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1.
Front Endocrinol (Lausanne) ; 13: 903505, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060944

RESUMO

Multiple studies have shown associations between exposure to endocrine disrupting chemicals (EDCs) and reduced fertility in women. However, little is known about the target organs of chemical disruption of female fertility. Here, we focus on the hormone-sensitive uterine lining, the endometrium, as a potential target. Decidualization is the morphological and functional change that endometrial stromal cells undergo to support endometrial receptivity, which is crucial for successful implantation, placentation, and pregnancy. We investigated the effect of nine selected EDCs on primary human endometrial stromal cell decidualization in vitro. The cells were exposed to a decidualization-inducing mixture in the presence or absence of 1 µM of nine different EDCs for nine days. Extent of decidualization was assessed by measuring the activity of cAMP dependent protein kinase, Rho-associated coiled-coil containing protein kinase, and protein kinase B in lysates using photoluminescent probes, and secretion of prolactin into the media by using ELISA. Decidualization-inducing mixture upregulated activity of protein kinases and prolactin secretion in cells derived from all women. Of the tested chemicals, dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB) and perfluorooctanesulfonic acid (PFOS) significantly reduced decidualization as judged by the kinase markers and prolactin secretion. In addition, bisphenol A (BPA) reduced prolactin secretion but did not significantly affect activity of the kinases. None of the EDCs was cytotoxic, based on the assessment of total protein content or activity of the viability marker casein kinase 2 in lysates. These results indicate that EDCs commonly present in the blood circulation of reproductive-aged women can reduce decidualization of human endometrial stromal cells in vitro. Future studies should focus on detailed hazard assessment to define possible risks of EDC exposure to endometrial dysfunction and implantation failure in women.


Assuntos
Decídua , Disruptores Endócrinos , Adulto , Células Cultivadas , Decídua/metabolismo , Disruptores Endócrinos/metabolismo , Feminino , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Gravidez , Prolactina/metabolismo , Células Estromais/metabolismo
2.
Int Breastfeed J ; 17(1): 66, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050767

RESUMO

BACKGROUND: Childbirth and lactation are intricate processes, involving several hormones, the most important of which are prolactin (a protein hormone) and cortisol (one of the glucocorticoids). The early postpartum period is crucial for both mother and newborn and has an impact on the lactation and breastfeeding process. METHODS: The study included 78 patients who were admitted to the Gynecology-Obstetrics Clinical Hospital in Poznan for labor induction and/or in the active phase of the first labor stage. The levels of cortisol and prolactin in serum were assessed in these women during admission in labor, during the third labor stage, and on the second day postpartum. The levels of cortisol and prolactin in the umbilical cord serum were assessed immediately after cord clamping. The "Protocol for the assessment of breast-suckling skills" was used to assess the neonatal breast-suckling skills on the second day postpartum. Some additional parameters were evaluated in mothers via a telephone interview at three and six months postpartum. The study was conducted from January to August 2020, however the study was suspended during April-July 2020 due to the SARS-CoV-2 pandemic, which led to restrictions in the hospital limiting access to the hospital wards unless necessary. RESULTS: Early breastfeeding with skin-to-skin contact was associated with low levels of hormones, cortisol levels were lower in serum (p = 0.0108) and umbilical vein (p = 0.0273) in mothers who breastfed immediately after childbirth. At three months postpartum, 88% of the mothers who did not offer a pacifier to the child during the first few days of life breastfed the child naturally (p = 0.037), and at six months, 96% of those who did not offer a pacifier continued to breastfeed (p = 0.0008). Multiple, statistically significant correlations were observed between the variables assessed according to the "Protocol for the assessment of breast-suckling skills" and breastfeeding after three months. CONCLUSIONS: Breastfeeding immediately after childbirth, appropriate assessment of the breast-suckling skills of newborns, avoiding pacifiers and infant formula feeding, and offering support to new mothers in the early days after childbirth seem to be important factors for sustaining breastfeeding after three and six months of childbirth.


Assuntos
Aleitamento Materno , COVID-19 , Criança , Feminino , Humanos , Hidrocortisona , Lactente , Recém-Nascido , Lactação , Período Periparto , Projetos Piloto , Gravidez , Prolactina/metabolismo , SARS-CoV-2
3.
Endocrinology ; 163(10)2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35922139

RESUMO

The pathogenesis of breast cancer is driven by multiple hormones and growth factors. One of these, prolactin (PRL), contributes to both mammary differentiation and oncogenesis, and yet the basis for these disparate effects has remained unclear. The focus of this review is to examine and place into context 2 recent studies that have provided insight into the roles of PRL receptors and PRL in tumorigenesis and tumor progression. One study provides novel evidence for opposing actions of PRL in the breast being mediated in part by differential PRL receptor (PRLr) isoform utilization. Briefly, homomeric complexes of the long isoform of the PRLr (PRLrL-PRLrL) promotes mammary differentiation, while heteromeric complexes of the intermediate and long PRLr (PRLrI-PRLrL) isoforms trigger mammary oncogenesis. Another study describes an immunodeficient, prolactin-humanized mouse model, NSG-Pro, that facilitates growth of PRL receptor-expressing patient-derived breast cancer xenografts. Evidence obtained with this model supports the interactions of physiological levels of PRL with estrogen and ERBB2 gene networks, the modulatory effects of PRL on drug responsiveness, and the pro-metastatic effects of PRL on breast cancer. This recent progress provides novel concepts, mechanisms and experimental models expected to renew interest in harnessing/exploiting PRLr signaling for therapeutic effects in breast cancer.


Assuntos
Neoplasias da Mama , Prolactina , Animais , Transformação Celular Neoplásica , Feminino , Humanos , Camundongos , Prolactina/metabolismo , Isoformas de Proteínas , Receptores da Prolactina/metabolismo
4.
Oxid Med Cell Longev ; 2022: 1735204, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35923861

RESUMO

We verified whether caffeinated coffee consumption influenced the concentrations of prolactin (PRL) and oxidative stress parameters: total antioxidant status (TAS), ferric reducing antioxidant power (FRAP), total oxidant status (TOS), oxidative stress index (OSI), advanced oxidation protein products (AOPP), uric acid (UA), total bilirubin (T-Bil), albumin (ALB), iron (Fe), calcium (Ca), magnesium (Mg), and inflammatory marker C-reactive protein (CRP)-in blood sera obtained at 15, 60, and 120 minutes after caffeinated coffee intake, in relation to the fasting point. The study participants were 33 young, healthy, nonsmoking volunteers (15 men, 18 women) aged 19-29 years. PRL concentrations significantly decreased (p < 0.05) after consumption, except at time point 15' in men (p > 0.05). In women, FRAP levels significantly increased over time, and significant changes were also observed for UA at 120' and ALB at 15'. In men, significant changes were found for levels of AOPP at 15', T-Bil and ALB at 15', iron at 60' and 120', and calcium at 120'. There were no significant differences in the levels of other examined parameters between the defined time points. In conclusion, the substances contained in caffeinated coffee decrease the level of prolactin and may also have an impact on selected parameters of oxidative stress, which could be the basis of future research focused on the identification of new therapeutic targets.


Assuntos
Antioxidantes , Café , Adulto , Produtos da Oxidação Avançada de Proteínas/metabolismo , Antioxidantes/metabolismo , Bilirrubina/metabolismo , Cálcio/metabolismo , Feminino , Humanos , Ferro , Masculino , Estresse Oxidativo , Prolactina/metabolismo , Ácido Úrico , Adulto Jovem
5.
Theriogenology ; 190: 73-80, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35963123

RESUMO

Prolactin (PRL) secretion by the anterior pituitary (AP) is responsive to changes in physiological conditions and many external factors that also affect brain neurosteroid levels. This study tested the hypothesis that neurosteroids can affect PRL secretion in sheep under basal, stressful and advanced pregnancy conditions. In Experiment 1, luteal-phase sheep were subjected to a three-day series of intracerebroventricular (icv.) control (n = 12) or allopregnanolone (AL, 4 × 15 µg/60 µL/30 min at 30-min intervals, n = 12) infusions. Acute stressful stimuli, isolation and partial movement restriction were applied on the third day of infusion to half of the animals in each group. In Experiment 2, pregnant sheep were subjected to a three-day series of icv. control (n = 6) or finasteride (4 × 25 µg/60 µL/30 min at 30-min intervals, n = 6) infusions during the 16th week of pregnancy. As a result, the relative abundance of PRL transcript increased in the AP of luteal-phase sheep treated with stress, AL and AL in combination with stress (P < 0.05 - P < 0.01) compared to controls. The level of PRL mRNA in stressed-AL-treated sheep was higher (P < 0.01) than in sheep only subjected to stress. The PRL protein content in the AP decreased in stressed-only sheep compared to controls (P < 0.05) and increased in stressed-AL-treated sheep compared to controls and other groups (P < 0.05 - P < 0.01). Plasma PRL concentration increased (P < 0.05 - P < 0.01) in stressed-only sheep compared to controls; AL infusion counteracted the stress-induced increase in PRL levels (P < 0.05 - P < 0.01) and had no effect in non-stressed animals. Inhibition of neurosteroid synthesis in the brain of pregnant sheep by finasteride caused transient increases (P < 0.05 - P < 0.001) in plasma PRL concentration compared to controls. In conclusion, the presented results indicate a bimodal effect of AL on PRL secretion in sheep: first at the molecular level - stimulation of PRL mRNA expression; second - inhibition of hormone release from pituitary lactotrophs. Both AL activities may involve various mechanisms regulating PRL secretion. In general, cerebral neurosteroids can affect the supply of pituitary PRL in the body under certain conditions, such as stress and pregnancy.


Assuntos
Neuroesteroides , Prolactina , Animais , Feminino , Finasterida , Hipófise/metabolismo , Gravidez , Prolactina/metabolismo , RNA Mensageiro , Ovinos
6.
Tumour Biol ; 44(1): 85-105, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35811548

RESUMO

INTRODUCTION: Prolactinomas are the most frequent pituitary tumor subtype. Despite most of them respond to medical treatment, a proportion are resistant and become a challenge in clinical management. Wnt/ß-Catenin pathway has been implicated in several cancers including pituitary tumors and other sellar region malignancies. Interestingly, Wnt/ß-Catenin inhibition augments the cytotoxicity of the chemotherapeutic agent Temozolomide (TMZ) in different cancers. TMZ is now being implemented as rescue therapy for aggressive pituitary adenoma treatment. However, the molecular mechanisms associated with TMZ action in pituitary tumors remain unclear. OBJECTIVES: Our aims in the present study were to evaluate differential ß-Catenin expression in human resistant prolactinomas and Wnt/ß-Catenin signaling activation and involvement in Prolactin (PRL) secreting experimental models treated with TMZ. RESULTS: We first evaluated by immunohistochemistry ß-Catenin localization in human resistant prolactinomas in which we demonstrated reduced membrane ß-Catenin in prolactinoma cells compared to normal pituitaries, independently of the Ki-67 proliferation indexes. In turn, in vivo 15 mg/kg of orally administered TMZ markedly reduced PRL production and increased prolactinoma cell apoptosis in mice bearing xenografted prolactinomas. Intratumoral ß-Catenin strongly correlated with Prl and Cyclin D1, and importantly, TMZ downregulated both ß-Catenin and Cyclin D1, supporting their significance in prolactinoma growth and as candidates of therapeutic targets. When tested in vitro, TMZ directly reduced MMQ cell viability, increased apoptosis and produced G2/M cell cycle arrest. Remarkably, ß-Catenin activation and VEGF secretion were inhibited by TMZ in vitro. CONCLUSIONS: We concluded that dopamine resistant prolactinomas undergo a ß-Catenin relocalization in relation to normal pituitaries and that TMZ restrains experimental prolactinoma tumorigenicity by reducing PRL production and ß-Catenin activation. Together, our findings contribute to the understanding of Wnt/ß-Catenin implication in prolactinoma maintenance and TMZ therapy, opening the opportunity of new treatment strategies for aggressive and resistant pituitary tumors.


Assuntos
Neoplasias Hipofisárias , Prolactinoma , Animais , Ciclina D1 , Humanos , Camundongos , Modelos Teóricos , Neoplasias Hipofisárias/patologia , Prolactina/metabolismo , Prolactina/uso terapêutico , Prolactinoma/tratamento farmacológico , Prolactinoma/metabolismo , Prolactinoma/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , beta Catenina
7.
Braz J Med Biol Res ; 55: e11976, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35857996

RESUMO

Non-biodegradable metals such as mercury accumulate in living organisms during life (bioaccumulation) and also within trophic webs (biomagnification) and may reach high concentrations in humans. The contamination of humans by mercury in drinking water and food may be common, in particular in riverside communities that have a diet rich in fish. In vitro studies of human cell lines exposed to the cytotoxic and mutagenic effects of methylmercury have shown that prolactin has potential cytoprotective properties and may act as a co-mitogenic factor and inhibitor of apoptosis. The present in vivo study investigated the protective potential of prolactin against the toxic effects of methylmercury in the mammal Mus musculus. Histological and biochemical analyses, together with biomarker of genotoxicity, were used to verify the protective potential of prolactin in mice exposed to methylmercury. The reduction in kidney and liver tissue damage was not significant. However, results of biochemical and genotoxic analyses were excellent. After prolactin treatment, a significant reduction was observed in biochemical parameters and mutagenic effects of methylmercury. The study results therefore indicated that prolactin has protective effects against the toxicity of methylmercury and allowed us to suggest the continuation of research to propose prolactin in the future, as an alternative to prevent the damage caused by mercury, especially in populations that are more exposed.


Assuntos
Mercúrio , Compostos de Metilmercúrio , Animais , Dano ao DNA , Peixes , Humanos , Mamíferos/metabolismo , Mercúrio/análise , Mercúrio/metabolismo , Mercúrio/toxicidade , Compostos de Metilmercúrio/toxicidade , Camundongos , Prolactina/metabolismo
8.
Horm Behav ; 144: 105217, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35785711

RESUMO

Prolactin, a hormone involved in vertebrate parental care, is hypothesized to inhibit reproductive hypothalamic-pituitary-gonadal (HPG) axis activity during parenting, thus maintaining investment in the current brood as opposed to new reproductive efforts. While prolactin underlies many parental behaviors in birds, its effects on other reproductive behaviors, such as courtship, remain unstudied. How prolactin affects neuropeptide and hormone receptor expression across the avian HPG axis also remains unknown. To address these questions, we administered ovine prolactin (oPRL) or a vehicle control to both sexes in experienced pairs of the biparental rock dove (Columba livia), after nest removal at the end of incubation. We found that oPRL promoted parental responses to novel chicks and stimulated crop growth compared to controls, consistent with other studies. However, we found that neither courtship behaviors, copulation rates nor pair maintenance differed with oPRL treatment. Across the HPG, we found oPRL had little effect on gene expression in hypothalamic nuclei, but increased expression of FSHB and hypothalamic hormone receptor genes in the pituitary. In the gonads, oPRL increased testes size and gonadotropin receptor expression, but did not affect ovarian state or small white follicle gene expression. However, the oviducts of oPRL-treated females were smaller and had lower estrogen receptor expression compared with controls. Our results highlight that some species, especially those that show multiple brooding, may continue to express mating behavior despite elevated prolactin. Thus, mechanisms may exist for prolactin to promote investment in parental care without concurrent inhibition of reproductive function or HPG axis activity.


Assuntos
Columbidae , Prolactina , Animais , Columbidae/metabolismo , Feminino , Expressão Gênica , Gônadas/metabolismo , Masculino , Prolactina/metabolismo , Prolactina/farmacologia , Reprodução/fisiologia , Ovinos
9.
Endocrinology ; 163(9)2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35863039

RESUMO

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 hCGß 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.


Assuntos
Neoplasias Hipofisárias , Prolactinoma , Animais , Feminino , Humanos , Cininas , Masculino , Camundongos , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Prolactina/metabolismo , Prolactinoma/genética , Prolactinoma/metabolismo , Receptor B2 da Bradicinina/agonistas , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Receptores da Bradicinina
10.
Front Endocrinol (Lausanne) ; 13: 883092, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757410

RESUMO

Background: The association of high serum prolactin and increased body weight is positive but controversial, therefore we hypothesized that additional factors such as diets and the impact of prolactin on brown adipose tissue may condition its metabolic effects. Methods: We used LacDrd2KO females with lifelong severe hyperprolactinemia due dopamine-D2 receptor deletion from lactotropes, and slow onset of metabolic disturbances, and compared them to their respective controls (Drd2 loxP/loxP ). Food intake, and binge eating was evaluated. We then challenged mice with a High Fat (HFD) or a Control Diet (CD) for 8 weeks, beginning at 3 months of age, when no differences in body weight are found between genotypes. At the end of the protocol brown and white adipose tissues were weighed, and thermogenic and lipogenic markers studied, using real time PCR (Ucp1, Cidea, Pgc1a, Lpl, adiponectin, Prlr) or immunohistochemistry (UCP1). Histochemical analysis of brown adipose tissue, and glucose tolerance tests were performed. Results: Hyperprolactinemic mice had increased food intake and binge eating behavior. Metabolic effects induced by a HFD were exacerbated in lacDrd2KO mice. Hyperprolactinemia aggravated HFD-induced body weight gain and glucose intolerance. In brown adipose tissue pronounced cellular whitening as well as decreased expression of the thermogenic markers Ucp1 and Pgc1a were observed in response to high prolactin levels, regardless of the diet, and furthermore, hyperprolactinemia potentiated the decrease in Cidea mRNA expression induced by HFD. In subcutaneous white adipose tissue hyperprolactinemia synergistically increased tissue weight, while decreasing Prlr, Adiponectin and Lpl mRNA levels regardless of the diet. Conclusions: Pathological hyperprolactinemia has a strong impact in brown adipose tissue, lowering thermogenic markers and evoking tissue whitening. Furthermore, it modifies lipogenic markers in subcutaneous white adipose, and aggravates HFD-induced glucose intolerance and Cidea decrease. Therefore, severe high prolactin levels may target BAT function, and furthermore represent an adjuvant player in the development of obesity induced by high fat diets.


Assuntos
Intolerância à Glucose , Hiperprolactinemia , Adiponectina/farmacologia , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Intolerância à Glucose/metabolismo , Hiperprolactinemia/metabolismo , Hiperprolactinemia/patologia , Camundongos , Obesidade/metabolismo , Prolactina/metabolismo , RNA Mensageiro/metabolismo , Aumento de Peso
11.
Front Endocrinol (Lausanne) ; 13: 905756, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721729

RESUMO

The term inflammatory arthritis defines a family of diseases, including rheumatoid arthritis (RA), caused by an overactive immune system, and influenced by host aspects including sex, reproductive state, and stress. Prolactin (PRL) is a sexually dimorphic, reproductive, stress-related hormone long-linked to RA under the general assumption that it aggravates the disease. However, this conclusion remains controversial since PRL has both negative and positive outcomes in RA that may depend on the hormone circulating levels, synthesis by joint tissues, and complex interactions at the inflammatory milieu. The inflamed joint is rich in matrix metalloproteases that cleave PRL to vasoinhibin, a PRL fragment with proinflammatory effects and the ability to inhibit the hyperpermeability and growth of blood vessels. This review addresses this field with the idea that explanatory mechanisms lie within the PRL/vasoinhibin axis, an integrative framework influencing not only the levels of systemic and local PRL, but also the proteolytic conversion of PRL to vasoinhibin, as vasoinhibin itself has dual actions on joint inflammation. In this review, we discuss recent findings from mouse models suggesting the upregulation of endogenous vasoinhibin by the pro-inflammatory environment and showing dichotomous actions and signaling mechanisms of PRL and vasoinhibin on joint inflammation that are cell-specific and context-dependent. We hypothesize that these opposing actions work together to balance the inflammatory response and provide new insights for understanding the pathophysiology of RA and the development of new treatments.


Assuntos
Artrite Reumatoide , Prolactina , Animais , Inflamação , Camundongos , Prolactina/metabolismo , Ligação Proteica
12.
Reprod Biomed Online ; 45(2): 202-210, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35773140

RESUMO

RESEARCH QUESTION: Does ageing affect endometrial stromal cell function and gene expression involved in decidualization? DESIGN: Stromal cells were isolated and cultured (98% purity) from pipelle endometrial biopsies obtained from female donors, at the proliferative phase of the menstrual cycle. Initially, 28 samples were collected (age range 25-46 years). These samples were divided into two groups: 25-35 years and 36-46 years. Cell proliferation assays were carried out to determine changes in stromal cell proliferation, in vitro, between the two groups. In addition, mRNA and protein expression of decidualization factors, BMP2 and STAT3, were analysed for the same age groups and samples using real-time polymerase chain reaction and western blot analysis, respectively. Finally, another 12 pipelle endometrial biopsies (age range 25-46 years) were used in separate in-vitro decidualization experiments. The mRNA expression of decidualization markers, prolactin and IGFBP-1 were analysed in cultured stromal cells after adding 8-bromo-cAMP. RESULTS: A statistically significant decrease was observed in stromal cell proliferation with increasing age (P = 0.0006). Messenger RNA expression of BMP2 and STAT3 were found to decrease (P = 0.0167; P = 0.0037, respectively) in the older age group. In addition, BMP2 and STAT3 protein expression between the samples analysed changed significantly (P = 0.0085; P = 0.0463, respectively) with increasing age. In-vitro induced decidualization experiments showed significant changes in stromal cell mRNA expression of decidualization markers (IGFBP1 and prolactin) between different age groups. CONCLUSION: Ageing affected endometrial cell function and gene expression. Changes in cell function and expression of associated molecules that differ in the ageing endometrium can help understand the causes of infertility.


Assuntos
Decídua , Prolactina , Adulto , Proliferação de Células , Células Cultivadas , Senescência Celular , Decídua/metabolismo , Endométrio/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Prolactina/metabolismo , RNA Mensageiro/metabolismo , Células Estromais/metabolismo
13.
Front Endocrinol (Lausanne) ; 13: 753416, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35663305

RESUMO

Background: Recurrent implantation failure (RIF) is a disease associated with endometrial receptivity dysfunction. Retinoic acid receptor alpha (RARα) is an important protein in many biological processes, such as differentiation and development. However, the exact underlying mechanism whereby RARα affects RIF remains unknown. This study investigated RARα expression and its contribution in the mid-luteal phase endometria of patients with RIF. Methods: The expression levels of RARα and CCAAT/enhancer-binding protein (C/EBP) ß in the endometria of the RIF and normal group were investigated using western blotting and immunohistochemistry. In in vitro experiments, immortal telomerase-transformed human endometrial stromal cells (T-HESCs) were incubated with medroxyprogesterone-17-acetate (MPA) and cyclic adenosine monophosphate (cAMP) for 4 days to induce decidualization. The expression levels of the decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1) were determined using quantitative polymerase chain reaction. RARα was knocked down using a small interfering RNA, and C/EBPß was overexpressed from an adenoviral vector. The transcriptional regulation of CEBPB by RARα was determined by chromatin immunoprecipitation (ChIP) assay and luciferase assays. Results: We found that the expression levels of RARα decreased in the mid-luteal endometria of RIF patients. After 4 days of decidualization induction in vitro, RARα knockdown impaired the decidualization of T-HESCs and downregulated the expression of C/EBPß. The restoration of C/EBPß expression rescued the RARα knockdown-induced suppression of T-HESC decidualization. In ChIP analysis of lysates from decidualized T-HESCs, the CEBPB promoter region was enriched in chromatin fragments pulled down using an anti-RARα antibody. However, the relationship between CEBPB transcription and RARα expression levels was only observed when the decidualization of T-HESCs was induced by the addition of cAMP and MPA. To identify the binding site of RARα/retinoid X receptor α, we performed luciferase assays. Mutation of the predicted binding site in CEBPB (-2,009/-1,781) decreased the transcriptional activity of the reporter. To confirm this mechanism, the expression levels of C/EBPß in the mid-luteal endometria of RIF patients were determined and found to decrease with decreased RARα expression levels. Conclusion: A deficiency of RARα expression in the mid-luteal endometrium inhibits decidualization due to the downregulation of CEBPB transcription. This is a potential mechanism contributing to RIF.


Assuntos
Decídua , Endométrio , Receptor alfa de Ácido Retinoico/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , AMP Cíclico/metabolismo , Decídua/metabolismo , Feminino , Humanos , Prolactina/metabolismo , Células Estromais/metabolismo
14.
J Anim Sci ; 100(7)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35772766

RESUMO

Heat stress (HS) compromises almost every aspect of animal agriculture including reproduction. In pigs, this infecundity is referred to as seasonal infertility (SI), a phenotype including ovarian dysfunction. In multiple species, HS-induced hyperprolactinemia has been described; hence, our study objectives were to characterize and compare HS effects on circulating prolactin (PRL) and ovarian Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling during the follicular (FOL) or luteal (LUT) phases of the estrous cycle in postpubertal gilts. Gilts were estrus synchronized using altrenogest and environmental treatments began immediately after altrenogest withdrawal. For the FOL study: postpubertal gilts were allocated to constant thermoneutral (TN; n = 6; 20 ± 1.2 °C) or cyclical HS (n = 6; 25 to 32 ± 1.2 °C) conditions for 5 d. In the LUT study: postpubertal gilts were assigned to either TN (n = 7; 20 ± 2.6 °C) or cyclical HS (n = 7; 32 to 35 ± 2.6 °C) conditions from 2 to 12 days postestrus (dpe). Blood was collected by jugular venipuncture for PRL quantification on day 5 in the FOL and on day 0 and day 12 in the LUT gilts. Ovaries and corpora lutea (CL) were obtained from euthanized FOL and LUT gilts on day 5 and day 12, respectively. Western blotting was performed to quantify prolactin receptor (PRLR) and JAK/STAT pathway protein abundance. In the FOL phase, no difference (P = 0.20) in circulating PRL between thermal groups was observed. There was no effect (P ≥ 0.34) of HS on PRLR, signal transducer and activator of transcription 3 (STAT3), signal transducer and activator of transcription 5α (STAT5α), and phosphorylated signal transducer and activator of transcription α/ß tyrosine 694/699 (pSTAT5α/ßTyr694/699) abundance and Janus kinase 2 (JAK2), phosphorylated janus kinase 2 tyrosine 1007/1008 (pJAK2Tyr1007/1008), STAT1, phosphorylated signal transducer and activator of transcription 1 tyrosine 701 (pSTAT1Tyr701), phosphorylated signal transducer and activator of transcription 1 serine 727 (pSTAT1Ser727), and phosphorylated signal transducer and activator of transcription 3 tyrosine 705 (pSTAT3Tyr705) were undetectable in FOL gilt ovaries. Ovarian pSTAT5α/ßTyr694/699 abundance tended to moderately increase (4%; P = 0.07) in FOL gilts by HS. In the LUT phase, circulating PRL increased progressively from 2 to 12 dpe, but no thermal treatment-induced difference (P = 0.37) was noted. There was no effect (P ≥ 0.16) of HS on CL abundance of PRLR, pJAK2Tyr1007/1008, JAK2, STAT1, pSTAT1Tyr701, pSTAT1Ser727, pSTAT3Tyr705, STAT5α, or pSTAT5α/ßTyr694/699. In LUT phase, CL STAT3 abundance was increased (11%; P < 0.03) by HS. There was no impact of HS (P ≥ 0.76) on levels of pJAK2Tyr1007/1008 and pSTAT5α/ßTyr694/699 in LUT gilts; however, the CL pSTAT3Tyr705:STAT3 ratio tended to be decreased (P = 0.10) due to HS. These results indicate an HS-induced estrous cycle-stage-dependent effect on the ovarian JAK/STAT pathway, establishing a potential role for this signaling pathway as a potential contributor to SI.


Heat stress (HS) negatively affects reproduction in pigs, though the precise mechanisms are not understood. This study determined if HS impacts the JAK-STAT signaling pathway in the ovary during two stages of the estrous cycle: follicular and luteal. While circulating prolactin hormone level was unchanged, there were changes to some aspects of ovarian JAK-STAT signaling that could be involved in infertility induced in pigs during HS.


Assuntos
Transtornos de Estresse por Calor , Doenças dos Suínos , Animais , Feminino , Transtornos de Estresse por Calor/metabolismo , Transtornos de Estresse por Calor/veterinária , Resposta ao Choque Térmico , Janus Quinase 2/metabolismo , Janus Quinase 2/farmacologia , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Ovário/metabolismo , Prolactina/metabolismo , Receptores da Prolactina/genética , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/farmacologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/farmacologia , Transdução de Sinais , Suínos , Doenças dos Suínos/metabolismo , Tirosina/metabolismo
15.
Front Endocrinol (Lausanne) ; 13: 844397, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685211

RESUMO

Background: Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, affecting energy homeostasis and reproduction. The aim of this study was to investigate whether stress affected energy metabolism and reproduction through the glucocorticoid receptor on Kisspeptin neurons in the hypothalamus. Methods: Four groups included control group, chronic restraint stress group, Kisspeptin specific glucocorticoid receptor knock out group (KGRKO) and KGRKO+stress group. Body weight, food intake, estrous cycle of female mice, serum sex hormone levels, serum corticosterone and prolactin, Kisspeptin expression in the hypothalamus were measured. Results: The restraint stress group showed a significant weight loss compared with the control group. KGRKO+restraint stress group had a reduced weight loss, suggesting that restraint stress might partially affect the energy metabolism through GR on Kisspeptin neurons. In terms of reproductive function, the restraint stress group and the KGRKO+restraint stress group showed missing pre-estrus period or prolonged estrous cycles. Serum LH and FSH in KGRKO + restraint stress group decreased significantly compared with KGRKO group. However, no significant difference in the level of serum testosterone was observed. After restraint stress, the levels of serum cortisol and prolactin in male and female mice were significantly higher than the control group, and the hypothalamus Kiss1 gene mRNA expression and Kisspeptin protein expression were significantly decreased. Conclusion: Chronic restraint stress induced weight loss and negative changes in reproduction, which were partially mediated by glucocorticoid receptor on Kisspeptin neurons in the hypothalamus.


Assuntos
Kisspeptinas , Receptores de Glucocorticoides , Animais , Metabolismo Energético/fisiologia , Feminino , Hipotálamo/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Masculino , Camundongos , Neurônios/metabolismo , Prolactina/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Reprodução , Redução de Peso
16.
Gen Comp Endocrinol ; 326: 114071, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35697315

RESUMO

Salinity is one of the main physical properties that govern the distribution of fishes across aquatic habitats. In order to maintain their body fluids near osmotic set points in the face of salinity changes, euryhaline fishes rely upon tissue-level osmotically-induced responses and systemic endocrine signaling to direct adaptive ion-transport processes in the gill and other critical osmoregulatory organs. Some euryhaline teleosts inhabit tidally influenced waters such as estuaries where salinity can vary between fresh water (FW) and seawater (SW). The physiological adaptations that underlie euryhalinity in teleosts have been traditionally identified in fish held under steady-state conditions or following unidirectional transfers between FW and SW. Far fewer studies have employed salinity regimes that simulate the tidal cycles that some euryhaline fishes may experience in their native habitats. With an emphasis on prolactin (Prl) signaling and branchial ionocytes, this mini-review contrasts the physiological responses between euryhaline fish responding to tidal versus unidirectional changes in salinity. Three patterns that emerged from studying Mozambique tilapia (Oreochromis mossambicus) subjected to tidally-changing salinities include, 1) fish can compensate for continuous and marked changes in external salinity to maintain osmoregulatory parameters within narrow ranges, 2) tilapia maintain branchial ionocyte populations in a fashion similar to SW-acclimated fish, and 3) there is a shift from systemic to local modulation of Prl signaling.


Assuntos
Salinidade , Tilápia , Aclimatação/fisiologia , Animais , Brânquias/metabolismo , Osmorregulação , Prolactina/metabolismo , Água do Mar , Tilápia/metabolismo , Equilíbrio Hidroeletrolítico/fisiologia
17.
Reprod Biomed Online ; 45(3): 519-530, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35773139

RESUMO

RESEARCH QUESTION: Adenomyosis is a common uterine disorder of uncertain causes. Can transcriptomic analyses of the endometrium and myometrium reveal potential mechanisms underlying adenomyosis pathogenesis? DESIGN: Transcriptomic profiles of eutopic endometrium and myometrium from women with and without diffuse adenomyosis and with symptomatic FIGO type 2-5 fibroids in the proliferative phase of the menstrual cycle were assessed using RNA sequencing and bioinformatic analysis. Differentially expressed genes (DEG) and potential pathways were validated by quantitative reverse transcription polymerase chain reaction, immunoblotting and Masson staining, using additional clinical samples. RESULTS: Top biological processes in the endometrium of women with versus without adenomyosis, enriched from DEG, comprised inflammation, extracellular matrix (ECM) organization, collagen degradation and hyaluronan synthesis, which are key in cell migration and cell movement. Top biological processes enriched from DEG in the myometrium of women with versus without adenomyosis revealed ECM organization dysfunction, abnormal sensory pain perception and gamma aminobutyric acid (GABA) synaptic transmission. Dysregulation of prolactin signalling was also enriched in eutopic endometrium and in the myometrium of women with adenomyosis. CONCLUSIONS: Overall, our results support the invasive endometrium theory in the pathogenesis of adenomyosis, in which inflammation induces ECM remodelling resulting in a track for subsequent endometrial collective cell migration and onset of adenomyosis. Moreover, abnormal myometrial GABA synaptic transmission may contribute to dysmenorrhoea in women with adenomyosis and is a possible target for novel therapeutic development. Prolactin signalling abnormalities may serve as another opportunity for therapeutic intervention.


Assuntos
Adenomiose , Endometriose , Adenomiose/patologia , Movimento Celular , Endometriose/patologia , Endométrio/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Prolactina/metabolismo , Transcriptoma , Ácido gama-Aminobutírico/genética , Ácido gama-Aminobutírico/metabolismo
18.
Int Immunopharmacol ; 108: 108901, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35729834

RESUMO

Memory loss is the most common occurrence of dementia in the elderly population. Evidence shows 1,2-Diacetylbenzene (DAB) can exacerbate cerebral dysfunction. The molecular mechanisms involved in DAB actions in the hippocampus have not been well elucidated to date. qPCR, western blot, Morris water maze, and RNAseq analysis were used to identify the association between inflammation and hyperphosphorylated tau in male DAB-treated mice (1 or 5 mg/kg/day), rats (3 mg/kg/day), in vitro BV2 microglial cells (1 or 5 µM), and the hippocampal transcriptome of male DAB-treated rats. We found that DAB induces memory deficits by activating pro-inflammatory cytokines as well as down-regulating memory and learning genes. Several genes involved in learning, memory, and behavior induced by DAB (e.g., PRL, Pit-1, PRLR, Ttr, Notch2, Ntsr1, C5ar2, Cd74) were not changed or downregulated in young rats, but upregulated in old rats. Detoxification pathways were upregulated in young rats treated with DAB, whereas prolactin (PRL) signaling pathways were upregulated in old DAB-treated rats. Further work is needed to gain a better understanding of the roles of PRL during aging.


Assuntos
Citocinas , Prolactina , Acetofenonas/farmacologia , Idoso , Animais , Citocinas/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/metabolismo , Camundongos , Prolactina/metabolismo , Prolactina/farmacologia , Ratos , Receptor da Anafilatoxina C5a/metabolismo
19.
Turk J Pediatr ; 64(2): 375-380, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35611427

RESUMO

BACKGROUND: Chronic kidney disease (CKD) may lead to increase in serum levels of peptide hormones as a result of changes in peripheral metabolism. The pathogenesis of uremic hyperprolactinemia in CKD is not fully understood. Plasma prolactin levels are elevated in women, pubertal girls, and also in men with chronic kidney disease. But this is not comon in prepubertal boys. Also in prepubertal children and postmenopausal women, hyperprolactinemia rarely results in galactorrhea. We aimed to discuss hyperprolactinemia and galactorrhea in a 12-year-old male with CKD. CASE: A twelve-year-old boy with chronic kidney disease (CKD) suffered from bilateral galactorrhea. He was on follow-up at Pediatric Nephrology Department from the age of two due to bilateral dysplastic kidney. On physical examination, his weight was - 0.59 SDS, height was -2.82 SDS, Blood pressure was 115 / 72 (75p), stretched penis length was 6 cm, testicular volume was 3mL / 3mL, pubic hair was Tanner Stage 1, breast examination did not reveal plaque on bilateral breast. He was receiving recombinant erythropoietin, sodium bicarbonate, polystyrene sulfonate, calcium acetate, and calcitriol treatments. Glomerular filtration rate was 23ml/min/1.73 m2 (CKD stage IV). Serum prolactin (PRL) was > 200 µg/L (N, 2.64-13.13). The pituitary adenoma was excluded with pituitary and cranial magnetic resonance imaging (gadolinium). Cabergoline (0.5 mg/ twice weekly) was initiated to decrease PRL levels and reduce galactorrhea. In the second week of treatment, serum PRL level was suppressed (0.4 µg/L) and galactorrhea was completely resolved. CONCLUSIONS: Although uremic hyperprolactinemia is very rarely seen in childhood, it is important to evaluate, and initiate an appropriate treatment since it is associated with delayed puberty and infertility in adulthood in many cases.


Assuntos
Galactorreia , Hiperprolactinemia , Insuficiência Renal Crônica , Adulto , Amenorreia , Criança , Feminino , Galactorreia/etiologia , Humanos , Hiperprolactinemia/complicações , Masculino , Gravidez , Prolactina/metabolismo , Insuficiência Renal Crônica/complicações
20.
Hormones (Athens) ; 21(2): 209-219, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35545690

RESUMO

Prolactin, a pituitary hormone that was discovered about 80 years ago and is primarily known for its functions in mammary gland development and lactation, is now known to participate in numerous functions across different phylogenetic groups. Fundamentally known for its secretion from lactotroph cells in adenohypophysis region of pituitary gland, newer studies have demonstrated a number of extrapituitary sites which secrete prolactin, where it acts in an autocrine, paracrine, and endocrine manner to regulate essential physiological and biochemical processes. These sites include lymphocytes, epithelial cells of lactating mammary glands, breast cancer cells of epithelial origin, and the placenta. The placenta is one of the most important organs secreting prolactin; however, its role in placental biology has not to date been reviewed comprehensively. This review elaborates upon the various facets of prolactin hormone, including prolactin production and its post-translational modifications and signaling. Major emphasis is placed on placental prolactin and its potential roles, ranging from the role of prolactin in angiogenesis, preeclampsia, maternal diabetes, and anti-apoptosis, among others.


Assuntos
Placenta , Prolactina , Feminino , Humanos , Lactação , Hipófise/metabolismo , Hipófise/fisiologia , Placenta/metabolismo , Placenta/fisiologia , Gravidez/metabolismo , Gravidez/fisiologia , Prolactina/metabolismo , Prolactina/fisiologia , Transdução de Sinais
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