RESUMO
The harderian gland (HG) is a gland located at the base of the nictating membrane and fills the inferomedial aspect of the orbit in rodents. It is under the influence of the hypothalamic-pituitary-gonadal axis and, because of its hormone receptors, it is a target tissue for prolactin (PRL) and sex steroid hormones (estrogen and progesterone). In humans and murine, the anterior surface of the eyes is protected by a tear film synthesized by glands associated with the eye. In order to understand the endocrine changes caused by hyperprolactinemia in the glands responsible for the formation of the tear film, we used an animal model with metoclopramide-induced hyperprolactinemia (HPRL). Given the evidences that HPRL can lead to a process of cell death and tissue fibrosis, the protein expression of small leucine-rich proteoglycans (SLRPs) was analyzed through immunohistochemistry in the HG of the non- and the pregnant female mice with hyperprolactinemia. The SRLPs are related to collagen fibrillogenesis and they participate in pro-apoptotic signals. Our data revealed that high prolactin levels and changes in steroid hormones (estrogen and progesterone) can lead to an alteration in the amount of collagen, and in the structure of type I and III collagen fibers through changes in the amounts of lumican and decorin, which are responsible for collagen fibrillogenesis. This fact can lead to the impaired functioning of the HG by excessive apoptosis in the HG of the non- and the pregnant female mice with HPRL and especially in the HG of pregnancy-associated hyperprolactinemia.
Assuntos
Glândula de Harder , Hiperprolactinemia , Gravidez , Humanos , Camundongos , Feminino , Animais , Proteoglicanas/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Hiperprolactinemia/induzido quimicamente , Hiperprolactinemia/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Decorina/metabolismo , Prolactina/efeitos adversos , Prolactina/análise , Prolactina/metabolismo , Progesterona , Glândula de Harder/metabolismo , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Estrogênios/efeitos adversos , Estrogênios/análise , Estrogênios/metabolismoRESUMO
In mammals, gestation is considered a physiological hyperprolactinemia status. Prolactin (PRL) is one of the modulators of gonadotropin-releasing hormone (GnRH) neurons function. The South American plains vizcacha (Lagostomus maximus) is a unique model to study the regulation of hypothalamic GnRH neurons by direct and indirect steroid-dependent pathways. The aim was to characterize the hypothalamic expression of endocrine markers in vizcacha during gestation as well as their response to experimental induced hyperprolactinemia. The possible involvement of PRL regulatory pathways on GnRH in the context of hypothalamic and pituitary reactivation in mid-gestating vizcachas was discussed. Using two in vivo approaches, we determined changes in the hypothalamic expression and distribution of prolactin receptor (PRLR), tyrosine hydroxylase (TH), and dopamine type 2 receptor. A significant increment in the number of tuberoinfundibular dopaminergic (TIDA) neurons was determined in the arcuate nucleus from early to term pregnancy. On the other hand, at preoptic area, the number of both TH+PRLR+ and GnRH+PRLR+ double-labeled neurons significantly decreased at mid-pregnancy probably allowing the recovery of GnRH expression indicating that both types of neurons may represent the key points of PRL indirect and direct pathways modulating GnRH. Moreover, in a model of induced hyperprolactinemic vizcachas, the inhibitory effect of PRL on GnRH at both expression and delivery levels were confirmed. These results suggest the concomitant participation of both PRL regulatory pathways on GnRH modulation and pinpoint the key role of PRL on GnRH expression enabling the recovery of the hypothalamic activity during the gestation in this species.
Assuntos
Hormônio Liberador de Gonadotropina , Hiperprolactinemia , Gravidez , Feminino , Animais , Hormônio Liberador de Gonadotropina/metabolismo , Receptores da Prolactina/metabolismo , Hormônios Liberadores de Hormônios Hipofisários/metabolismo , Hormônios Liberadores de Hormônios Hipofisários/farmacologia , Hiperprolactinemia/metabolismo , Hipotálamo/metabolismo , Roedores/metabolismo , Neurônios Dopaminérgicos/metabolismoRESUMO
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 PesoRESUMO
Background: Hypothyroidism causes ovarian dysfunction and infertility in women, in addition to being associated with hyperprolactinemia and reduced hypothalamic expression of kisspeptin (Kp). However, it remains unknown whether and how Kp is able to reverse the ovarian dysfunction caused by hypothyroidism. Methods: Hypothyroidism was induced in adult female Wistar rats using 6-propyl-2-thiouracil for 3 months. In the last month, half of the animals received Kp10. Blood samples were collected for dosage of free thyroxine, thyrotropin (TSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2), and uteruses and ovaries were collected for histomorphometry. Body and ovarian weight and the number of corpora lutea were also evaluated. Half of the brains were evaluated by immunohistochemistry to Kp, and the other half had the arcuate nucleus of hypothalamus (ARC) and preoptic area microdissected for gene evaluation of Kiss1, Nkb, Pdyn, and Gnrh1. The pituitary gland and corpora lutea were also dissected for gene evaluation. Results: Hypothyroidism kept the animals predominantly acyclic and promoted a reduction in ovarian weight, number of corpora lutea, endometrial thickness, number of endometrial glands, and plasma LH, in addition to increasing the luteal messenger RNA (mRNA) expression of Star and Cyp11a1 and reducing 20αHsd. An increase in plasma PRL and P4 levels was also caused by hypothyroidism. Kp immunoreactivity and Kiss1 and Nkb mRNA levels in the ARC and Kiss1 in the anteroventral periventricular nucleus of hypothalamus were reduced in hypothyroid rats. Hypothyroid animals had lower pituitary gene expression of Gnrhr, Lhb, Prl, and Drd2, and an increase in Tshb. The treatment with Kp10 restored estrous cyclicality, plasma LH, ovarian and uterine morphology, and Cyp11a1, 3ßHsd, and 20αHsd mRNA levels in the corpora lutea. Kp10 treatment did not alter gene expression for Kiss1 or Nkb in the ARC of hypothyroid rats. Nevertheless, Kp10 increased Lhb mRNA levels and reduced Tshb in the pituitary compared with the hypothyroid group. Conclusions: The present findings characterize the inhibitory effects of hypothyroidism on the hypothalamic-pituitary-gonadal axis in female rats and demonstrate that Kp10 is able to reverse the ovarian dysfunction caused by hypothyroidism, regardless of hyperprolactinemia.
Assuntos
Hiperprolactinemia , Hipotireoidismo , Feminino , Animais , Ratos , Kisspeptinas/genética , Kisspeptinas/metabolismo , Kisspeptinas/farmacologia , Hiperprolactinemia/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Ratos Wistar , Hormônio Luteinizante , Núcleo Arqueado do Hipotálamo/metabolismo , Prolactina/metabolismo , Prolactina/farmacologia , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Sarcoidosis is a systemic inflammatory disease of unknown etiology that can affect virtually any organ. Löfgren syndrome, characterized by erythema nodosum, hilar lymphadenopathy, fever and polyarthritis, represents only 20-30% of the cases of sarcoidosis. Only 2- 10% of the cases feature hypercalcemia. CASE: The case of a 42-year-old Hispanic woman with a history of erythema nodosum and three weeks of nausea, emesis, constipation, asthenia, adynamia, polydipsia, and somnolence, concomitant with hypercalcemia, but normal parathyroid hormone (PTH) and 25-hydroxyvitamin D has been presented. The initial diagnostic approach was based upon the suspicion of multiple myeloma or bone metastases; however, further findings of bilateral hilar lymphadenopathy, elevated serum angiotensin-converting enzyme (ACE) and a right inguinal lymphadenomegaly suggested an alternate diagnosis. Biopsy of the latter supported sarcoidosis as the diagnosis. She was successfully treated in the hospital with zoledronic acid and as an outpatient with immunosuppressive therapy. Persistence of a previously undisclosed symptom of oligomenorrhea led to the detection of hyperprolactinemia secondary to hypophyseal infiltration, refractory to immunosuppressive therapy but with an adequate response to cabergoline. CONCLUSION: This case strays from Löfgren Syndrome's expected behavior, presenting a more progressive, multisystemic disease. This case report was written in adherence to the CARE guidelines of 2013 to include information in it.
Assuntos
Eritema Nodoso/diagnóstico por imagem , Eritema Nodoso/metabolismo , Hipercalcemia/diagnóstico por imagem , Hipercalcemia/metabolismo , Sarcoidose/diagnóstico por imagem , Sarcoidose/metabolismo , Adulto , Eritema Nodoso/complicações , Feminino , Humanos , Hipercalcemia/complicações , Hiperprolactinemia/complicações , Hiperprolactinemia/diagnóstico por imagem , Hiperprolactinemia/metabolismo , Sarcoidose/complicações , SíndromeRESUMO
PURPOSE: We have previously shown that domperidone-induced short-term hyperprolactinemia reduces the lung's allergic inflammatory response in an ovalbumin antigenic challenge model. Since purinergic receptor P2X7R activity leads to proinflammatory cytokine release and is possibly related to the pathogenesis of allergic respiratory conditions, the present study was designed to investigate a possible involvement of purinergic and prolactin receptors in this phenomenon. METHODS: To induce hyperprolactinemia, domperidone was injected intraperitoneally in rats at a dose of 5.1 mg × kg-1 per day for 5 days. P2X7 expression was evaluated by lung immunohistochemistry while prolactin receptor expression in bronchoalveolar lavage leukocytes was analyzed through flow cytometry. RESULTS: Previous reports demonstrated that rats subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, especially granulocytes. Here, it is revealed that hyperprolactinemia promotes an increased expression of prolactin receptors in granulocytes. Also, increased expression of purinergic P2X7R observed in allergic animals was significantly reduced by hyperprolactinemia. CONCLUSIONS: Both purinergic and prolactin receptor expression changes occur during the anti-asthmatic effect of hyperprolactinemia.
Assuntos
Asma/metabolismo , Hiperprolactinemia/metabolismo , Pulmão/metabolismo , Receptores Purinérgicos P2X7/biossíntese , Animais , Asma/induzido quimicamente , Asma/imunologia , Expressão Gênica , Hiperprolactinemia/imunologia , Contagem de Leucócitos/tendências , Pulmão/imunologia , Masculino , Ovalbumina/toxicidade , Ratos , Ratos Wistar , Receptores Purinérgicos P2X7/genética , Fatores de TempoRESUMO
BACKGROUND: Few studies evaluated the use of cabergoline (CAB) for acromegaly treatment in monotherapy or in combination with first-generation somatostatin receptor ligands (SRLs). AIM: To evaluate the efficacy, predictors of response and safety of CAB treatment in acromegaly both in monotherapy and in combination with SRLs. METHODS: We retrospectively collected demographic, biochemical, tumour and treatment data. Short-term disease control was defined as random GH level < 1.0 µg/L and normal age-matched IGF-I level after 3-6 months of treatment with the higher dose used. Long-term disease control was defined as maintenance of normal GH and IGF-I levels at the last visit (at least 9 months of treatment). RESULTS: Eighty-two patients were studied. The median total time of treatment in monotherapy or in combination with SRLs was 14 months (3-124) and 34 months (3-88), respectively. Short-term disease control was observed in 6 (21%) patients in the monotherapy group and in 20 (32%) in the combination group. Treatment escape was observed in 1 patient after 16 months of CAB monotherapy and in 6 (30%) patients with combination therapy (after a median of 38 months), resulting in long-term disease control of 18% and 23%, respectively. Hyperprolactinemia was a predictor of response to monotherapy and pretreatment GH level to combination treatment. CONCLUSION: We presented the results of the largest single-centre study with CAB in monotherapy and in combination with SRL. The efficacy of CAB in acromegaly seems to be lower than that of other drugs, and treatment escape may occur after a long-term follow-up.
Assuntos
Acromegalia/tratamento farmacológico , Acromegalia/metabolismo , Cabergolina/uso terapêutico , Receptores de Somatostatina/metabolismo , Adulto , Idoso , Feminino , Humanos , Hiperprolactinemia/tratamento farmacológico , Hiperprolactinemia/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Somatostatina/agonistas , Estudos Retrospectivos , Adulto JovemRESUMO
We studied the impact of high prolactin titers on liver and adipocyte gene expression related to glucose and insulin homeostasis in correlation with obesity onset. To that end we used mutant female mice that selectively lack dopamine type 2 receptors (D2Rs) from pituitary lactotropes (lacDrd2KO), which have chronic high prolactin levels associated with increased body weight, marked increments in fat depots, adipocyte size, and serum lipids, and a metabolic phenotype that intensifies with age. LacDrd2KO mice of two developmental ages, 5 and 10 mo, were used. In the first time point, obesity and increased body weight are marginal, although mice are hyperprolactinemic, whereas at 10 mo there is marked adiposity with a 136% increase in gonadal fat and a 36% increase in liver weight due to lipid accumulation. LacDrd2KO mice had glucose intolerance, hyperinsulinemia, and impaired insulin response to glucose already in the early stages of obesity, but changes in liver and adipose tissue transcription factors were time and tissue dependent. In chronic hyperprolactinemic mice liver Prlr were upregulated, there was liver steatosis, altered expression of the lipogenic transcription factor Chrebp, and blunted response of Srebp-1c to refeeding at 5 mo of age, whereas no effect was observed in the glycogenesis pathway. On the other hand, in adipose tissue a marked decrease in lipogenic transcription factor expression was observed when morbid obesity was already settled. These adaptive changes underscore the role of prolactin signaling in different tissues to promote energy storage.
Assuntos
Adipócitos/metabolismo , Hepatócitos/metabolismo , Hiperprolactinemia/genética , Fígado/metabolismo , Obesidade/genética , Receptores de Dopamina D2/genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Ensaio de Imunoadsorção Enzimática , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Expressão Gênica , Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase/genética , Hiperprolactinemia/metabolismo , Imuno-Histoquímica , Insulina/metabolismo , Lactotrofos/metabolismo , Lipogênese/genética , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Obesidade/metabolismo , Radioimunoensaio , Reação em Cadeia da Polimerase em Tempo Real , Receptores da Prolactina/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/genética , Regulação para CimaRESUMO
We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1ß and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1ß expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny.
Assuntos
Adiposidade , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/etiologia , Resistência à Insulina , Lactação , Óleo de Semente do Linho/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Dislipidemias/imunologia , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Hiperprolactinemia/etiologia , Hiperprolactinemia/imunologia , Hiperprolactinemia/metabolismo , Hiperprolactinemia/patologia , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Leptina/sangue , Masculino , PPAR gama/metabolismo , Distribuição Aleatória , Ratos Wistar , Fatores Sexuais , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismo , Gordura Subcutânea/patologiaRESUMO
The metabolic syndrome is a growing epidemic; it increases the risk for diabetes, cardiovascular disease, fatty liver, and several cancers. Several reports have indicated a link between hormonal imbalances and insulin resistance or obesity. Transgenic (TG) female mice overexpressing the human chorionic gonadotropin ß-subunit (hCGß+ mice) exhibit constitutively elevated levels of hCG, increased production of testosterone, progesterone and prolactin, and obesity. The objective of this study was to investigate the influence of hCG hypersecretion on possible alterations in the glucose and lipid metabolism of adult TG females. We evaluated fasting serum insulin, glucose, and triglyceride levels in adult hCGß+ females and conducted intraperitoneal glucose and insulin tolerance tests at different ages. TG female mice showed hyperinsulinemia, hypertriglyceridemia, and dyslipidemia, as well as glucose intolerance and insulin resistance at 6 months of age. A 1-week treatment with the dopamine agonist cabergoline applied on 5-week-old hCGß+ mice, which corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, effectively prevented the metabolic alterations. These data indicate a key role of the hyperprolactinemia-induced gonadal dysfunction in the metabolic disturbances of hCGß+ female mice. The findings prompt further studies on the involvement of gonadotropins and prolactin on metabolic disorders and might pave the way for the development of new therapeutic strategies.
Assuntos
Gonadotropina Coriônica Humana Subunidade beta/metabolismo , Intolerância à Glucose/metabolismo , Hiperinsulinismo/metabolismo , Hiperprolactinemia/metabolismo , Hipertrigliceridemia/metabolismo , Resistência à Insulina/fisiologia , Animais , Glicemia/metabolismo , Cabergolina , Gonadotropina Coriônica Humana Subunidade beta/genética , Ergolinas/uso terapêutico , Feminino , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/genética , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/genética , Hiperprolactinemia/tratamento farmacológico , Hiperprolactinemia/genética , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/genética , Insulina/sangue , Camundongos , Camundongos Transgênicos , Prolactina/sangue , Triglicerídeos/sangueRESUMO
The aim of this study was to evaluate the effects of metoclopramide-induced hyperprolactinemia on the prolactin (PRL) and prolactin receptor's (PRLR) expression in the adrenal. For this purpose, a total of 12 animals with intact ovaries were allocated to two groups: G1 (saline solution) and G2 (metoclopramide). A total of 30 oophorectomized animals was randomized to five subgroups: G3 (saline solution), G4 (metoclopramide), G5 (metoclopramide + 17ß-estradiol), G6 (metoclopramide + progesterone), and G7 (metoclopramide + 17ß-estradiol + progesterone). Immunohistochemical analyses were evaluated semi-quantitatively. For PRLR, the area fraction of labeled cells (ALC) varied from 1 (0-10%) to 3 (> 50%). Based on the mean of the immunostaining intensity, G2 and G4 showed strong expression; G6 and G7 presented a mild reaction; and G1, G3, and G5 exhibited a weak reaction. Concerning PRL, the ALC varied from 1 (0-10%) to 3 (> 50%), and groups G6 and G7 showed a strong reaction; G2, G4, and G5 showed a mild reaction; and G1 and G3 exhibited a weak reaction. These findings suggest that metoclopramide-induced hyperprolactinemia increases PRL expression in the adrenal glands of mice. Furthermore, progesterone alone or in association with estrogen also increases PRL expression, but to a lesser extent.
Assuntos
Glândulas Suprarrenais/química , Hiperprolactinemia/induzido quimicamente , Metoclopramida/administração & dosagem , Prolactina/análise , Receptores da Prolactina/análise , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Estradiol/administração & dosagem , Estrogênios/sangue , Feminino , Hiperprolactinemia/metabolismo , Imuno-Histoquímica , Camundongos , Ovariectomia , Progesterona/administração & dosagem , Progesterona/sangue , Prolactina/sangueRESUMO
UNLABELLED: Evidence indicates that prolactin plays a crucial role in the normal function and development of the prostate, but abnormal high levels of the hormone are associated with hyperplasia and cancer of the gland. AIMS: The present study was designed to describe the progressive specific histological abnormalities in the prostate of rats with chronic hyperprolactinemia. MATERIAL AND METHODS: Prolactin was administered during 4; 12 or 24 weeks, and the resulting prostatic alterations were compared with control rats, and also with those treated with testosterone, or the combination of prolactin + testosterone. RESULTS: Rats treated with prolactin, testosterone or prolactin + testosterone expressed precancerous histological abnormalities in the dorsolateral and ventral portions of the prostate as early as in 4 weeks of treatment, but in all cases the malignancy increased after 12 or 24 weeks of treatment. CONCLUSION: Our study confirms that chronic hyperprolactinemia is a cause of prostate precancerous pathologies.
Assuntos
Hiperprolactinemia/complicações , Prolactina/metabolismo , Próstata/patologia , Neoplasias da Próstata/etiologia , Animais , Hiperprolactinemia/metabolismo , Masculino , Prolactina/administração & dosagem , Neoplasias da Próstata/patologia , Ratos , Ratos Wistar , Testosterona/administração & dosagem , Testosterona/metabolismoRESUMO
The development of genetically modified animals has been useful to understand the mechanisms involved in the regulation of the gonadotropin function. It is well known that alterations in the secretion of a single hormone is capable of producing profound reproductive abnormalities. Human chorionic gonadotropin (hCG) is a glycoprotein hormone normally secreted by the human placenta, and structurally and functionally it is related to pituitary LH. LH and hCG bind to the same LH/hCG receptor, and hCG is often used as an analog of LH to boost gonadotropin action. There are many physiological and pathological conditions where LH/hCG levels and actions are elevated. In order to understand how elevated LH/hCG levels may impact on the hypothalamic-pituitary-gonadal axis we have developed a transgenic mouse model with chronic hCG hypersecretion. Female mice develop many gonadal and extragonadal phenotypes including obesity, infertility, hyperprolactinemia, and pituitary and mammary gland tumors. This article summarizes recent findings on the mechanisms involved in pituitary gland tumorigenesis and hyperprolactinemia in the female mice hypersecreting hCG, in particular the relationship of progesterone with the hyperprolactinemic condition of the model. In addition, we describe the role of hyperprolactinemia as the main cause of infertility and the phenotypic abnormalities in these mice, and the use of dopamine agonists bromocriptine and cabergoline to normalize these conditions.
Assuntos
Gonadotropina Coriônica/metabolismo , Hiperprolactinemia/metabolismo , Receptores do LH/metabolismo , Animais , Gonadotropina Coriônica/genética , Modelos Animais de Doenças , Feminino , Hiperprolactinemia/genética , Camundongos , Camundongos Transgênicos , Hipófise/metabolismo , Receptores do LH/genéticaRESUMO
Prolactin (PRL) is known to suppress LH secretion. Kisspeptin neurons regulate LH secretion and express PRL receptors. We investigated whether PRL acts on kisspeptin neurons to suppress LH secretion in lactating (Lac) and virgin rats. Lac rats displayed high PRL secretion and reduced plasma LH and kisspeptin immunoreactivity in the arcuate nucleus (ARC). Bromocriptine-induced PRL blockade significantly increased ARC kisspeptin and plasma LH levels in Lac rats but did not restore them to the levels of non-Lac rats. Bromocriptine effects were prevented by the coadministration of ovine PRL (oPRL). Virgin ovariectomized (OVX) rats treated with either systemic or intracerebroventricular oPRL displayed reduction of kisspeptin expression in the ARC and plasma LH levels, and these effects were comparable with those of estradiol treatment in OVX rats. Conversely, estradiol-treated OVX rats displayed increased kisspeptin immunoreactivity in the anteroventral periventricular nucleus, whereas oPRL had no effect in this brain area. The expression of phosphorylated signal transducer and activator of transcription 5 was used to determine whether kisspeptin neurons in the ARC were responsive to PRL. Accordingly, intracerebroventricular oPRL induced expression of phosphorylated signal transducer and activator of transcription 5 in the great majority of ARC kisspeptin neurons in virgin and Lac rats. We provide here evidence that PRL acts on ARC neurons to inhibit kisspeptin expression in female rats. During lactation, PRL contributes to the inhibition of ARC kisspeptin. In OVX rats, high PRL levels suppress kisspeptin expression and reduce LH release. These findings suggest a pathway through which hyperprolactinemia may inhibit LH secretion and thereby cause infertility.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Neurônios/metabolismo , Prolactina/metabolismo , Animais , Bromocriptina/química , Estradiol/metabolismo , Feminino , Hiperprolactinemia/metabolismo , Imuno-Histoquímica , Fosforilação , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Fator de Transcrição STAT5/metabolismo , OvinosRESUMO
Prolactin (PRL) plays an important role in modulating the immune response. In B cells, PRL enhances antibody production, including antibodies with self-specificity. In this study, our aims were to determine the level of PRL receptor expression during bone-marrow B-cell development and to assess whether the presence of high PRL serum concentrations influences absolute numbers of developing populations and disease outcome in lupus-prone murine models. We observed that the PRL-receptor is expressed in early bone-marrow B-cell; the expression in lupus-prone mice, which had the highest level of expression in pro-B cells and immature cells, differed from that in wild-type mice. These expression levels did not significantly change in response to hyperprolactinemia; however, populations of pro-B and immature cells from lupus-prone strains showed a decrease in the absolute numbers of cells with high PRL-receptor expression in response to PRL. Because immature self-reactive B cells are constantly being eliminated, we assessed the expression of survival factor BIRC5, which is more highly expressed in both pro-B and immature B-cells in response to PRL and correlates with the onset of disease. These results identify an important role of PRL in the early stages of the B-cell maturation process: PRL may promote the survival of self-reactive clones.
Assuntos
Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Prolactina/metabolismo , Animais , Anticorpos Antinucleares/imunologia , Linfócitos B/metabolismo , Modelos Animais de Doenças , Feminino , Hiperprolactinemia/genética , Hiperprolactinemia/imunologia , Hiperprolactinemia/metabolismo , Imunofenotipagem , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Lúpus Eritematoso Sistêmico/genética , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos MRL lpr , Prolactina/sangue , Receptores da Prolactina/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , SurvivinaRESUMO
Female infertility is often associated with deregulation of hormonal networks, and hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis affecting the reproductive functions. We have shown previously that transgenic female mice overexpressing human chorionic gonadotropin ß-subunit (hCGß+ mice), and producing elevated levels of bioactive LH/hCG, exhibit increased production of testosterone and progesterone, are overweight and infertile, and develop hyperprolactinemia associated with pituitary lactotrope adenomas in adult age. In the present study, we analyzed the influence of the hyperprolactinemia of hCGß+ females on their reproductive phenotype by treating them with the dopamine agonists, bromocriptine and cabergoline. Long-term bromocriptine treatment of adult mice was effective in the control of obesity, pituitary growth, and disturbances in the hormone profile, demonstrating that hyperprolactinemia was the main cause of the hCGß+ female phenotype. Interestingly, short-term treatment (1 wk) with cabergoline applied on 5-wk-old mice corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, prevented pituitary overgrowth, normalized gonadal function, and recovered fertility of adult hCGß+ females after hormone-induced and natural ovulation. The same cabergoline treatment in the short term applied on 3-month-old hCGß+ females failed to recover their reproductive function. Hence, we demonstrated that the short-term cabergoline treatment applied at a critical early stage of the phenotype progression effectively prevented the hyperprolactinemia-associated reproductive dysfunction of hCG-overproducing females.
Assuntos
Gonadotropina Coriônica/metabolismo , Hiperprolactinemia/complicações , Infertilidade/complicações , Infertilidade/metabolismo , Animais , Bromocriptina/farmacologia , Cabergolina , Modelos Animais de Doenças , Ergolinas/farmacologia , Feminino , Fertilidade , Regulação da Expressão Gênica , Humanos , Hiperprolactinemia/metabolismo , Camundongos , Camundongos Transgênicos , Ovulação , Fenótipo , Fatores de TempoRESUMO
BACKGROUND: Prolactin is secreted from the pituitary gland and other organs, as well as by cells such as lymphocytes. Prolactin has an immunostimulatory effect and is associated with autoimmune diseases that are characterised by abnormal B cell activation, such as systemic lupus erythematosus (SLE). Our aim was to determine if different splenic B cell subsets express the prolactin receptor and if the presence of prolactin influences these B cell subsets and correlates with development of lupus. RESULTS: Using real-time PCR and flow cytometry, we found that different subsets of immature (transitional) and mature (follicular, marginal zone) B cells express different levels of the prolactin receptor and are differentially affected by hyperprolactinaemia. We found that transitional B cells express the prolactin receptor at higher levels compared to mature B cells in C57BL/6 mice and the lupus-prone MRL/lpr and MRL mouse strains. Transitional-1 (T1) B cells showed a higher level of prolactin receptor expression in both MRL/lpr and MRL mice compared to C57BL/6 mice. Hyperprolactinaemia was induced using metoclopramide, which resulted in the development of early symptoms of SLE. We found that T1 B cells are the main targets of prolactin and that prolactin augments the absolute number of T1 B cells, which reflects the finding that this B cell subpopulation expresses the highest level of the prolactin receptor. CONCLUSIONS: We found that all B cell subsets express the prolactin receptor but that transitional B cells showed the highest prolactin receptor expression levels. Hyperprolactinaemia in mice susceptible to lupus accelerated the disease and increased the absolute numbers of T1 and T3 B cells but not of mature B cells, suggesting a primary effect of prolactin on the early stages of B cell maturation in the spleen and a role of prolactin in B cell differentiation, contributing to SLE onset.
Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Receptores da Prolactina/metabolismo , Animais , Subpopulações de Linfócitos B/metabolismo , Feminino , Expressão Gênica , Centro Germinativo/metabolismo , Hiperprolactinemia/imunologia , Hiperprolactinemia/metabolismo , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Prolactina/administração & dosagem , Receptores da Prolactina/genética , Baço/citologia , Baço/metabolismoRESUMO
The relationship between prolactin (PRL) and the immune system has been demonstrated in the last two decades and has opened new windows in the field of immunoendocrinology. However, there are scarce reports about PRL in primary antiphospholipid syndrome (pAPS). The objective of this study was to evaluate PRL levels in patients with pAPS compared to healthy controls and to investigate their possible clinical associations. Fifty-five pAPS patients according to Sapporo criteria were age- and sex-matched with 41 healthy subjects. Individuals with secondary causes of hyperprolactinemia (HPRL) were excluded; demographic, biometric, and clinical data, PRL levels, antiphospholipid antibodies, inflammatory markers, and other routine laboratory findings were analyzed. PRL levels were similar between pAPS and healthy controls (8.94 ± 7.02 versus 8.71 ± 6.73 ng/mL, P = .876). Nine percent of the pAPS patients and 12.1% of the control subjects presented HPRL (P = .740). Comparison between the pAPS patients with hyper- and normoprolactinemia revealed no significant differences related to anthropometrics, clinical manifestations, medications, smoking, and antiphospholipid antibodies (P > .05). This study showed that HPRL does not seem to play a role in clinical manifestations of the pAPS, differently from other autoimmune rheumatic diseases.
Assuntos
Síndrome Antifosfolipídica/imunologia , Prolactina/imunologia , Adulto , Anticorpos Antifosfolipídeos/sangue , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/complicações , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Proteína C-Reativa/metabolismo , Feminino , Humanos , Hiperprolactinemia/complicações , Hiperprolactinemia/metabolismo , Inflamação/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: The effects of short-term 5-day and long-term 30-day hyperprolactinemia induced by domperidone (1.7 mg/kg/day, s.c.) or ectopic pituitary graft on the acute inflammatory response induced by carrageenan were evaluated in male rats. Both models of hyperprolactinemia effectively increased serum prolactin (PRL) levels. METHODS: The volume in milliliters of inflammatory edema was measured by plethysmography 1, 2, 3, 4, 6, 8 and 24 h after carrageenan injection. The areas under the inflammatory time-response curves were compared. Additionally, the effects of hyperprolactinemia on body weight and serum corticosterone levels were evaluated. RESULTS: In both domperidone-treated and pituitary graft-implanted animals, short-term 5-day hyperprolactinemia increased the inflammatory response, while long-term 30-day hyperprolactinemia had anti-inflammatory effects. Body weight was not affected by either short- or long-term hyperprolactinemia. CONCLUSION: These results show that PRL has biphasic effects on the carrageenan-induced inflammatory response.
Assuntos
Edema/imunologia , Hiperprolactinemia/imunologia , Inflamação/imunologia , Neuroimunomodulação/fisiologia , Animais , Peso Corporal , Carragenina/toxicidade , Corticosterona/sangue , Edema/induzido quimicamente , Edema/metabolismo , Membro Posterior/patologia , Hiperprolactinemia/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Irritantes/toxicidade , Masculino , Pletismografia , Prolactina/sangue , Radioimunoensaio , Ratos , Ratos WistarRESUMO
Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during normal aging is associated in the female rat with chronic hyperprolactinemia. We assessed the effectiveness of glial cell line-derived neurotrophic factor (GDNF) gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. Young (2.5 months) and senile (29 months) rats received a bilateral intrahypothalamic injection (10(10) pfu) of either an adenoviral vector expressing the gene for beta-galactosidase; (Y-betagal and S-betagal, respectively) or a vector expressing rat GDNF (Y-GDNF and S-GDNF, respectively). Transgenic GDNF levels in supernatants of GDNF adenovector-transduced N2a neuronal cell cultures were 25+/-4 ng/ml, as determined by bioassay. In the rats, serum prolactin (PRL) was measured at regular intervals. On day 17 animals were sacrificed and neuronal nuclear antigen (NeuN) and tyrosine hydroxylase (TH) immunoreactive cells counted in the arcuate-periventricular hypothalamic region. The S-GDNF but not the S-betagal rats, showed a significant reduction in body weight. The chronic hyperprolactinemia of the senile females was significantly ameliorated in the S-GDNF rats (P<0.05) but not in the S-betagal rats. Neither age nor GDNF induced significant changes in the number of NeuN and TH neurons. We conclude that transgenic GDNF ameliorates chronic hyperprolactinemia in aging female rats, probably by restoring TIDA neuron function.