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International Journal of Medical... 2020Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance... (Observational Study)
Observational Study
Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas.
Topics: Adolescent; Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Bromocriptine; Cell Line, Tumor; Cyclin D1; Drug Resistance, Neoplasm; Estradiol; Estrogen Receptor alpha; Female; Fulvestrant; Humans; Hypophysectomy; MAP Kinase Signaling System; Male; Middle Aged; Neoplasm Recurrence, Local; Pituitary Gland; Pituitary Neoplasms; Prolactin; Prolactinoma; Rats; Receptors, Prolactin; Young Adult
PubMed: 33173437
DOI: 10.7150/ijms.51176 -
Diabetologia Jul 2016Pregnancy is a key mammalian reproductive event in which growth and differentiation of the fetus imposes extra metabolic and hormonal demands on the mother. Its... (Review)
Review
Pregnancy is a key mammalian reproductive event in which growth and differentiation of the fetus imposes extra metabolic and hormonal demands on the mother. Its successful outcome depends on major changes in maternal blood circulation, metabolism and endocrine function. One example is the endocrine pancreas, where beta cells undergo a number of changes in pregnancy that result in enhanced functional beta cell mass in order to compensate for the rising metabolic needs for maternal insulin. During the last 5 years, a series of studies have increased our understanding of the molecular events involved in this functional adaptation. In the mouse, a prominent functional change during pregnancy is the capacity of some beta cells to produce serotonin. In this review we will discuss the mechanism and potential effects of pregnancy-related serotonin production in beta cells, considering functional consequences at the local intra-islet and systemic level.
Topics: Animals; Female; Insulin-Secreting Cells; Islets of Langerhans; Mice; Pregnancy; Receptors, Prolactin; Serotonin; Tryptophan Hydroxylase
PubMed: 27056372
DOI: 10.1007/s00125-016-3951-2 -
Scientific Reports Dec 2019Although prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to...
Although prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to explore their contribution in GBM pathogenesis. We detected PRL and PRLR in all GBM cell lines tested. PRLR activation or overexpression using plasmid transfection increased proliferation, viability, clonogenicity, chemoresistance and matrix metalloproteinase activity in GBM cells, while PRLR antagonist ∆1-9-G129R-hPRL reduced their proliferation, viability, chemoresistance and migration. Meta-analysis of transcriptomic data indicated that PRLR was expressed in all grade II-III glioma (GII-III) and GBM samples. PRL was upregulated in GBM biopsies when compared to GII-III. While in the general population tumour PRL/PRLR expression did not correlate with patient survival, biological sex-stratified analyses revealed that male patients with PRL/PRLR GBM performed worse than PRL/PRLR GBM. In contrast, all male PRL/PRLR GII-III patients were alive whereas only 30% of PRL/PRLR GII-III patients survived after 100 months. Our study suggests that PRLR may be involved in GBM pathogenesis and could constitute a therapeutic target for its treatment. Our findings also support the notion that sexual dimorphism should be taken into account to improve the care of GBM patients.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Glioblastoma; Glioma; Humans; Male; Plasmids; Prolactin; Protein Binding; Rats; Receptors, Prolactin; Signal Transduction; Treatment Outcome
PubMed: 31862900
DOI: 10.1038/s41598-019-55860-x -
Domestic Animal Endocrinology Jul 2016Recent studies have shown that, in conjunction with dynamic changes in the secretion of GnRH from the hypothalamus, paracrine interactions within the pituitary gland... (Review)
Review
Recent studies have shown that, in conjunction with dynamic changes in the secretion of GnRH from the hypothalamus, paracrine interactions within the pituitary gland play an important role in the regulation of fertility during the annual reproductive cycle. Morphological studies have provided evidence for close associations between gonadotropes and lactotropes and gap junction coupling between these cells in a variety of species. The physiological significance of this cellular interaction was supported by subsequent studies revealing the expression of prolactin receptors in both the pars distalis and pars tuberalis regions of the pituitary. This cellular interaction is critical for adequate gonadotropin output because, in the presence of dopamine, prolactin can negatively regulate the LH response to GnRH. Receptor signaling studies showed that signal convergence at the level of protein kinase C and phospholipase C within the gonadotrope underlies the resulting inhibition of LH secretion. Although this is a conserved mechanism present in all species studied so far, in seasonal breeders such as the sheep and the horse, this mechanism is regulated by photoperiod, as it is only apparent during the long days of spring and summer. At this time of year, the nonbreeding season of the sheep coincides with the breeding season of the horse, indicating that this inhibitory system plays different roles in short- and long-day breeders. Although in the sheep, it contributes to the complete suppression of the reproductive axis, in the horse, it is likely to participate in the fine-tuning of gonadotropin output by preventing gonadotrope desensitization. The photoperiodic regulation of this inhibitory mechanism appears to rely on alterations in the folliculostellate cell population. Indeed, electron microscopic studies have recently shown increased folliculostellate cell area together with upregulation of their adherens junctions during the spring and summer. The association between gonadotropes and lactotropes could also underlie an interaction between the gonadotropic and prolactin axes in the opposite direction. In support of this alternative, a series of studies have demonstrated that GnRH stimulates prolactin secretion in sheep through a mechanism that does not involve the mediatory actions of LH or FSH and that this stimulatory effect of GnRH on the prolactin axis is seasonally regulated. Collectively, these findings highlight the importance of intercellular communications within the pituitary in the control of gonadotropin and prolactin secretion during the annual reproductive cycle in seasonal breeders.
Topics: Animals; Livestock; Photoperiod; Pituitary Gland; Reproduction; Seasons
PubMed: 27345316
DOI: 10.1016/j.domaniend.2016.01.002 -
Cephalalgia : An International Journal... Mar 2022Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short...
OBJECTIVE
Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short (PRLR-S) receptor isoforms.
BACKGROUND
The majority of patients with chronic migraine and medication overuse headache are female. Prolactin is present at higher levels in women and increases migraine. Prolactin signaling at the PRLR-S selectively sensitizes nociceptors in female rodents, while expression of the PRLR-L is protective.
METHODS
Medication overuse headache was modeled by repeated sumatriptan administration in male and female mice. Periorbital and hindpaw cutaneous allodynia served as a surrogate of migraine-like pain. PRLR-L and PRLR-S isoforms were measured in the trigeminal ganglion with western blotting. Possible co-localization of PRLR with serotonin 5HT1B and 5HT1D receptors was determined with RNAscope. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was co-administered with sumatriptan. Nasal administration of CRISPR/Cas9 plasmid was used to edit expression of both PRLR isoforms.
RESULTS
PRLR was co-localized with 5HT1B or 5HT1D receptors in the ophthalmic region of female trigeminal ganglion. A single injection of sumatriptan increased serum PRL levels in female mice. Repeated sumatriptan promoted cutaneous allodynia in both sexes but down-regulated trigeminal ganglion PRLR-L, without altering PRLR-S, only in females. Co-administration of sumatriptan with cabergoline prevented allodynia and down-regulation of PRLR-L only in females. CRISPR/Cas9 editing of both PRLR isoforms in the trigeminal ganglion prevented sumatriptan-induced periorbital allodynia in females.
INTERPRETATION
We identified a sexually dimorphic mechanism of migraine chronification that involves down-regulation of PRLR-L and increased signaling of circulating prolactin at PRLR-S. These studies reveal a previously unrecognized neuroendocrine mechanism linking the hypothalamus to nociceptor sensitization that increases the risk of migraine pain in females and suggest opportunities for novel sex-specific therapies including gene editing through nasal delivery of CRISPR/Cas9 constructs.
Topics: Animals; Female; Headache Disorders, Secondary; Humans; Hyperalgesia; Male; Mice; Migraine Disorders; Prolactin; Sumatriptan
PubMed: 34510920
DOI: 10.1177/03331024211039813 -
Journal of Cellular and Molecular... Nov 2021Breast cancer, a hormone-dependent tumour, generally includes four molecular subtypes (luminal A, luminal B, HER2 enriched and triple-negative) based on oestrogen... (Review)
Review
Breast cancer, a hormone-dependent tumour, generally includes four molecular subtypes (luminal A, luminal B, HER2 enriched and triple-negative) based on oestrogen receptor, progesterone receptor and human epidermal growth factor receptor-2. Multiple hormones in the body regulate the development of breast cancer. Endocrine therapy is one of the primary treatments for hormone-receptor-positive breast cancer, but endocrine resistance is the primary clinical cause of treatment failure. Prolactin (PRL) is a protein hormone secreted by the pituitary gland, mainly promoting mammary gland growth, stimulating and maintaining lactation. Previous studies suggest that high PRL levels can increase the risk of invasive breast cancer in women. The expression levels of PRL and PRLR in breast cancer cells and breast cancer tissues are elevated in most ER and ER tumours. PRL activates downstream signalling pathways and affects endocrine therapy resistance by combining with prolactin receptor (PRLR). In this review, we illustrated and summarized the correlations between endocrine therapy resistance in breast cancer and PRL, as well as the pathophysiological mechanisms and clinical practices. The study on PRL and its receptor would help explore reversing endocrine therapy-resistance for breast cancer.
Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Clinical Decision-Making; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Neoplastic Stem Cells; Prolactin; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Tumor Microenvironment
PubMed: 34651424
DOI: 10.1111/jcmm.16946 -
Pathology Oncology Research : POR Apr 2015Prolactin receptor (PRLR) overexpression could play a role in tumorigenesis. The aim of this study was to determine prolactin (PRL) and PRLR expression in biopsies from... (Comparative Study)
Comparative Study
Prolactin receptor (PRLR) overexpression could play a role in tumorigenesis. The aim of this study was to determine prolactin (PRL) and PRLR expression in biopsies from patients with precursor lesions and uterine cervical cancer. PRLR expression was analyzed in 63 paraffin-embedded biopsies of uterine cervical tissue. In total, eleven low-grade squamous intraepithelial lesions (LSIL), 23 high-grade squamous intraepithelial lesions (HSIL), 21 uterine cervical cancers (UCC) and 8 normal epithelium (NE) were examined using immunoperoxidase staining and Western blot analysis. Additionally, PRL expression was identified in human cervical cancer serum and tissues. The PRLR expression was found to be significantly increased in cervical cancer in comparison with normal tissue and precursor lesions (P < 0.0003). The presence of the long isoform of the PRLR was observed only in cervical cancer tissues. Serum PRL levels were normal in all samples and local prolactin expression was similar in precursor lesions and cervical cancer by Western blot analysis. Our data suggest a possible role for PRLR in the progression of cervical cancer.
Topics: Biopsy; Cell Line, Tumor; Cervix Uteri; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Neoplasm Grading; Prolactin; Receptors, Prolactin; Signal Transduction; Uterine Cervical Neoplasms; Uterine Cervical Dysplasia
PubMed: 24990775
DOI: 10.1007/s12253-014-9814-6 -
Prolactin receptor gene polymorphism and the risk of recurrent pregnancy loss: a case-control study.Journal of Obstetrics and Gynaecology :... Feb 2018Since the first study was published reporting the candidate association between the prolactin receptor gene intron C/T polymorphism (rs37389) and recurrent miscarriage,...
Since the first study was published reporting the candidate association between the prolactin receptor gene intron C/T polymorphism (rs37389) and recurrent miscarriage, no replication study has been performed. In this study, we investigated the role of the prolactin receptor gene C/T polymorphism in 311 Korean women with recurrent pregnancy loss and 314 controls. Genotyping for prolactin receptor gene intron C/T polymorphism was performed using a TaqMan assay. The significance of difference in the genotype distribution was assessed using a chi-square test, and continuous variables were compared using a Student's t-test. The genotype distribution of the prolactin receptor gene C/T polymorphism in the recurrent pregnancy loss group did not differ from that in the control group (CC/CT/TT rates were 49.8%/41.5%/8.7% and 52.5%/37.6%/9.9% for the recurrent pregnancy loss patient and control groups, respectively, p = .587). When the analysis was restricted to patients with three or more consecutive spontaneous miscarriages or patients without prior live birth, there were also no differences in the genotype distribution between these subgroups and controls. In conclusion, the findings of the current study suggest that the prolactin receptor gene intron C/T polymorphism is not a major determinant of the development of recurrent pregnancy loss. Impact statement What is already known: Many studies have investigated whether there is a genetic component for the risk of recurrent pregnancy loss. Recently, one study investigated whether genetic polymorphisms involved in the regulation of the hypothalamic-pituitary-ovarian axis would be associated with recurrent miscarriage. Among 35 polymorphisms in 20 candidate genes, genotype distribution with regard to the prolactin receptor gene intron C/T polymorphism (rs37389) differed between the recurrent miscarriage and the control groups. Since this study reporting the candidate association between the prolactin receptor gene and recurrent miscarriage, no replication study has been performed. What the results of this study add: The genotype distribution of the prolactin receptor gene C/T polymorphism in the recurrent miscarriage group did not differ from that in the control group. What the implications are of these findings: Our study may be useful in that it is the first replication study since the initial report of the association of prolactin receptor gene polymorphism with recurrent miscarriage. Although no association was found, the potential role of prolactin in pregnancy loss needs to be further investigated because prolactin and its receptor have been postulated to play an important role in the maintenance of normal pregnancy.
Topics: Abortion, Habitual; Adult; Case-Control Studies; Cell Cycle Proteins; Chi-Square Distribution; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Polymorphism, Single Nucleotide; Pregnancy; Real-Time Polymerase Chain Reaction; Receptors, Prolactin; Risk Factors; S100 Calcium Binding Protein A6
PubMed: 28980840
DOI: 10.1080/01443615.2017.1351932 -
Journal of Neuroendocrinology Jul 2023Maternal interactions with offspring are highly rewarding, which reinforces expression of essential caregiving behaviours that promote offspring survival. In rats, the...
Maternal interactions with offspring are highly rewarding, which reinforces expression of essential caregiving behaviours that promote offspring survival. In rats, the rewarding effect of pups depends on reproductive state, with lactating females specifically developing strong preferences for pup-associated contexts. Whether this also occurs in mice is unknown, hence we aimed to characterise pup-related preference across reproductive states in female mice. In a conditioned place preference (CPP) test, pups were a rewarding stimulus to female mice prior to lactation, with virgin and pregnant females developing a preference for a pup-associated context. We have previously shown that lactogenic hormones, acting through the prolactin receptor (Prlr), play an important role in maternal motivation. Here, we aimed to investigate whether Prlr action is important for pup-related reward behaviour in mice. We showed that prolactin itself had a reinforcing effect in a CPP test, and that exposure to pups increased blood prolactin levels in virgin female mice. Prlr expression in CamKIIα-expressing neurons and GABAergic neurons has previously been shown to be important for different aspects of parental behaviour. However, we found that conditional Prlr deletion from either of these neuronal populations did not disrupt the development of a preference for pup-associated contexts in pregnant female mice, indicating that lactogenic action on these populations is not necessary for the rewarding effect of pups. Together, these data show that while lactogenic hormones likely contribute to a rewarding effect of pups, their action on two key neuronal populations is not necessary for this effect in female mice.
Topics: Pregnancy; Humans; Animals; Mice; Rats; Female; Prolactin; Lactation; Maternal Behavior; Receptors, Prolactin; Reward; GABAergic Neurons
PubMed: 36691950
DOI: 10.1111/jne.13232 -
Theriogenology Jul 2023Physiological mechanisms of seasonal changes in testicular function in birds are not fully elucidated. The balance between androgens and estrogens and testis sensitivity...
Physiological mechanisms of seasonal changes in testicular function in birds are not fully elucidated. The balance between androgens and estrogens and testis sensitivity for gonadotropin and gonadal steroids are still unclear. The aim of the study was to examine: (1) the changes in circulating and intra-testicular steroid hormone levels and their relationship; (2) the mRNA expression of testicular gonadotropin, prolactin (PRL), progesterone (P4), androgen, and estrogen receptors, and (3) key steroidogenesis processes-related genes with immunofluorescent localization of aromatase in gander testes during the annual period. Testes from ganders (n = 25) in the first reproduction season were obtained at five breeding stages, i.e., prebreeding (PrB), peak of reproduction (PR), postbreeding (PoB), nonbreeding (NB), and onset of reproduction (OR). Males were kept under breeding conditions. It was found that plasma P4 levels decreased at the PoB and NB stages, whereas intra-testicular P4 was the highest in the NB stage. Intra-testicular estradiol (E2) levels were higher at the PoB and NB stages than the other stages, whereas testosterone (T) levels showed a nearly opposite pattern. The plasma estradiol-to-testosterone ratios were higher at the PrB, PoB and NB stages compared to other stages. The transcript abundances for luteinizing hormone receptor (LHR), PRL receptor (PRLR), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) also change in testicular tissue during the annual period. Moreover, StAR mRNA expression was upregulated at the PoB and NB stages, and CYP11A1 transcript level was the highest at the PoB stage. Stage-dependent changes in the CYP19A1 mRNA and aromatase protein levels with higher abundances of transcript at PoB and NB stages and protein at the NB stage were observed. Localization and immunofluorescent signal intensity for aromatase also differed in relation to the examined stages. It may be suggested that differential E2 levels, as well as aromatase expression and localization across annual stages are responsible for the seasonal activation/inactivation stages of testis spermatogenesis in domestic ganders. These data strongly suggest a role of aromatase in the control of gander steroidogenesis as changes in this enzyme level are associated with alternation in gonadal steroid hormones. In addition, joint action with others hormones, like PRL and LH, seems to be important in the final effect of seasonal reproduction potential.
Topics: Animals; Male; Androgens; Aromatase; Estradiol; Gene Expression; Gonadal Steroid Hormones; Prolactin; Receptors, Estrogen; RNA, Messenger; Testis; Testosterone; Gonadotropins; Steroids; Geese
PubMed: 37105092
DOI: 10.1016/j.theriogenology.2023.04.019