥ 55%) at 6-month follow-up as assessed by cardiac magnetic resonance imaging.ResultsReduced RVEF at initial presentation was associated with a lower rate of full cardiac recovery at 6-month follow-up (patients with RV dysfunction: 58% vs. patients with normal RV function: 81%; p = 0.027). RVEF increased from 38 ± 7 to 53 ± 11% with a delta-RVEF of + 15 ± 12% in the 1W group, and from 35 ± 9 to 58 ± 7% with a Δ RVEF of + 23 ± 10% in the 8W group (Δ RVEF 1W vs 8W: p = 0.118). LVEF increased from 25 ± 8 to 46 ± 12% with a Δ LVEF of + 21 ± 11% in the 1W group, and from 22 ± 6 to 49 ± 10% with a Δ LVEF of + 27 ± 9% in the 8W group (Δ LVEF 1W vs 8W: p = 0.211). Full LV recovery was present in 50% of the 1W group and in 64% of the 8W group (p = 0.678). Full RV recovery was observed in 40% of the 1W group and in 79% of the 8W group (p = 0.092).ConclusionsDespite overall worse outcome in patients with RV dysfunction at baseline, bromocriptine treatment in PPCM patients with RV involvement was associated with a high rate of full RV and LV recovery, although no significant differences were observed between the short-term and long-term bromocriptine treatment regime. These findings suggest that bromocriptine in addition to standard heart failure therapy may be also effective in PPCM patients with biventricular impairment.

Participation of membrane progesterone receptor α in the inhibitory effect of progesterone on prolactin secretion.

The membrane progesterone receptors (mPRα, mPRβ, mPRγ, mPRδ and mPRε) are known to mediate rapid nongenomic progesterone functions in different cell types. However, the functions of these receptors in the pituitary have not been reported to date. In the present study, we show that the expression of mPRα was the highest among the mPRs in the rat anterior pituitary gland. Immunostaining of mPRα was detected in somatotrophs, gonadotrophs and lactotrophs. Interestingly, 63% of mPRα-positive cells within the pituitary were lactotrophs, suggesting that mPRα is involved in controlling prolactin (PRL) secretion in the pituitary. To test this hypothesis, rat pituitaries were incubated (1hour) with either progesterone (P4) or the mPRα-specific agonist Org OD 02-0. PRL secretion was then measured by radioimmunoassay. The results of this experiment revealed that both P4 and Org OD 02-0 decreased PRL secretion. Moreover, the results from the GH3 cell line (CCL-82.1) showed that P4 and Org OD 02-0 inhibited PRL release, although the nuclear PR agonist R5020 was ineffective. Our investigation of the cellular mechanisms behind mPRα activity indicated that both P4 and Org OD 02-0 decreased cAMP accumulation, whereas R5020 was ineffective. In addition, the Org OD 02-0-effect on PRL release was blocked by pretreatment with pertussis toxin, an inhibitor of Go/Gi proteins. Because transforming growth factor (TGF)β1 is a potent inhibitor of PRL secretion in lactotrophs, we lastly evaluated whether TGFβ1 was activated by progesterone and whether this effect was mediated by mPRα. Our results showed that P4 and Org OD 02-0, but not R5020, increased active TGFβ1 levels. This effect was not observed when cells were transfected with mPRα-small interfering RNA. Taken together, these data provide new evidence suggesting that mPRα mediates the progesterone inhibitory effect on PRL secretion through both decreases in cAMP levels and activation of TGFβ1 in the lactotroph population.

Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice.

Triclosan (TCS), a broad-spectrum antimicrobial agent, is widely used in clinical settings and various personal care products. The aim of this study was to evaluate the influence of TCS on reproductive endocrine and function. Here, we show that the exposure of adult female mice to 10 or 100 mg/kg/day TCS caused prolongation of diestrus, and decreases in antral follicles and corpora lutea within 2 weeks. TCS mice showed decreases in the levels of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone, and gonadotrophin-releasing hormone (GnRH) mRNA with the lack of LH surge and elevation of prolactin (PRL). TCS mice had lower kisspeptin immunoreactivity and kiss1 mRNA in anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). Moreover, the estrogen (E2)-enhanced AVPV-kisspeptin expression was reduced in TCS mice. In addition, the serum thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) in TCS mice were reduced with increases in levels of thyroid stimulating hormone (TSH) and thyroid releasing hormone (TRH). In TCS mice, the treatment with Levothyroxine (L-T4) corrected the increases in PRL, TSH and TRH; the administration of L-T4 or type-2 dopamine receptors agonist quinpirole inhibiting PRL release could rescue the decline of kisspeptin expression in AVPV and ARC; the treatment with L-T4, quinpirole or the GPR45 agonist kisspeptin-10 recovered the levels of serum LH and FSH and progesterone, and GnRH mRNA. Furthermore, TCS mice treated with L-T4 or quinpirole resumed regular estrous cycling, follicular development and ovulation. Together, these results indicate that exposing adult female mice to TCS (≥10 mg/kg) reduces thyroid hormones causing hyperprolactinemia that then suppresses hypothalamic kisspeptin expression, leading to deficits in reproductive endocrine and function.

Influence of postnatal prolactin modulation on the development and maturation of ventral prostate in young rats.

Besides androgenic dependence, other hormones also influence the prostate biology. Prolactin has been described as an important hormone associated with maintenance of prostatic morphophysiology; however, there is a lack of information on the involvement of prolactin during prostate development and growth. This study aimed to evaluate whether perinatal prolactin modulation interferes with rat ventral prostate (VP) development and maturation. Therefore, prolactin or bromocriptine (an inhibitor of prolactin release from the pituitary) were administered to Sprague Dawley rats from postnatal Day (PND) 12 to PND 21 or 35. Animals were then killed and serum hormonal quantification, VP morphological-stereological and immunohistochemical analyses and western blotting reactions were employed. Our results demonstrate that prolactin blockage increased serum testosterone on PND 21, which reflected an increase in anogenital distance. Although prolactin modulation did not interfere with VP weight, it modified VP morphology by dilating the acinar lumen and reducing epithelial cell height. Prolactin activated the signal transducer and activator of transcription (STAT) downstream pathway, increased androgen receptor expression and epithelial proliferation. In addition, prolactin and bromocriptine also increased expression of cytokeratin 18, a marker of luminal-differentiated cells. In conclusion, the VP responds to prolactin modulation through a mechanism of increasing the epithelial proliferative response and dynamics of cell differentiation, especially in animals treated for a more prolonged period.

Inhibiting prolactin by cabergoline accelerates mammary gland remodeling during the early dry period in dairy cows

The inhibition of prolactin release using cabergoline, a dopamine agonist, is an effective strategy to accelerate the changes in mammary secretion composition after drying-off. The objective of this study was to determine how cabergoline may affect mammary tissue remodeling during early involution. Holstein dairy cows were treated with either a single i.m. administration of 5.6 mg of cabergoline (Velactis, Ceva Santé Animale, Libourne, France, n = 7) or placebo (n = 7) at the time of drying-off. Mammary biopsy samples were collected 1 wk before drying-off (d -6), after 30 h of milk accumulation (d 1), and again 8 d following drying-off (d 8) to determine changes in gene expression, lactoferrin content, and cell turnover. Blood and mammary secretion samples were collected at d -6 and again at d 1, 2, 3, 4, 8, and 14 following the abrupt cessation of lactation to evaluate indicators of blood-milk barrier integrity and other markers of mammary tissue remodeling. Cabergoline induced less SLC2A1, BAX, CAPN2, and IGFBP5 mRNA expression. In contrast, cabergoline did not modify changes in cell proliferation and apoptosis. Following the cessation of lactation, changes in mammary secretion composition (Na+ and K+) and blood lactose concentrations were indicative of a loss in the blood-milk barrier function in both treatment groups. Cabergoline treatment affected only Na+ and K+ concentrations at d 1, suggesting a moderate increase in tight junction permeability. The increase in the activity of MMP9 and in mammary epithelial cell concentration in mammary secretions was greater in cabergoline-treated cows than in control cows, suggesting more mammary tissue remodeling. The increase in lactoferrin immunostaining in the mammary tissue occurred earlier for cabergoline-treated cows than for control cows, and was essentially localized in the stroma. Changes in some key markers of mammary involution suggest that cabergoline accelerates mammary gland remodeling. Thus, a single injection of cabergoline after the last milking would facilitate drying-off by enhancing mammary gland involution.

Identification of neuromedin U precursor-related peptide and its possible role in the regulation of prolactin release

The discovery of neuropeptides provides insights into the regulation of physiological processes. The precursor for the neuropeptide neuromedin U contains multiple consensus sequences for proteolytic processing, suggesting that this precursor might generate additional peptides. We performed immunoaffinity chromatography of rat brain extracts and consequently identified such a product, which we designated neuromedin U precursor-related peptide (NURP). In rat brain, NURP was present as two mature peptides of 33 and 36 residues. Radioimmunoassays revealed NURP immunoreactivity in the pituitary, small intestine, and brain of rats, with the most intense reactivity in the pituitary. Intracerebroventricular administration of NURP to both male and female rats robustly increased plasma concentrations of prolactin but not of other anterior pituitary hormones. In contrast, NURP failed to stimulate prolactin release from dispersed anterior pituitary cells. Pretreatment of rats with bromocriptine, a dopamine receptor agonist, blocked the prolactin-releasing activity of NURP. In rats pretreated with the antagonist sulpiride, intracerebroventricular administration of NURP did not increase plasma prolactin concentrations more than administration of saline. These data suggest that NURP induces prolactin release by acting indirectly on the pituitary; dopamine from the hypothalamus, which inhibits prolactin release, may be involved in this activity of NURP.