RESUMO
The aging female rat constitutes an interesting model of spontaneous and progressive age-related dopaminergic dysfunction as it allows assessing new therapeutic strategies for Parkinson's disease. Insulin-like growth factor I (IGF-I) is emerging as a powerful neuroprotective molecule, strongly induced in the central nervous system after different insults. We constructed a helper-dependent recombinant adenoviral vector (HDRAd-IGFI) harboring the gene for rat IGF-I. This was used to implement long-term IGF-I gene therapy in the hypothalamus of aged female rats, which display hypothalamic dopaminergic (DA) dysfunction and, as a consequence, chronic hyperprolactinemia. Rejuvenating long-term IGF-I gene therapy was implemented in young (3 months) and aged (24 months) female rats, which received a single intrahypothalamic injection of 4 × 109 viral particles of either HD-RAd-IGFI or HD-RAd-DsRed (control vector) and were sacrificed 119 days postinjection. In the young animals, neither vector modified serum prolactin (PRL) levels, but in the RAd-IGFI-injected aged rats a nearly full reversion of their hyperprolactinemic status was recorded. Morphometric analysis revealed a significant increase in the total number of tyrosine hydroxylase (TH)-positive cells in the hypothalamus of experimental compared with control aged animals (5874 ± 486 and 3390 ± 498, respectively). Our results indicate that IGF-I gene therapy in aged female rats is highly effective in rejuvenating the hypothalamic DA neuron groups.
Assuntos
Dopamina/metabolismo , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Hiperprolactinemia/terapia , Fator de Crescimento Insulin-Like I/genética , Rejuvenescimento , Adenoviridae/genética , Animais , Feminino , Hiperprolactinemia/genética , Hiperprolactinemia/patologia , Hipotálamo/citologia , Hipotálamo/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
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
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
OBJECTIVE: In children and adolescents treated with risperidone, hyperprolactinemia is a frequent complication that may have clinical repercussions. Several genes have been associated with this occurrence. The aim of this study was to evaluate the frequency of hyperprolactinemia in children and adolescents treated with risperidone, and its associations with clinical and pharmacological data and certain polymorphisms of the following genes: Dopamine receptor D2 (DRD2), 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C), cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), leptin (LEP), leptin receptor (LEPR), melanocortin 4 receptor (MC4R), and scavenger receptor class B, member 2 (SCARB2). METHODS: The study included patients using risperidone (8-20 years old) and healthy subjects not exposed to the medication. Psychopathological symptoms, doses, and duration of treatment with risperidone, sex, skin color, body mass index (BMI), use of other psychotropic drugs, and polymorphisms of DRD2, HTR2C, CYP2D6, LEP, LEPR, MC4R, and SCARB2 genes were evaluated. RESULTS: There were 120 patients and 197 individuals not exposed to risperidone who were evaluated. Among patients, hyperprolactinemia was found in 79 (65.8%) cases, with no differences regarding sex, skin color, or being in monotherapy with risperidone (26.7% of total patients) or not. The level of prolactin was not correlated, either in case or control groups, with chronological age, bone age, prescribed dose of risperidone, weight-adjusted dose of risperidone, or BMI (p > 0.05), but was negatively correlated with the treatment duration (r = -0.352, p = 0.001 among cases; and r = -0.324, p = 0.039 among controls). There were significant differences in use of risperidone between patients and healthy subjects without the medication in the frequency of the polymorphisms of the DRD2, HTR2C, and LEP genes. Considering both sexes together and also specifically among females, the occurrence of hyperprolactinemia was higher in the presence of the C allele of the rs6318 single nucleotide polymorphisms (SNP) of the HTR2C gene. CONCLUSIONS: This group of children and adolescents with or without isolated use of risperidone presented with a high frequency of hyperprolactinemia, although asymptomatic, and associated, when considering only females or both sexes together, with being a carrier of the C allele of the rs6318 SNP of the HTR2C gene.
Assuntos
Antipsicóticos/efeitos adversos , Hiperprolactinemia/genética , Receptor 5-HT2C de Serotonina/genética , Risperidona/efeitos adversos , Adolescente , Alelos , Antipsicóticos/uso terapêutico , Criança , Estudos Transversais , Feminino , Predisposição Genética para Doença , Humanos , Hiperprolactinemia/induzido quimicamente , Masculino , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/genética , Polimorfismo de Nucleotídeo Único , Prolactina/sangue , Risperidona/uso terapêuticoRESUMO
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) 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
BACKGROUND: GH insensitivity (GHI) syndrome caused by STAT5B mutations was recently reported, and it is characterized by extreme short stature and immune dysfunction. Treatment with recombinant human IGF1 (rhIGF1) is approved for patients with GHI, but the growth response to this therapy in patients with STAT5B mutations has not been reported. OBJECTIVES: To report the clinical features, molecular findings, and the short-term growth response to rhIGF1 therapy in patients with STAT5B mutation. SUBJECTS AND METHODS: Hormonal and immunological evaluations were performed in two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura. STAT5B genes were directly sequenced. The younger sibling was treated with rhIGF1 at a dose of 110 microg/kg BID. RESULTS: Both siblings had laboratory findings compatible with GHI associated with hyperprolactinemia. Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed. STAT5B sequence revealed a homozygous frameshift mutation (p.L142fsX161) in both siblings. The younger sibling (9.9 years of age) was treated with rhIGF1 at appropriate dosage, and he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy). The presence of a chronic illness could possibly be responsible for the poor result of rhIGF1 treatment. Further studies in patients with STAT5B defects are necessary to define the response to rhIGF1 treatment in this disorder. CONCLUSION: GHI associated with immune dysfunction, especially interstitial lung disease, and hyperprolactinemia is strongly suggestive of a mutation in STAT5B in both sexes.
Assuntos
Transtornos do Crescimento/genética , Hiperprolactinemia/genética , Doenças do Sistema Imunitário/genética , Fator de Transcrição STAT5/genética , Adulto , Criança , Pré-Escolar , Transtornos do Crescimento/terapia , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Masculino , Mutação , Proteínas Recombinantes/uso terapêutico , IrmãosRESUMO
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.
Assuntos
Envelhecimento/metabolismo , Terapia Genética/métodos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Hiperprolactinemia/genética , Hiperprolactinemia/terapia , Adenoviridae/genética , Animais , Antígenos Nucleares/metabolismo , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/metabolismo , Contagem de Células , Células Cultivadas , Doença Crônica/terapia , Feminino , Genes Reporter/genética , Vetores Genéticos/genética , Vetores Genéticos/farmacologia , Hiperprolactinemia/metabolismo , Lactotrofos/metabolismo , Microinjeções/métodos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Prolactina/análise , Prolactina/sangue , Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/genética , Resultado do Tratamento , Túber Cinéreo/metabolismo , Túber Cinéreo/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo , beta-Galactosidase/genéticaRESUMO
OBJECTIVE: To evaluate the effects of metoclopramide-induced hyperprolactinemia on the prolactin receptor of murine endometrium. DESIGN: Experimental study using the RNA extraction to detect tissue prolactin receptor isoforms by reverse-transcriptase polymerase chain reaction (RT-PCR). SETTING: University-based laboratory. ANIMAL(S): Seventy-two female swiss albino mice (Mus musculus), approximately 100 days old, were divided into six 12-animal groups: (GI) nonoophorectomized mice given vehicle; (GII) nonoophorectomized mice treated with metoclopramide; (GIII) oophorectomized mice treated with metoclopramide; (GIV) oophorectomized mice treated with metoclopramide and 17beta-estradiol; (GV) oophorectomized mice treated with metoclopramide and micronized progesterone; (GVI) oophorectomized mice treated with metoclopramide and a solution of 17beta-estradiol and micronized progesterone. INTERVENTION(S): Drugs were administered for 50 days. Following euthanasia, the middle portions of the uterine horns were removed, sectioned, and immediately frozen for RT-PCR procedures. Blood was collected for the dosage of prolactin and serum estrogen and progesterone using radioimmune assay. MAIN OUTCOME MEASURE(S): Identification of uterine prolactin receptor isoforms. RESULT(S): The PRL receptor and its isoform L were identified only in GI (control group) and GII (metoclopramide), the two groups with nonoophorectomized animals. The amount of PRL receptor mRNA and that of its isoform L from GII were the largest. No other isoforms of the prolactin receptor were identified in any of the groups. CONCLUSION(S): Our results suggest that replacement of estrogen and progestin may not increase the mRNA of endometrial PRL receptor in metoclopromide-induced hyperprolactinemia in rats after castration.
Assuntos
Endométrio/metabolismo , Hiperprolactinemia/genética , Receptores da Prolactina/genética , Animais , Modelos Animais de Doenças , Endométrio/efeitos dos fármacos , Estradiol/administração & dosagem , Estradiol/sangue , Feminino , Regulação da Expressão Gênica , Terapia de Reposição Hormonal , Hiperprolactinemia/induzido quimicamente , Hiperprolactinemia/metabolismo , Metoclopramida , Camundongos , Ovariectomia , Progesterona/administração & dosagem , Progesterona/sangue , Isoformas de Proteínas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: The implementation of gene therapy for the treatment of pituitary tumors emerges as a promising complement to surgery and may have distinct advantages over radiotherapy for this type of tumors. Up to now, suicide gene therapy has been the main experimental approach explored to treat experimental pituitary tumors. In the present study we assessed the effectiveness of insulin-like growth factor I (IGF-I) gene therapy for the treatment of estrogen-induced prolactinomas in rats. RESULTS: Female Sprague Dawley rats were subcutaneously implanted with silastic capsules filled with 17-beta estradiol (E2) in order to induce pituitary prolactinomas. Blood samples were taken at regular intervals in order to measure serum prolactin (PRL). As expected, serum PRL increased progressively and 23 days after implanting the E2 capsules (Experimental day 0), circulating PRL had undergone a 3-4 fold increase. On Experimental day 0 part of the E2-implanted animals received a bilateral intrapituitary injection of either an adenoviral vector expressing the gene for rat IGF-I (RAd-IGFI), or a vector (RAd-GFP) expressing the gene for green fluorescent protein (GFP). Seven days post vector injection all animals were sacrificed and their pituitaries morphometrically analyzed to evaluate changes in the lactotroph population. RAd-IGFI but not RAd-GFP, induced a significant fall in serum PRL. Furthermore, RAd-IGFI but not RAd-GFP significantly reversed the increase in lactotroph size (CS) and volume density (VD) induced by E2 treatment. CONCLUSION: We conclude that IGF-I gene therapy constitutes a potentially useful intervention for the treatment of prolactinomas and that bioactive peptide gene delivery may open novel therapeutic avenues for the treatment of pituitary tumors.
Assuntos
Terapia Genética , Hiperprolactinemia/patologia , Hiperprolactinemia/terapia , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/uso terapêutico , Prolactinoma/patologia , Prolactinoma/terapia , Animais , Tamanho Celular , Feminino , Proteínas de Fluorescência Verde/metabolismo , Hiperprolactinemia/genética , Lactotrofos/patologia , Prolactina/sangue , Prolactinoma/genética , Ratos , Ratos Sprague-Dawley , Timidina Quinase/metabolismo , TransgenesRESUMO
Como os mecanismos envolvidos na resistência dos prolactinomas aos agonistas dopaminérgicos (AD) ainda não foram completamente elucidados, o objetivo deste estudo foi obter novas informações sobre as diferenças moleculares que existem entre prolactinomas sensíveis e resistentes aos AD. Avaliamos a expressão de 7 genes pela Reação de Polimerase em cadeia em tempo real: receptor de dopamina tipo 2, fator de crescimento do nervo beta e seu receptor, receptor de estrógeno alfa e beta, pituitary tumor transforming gene e metalotioneína 3 em tecido tumoral de 22 pacientes. Os pacientes foram classificados como sensíveis ou resistentes aos AD de acordo com sua resposta clínica e laboratorial aos AD e a expressão gênica foi comparada a esta classificação / As the mechanisms involved in the resistance of prolactinomas to dopamine agonist (DA) are not fully understood, the aim of this study was to get new insights in molecular differences between prolactinomas responsive and resistant to DA. We evaluated the expression of 7 genes by Real Time Polimerase Chain Reaction: dopamine receptor type 2, nerve growth factor beta and its receptor, estrogen receptor alfa and beta, pituitary tumor transforming gene and methalotionein 3 in tumor tissue of 22 patients. Patients were classified as responsive or resistant to DA accordingly to their clinical and laboratorial response and gene expression was compared to this classification...
Assuntos
Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Humanos , Expressão Gênica , Hiperprolactinemia/genética , Prolactinoma/genética , Agonistas de Dopamina , Fator de Crescimento Neural , Receptor de Fator de Crescimento Neural , Receptores Dopaminérgicos , Receptores de EstrogênioRESUMO
Circulating human Prolactin (PRL) exists in different variants related to posttranslational modifications, dimerization or association with other serum proteins. Compared to monomeric prolactin these variants usually have little or no biologic activity and include BigBig (BB PRL), Big (B PRL), and Glycosylated forms (G PRL). The aim of the present study was to assess levels of BB PRL, B PRL, little PRL (L PRL) and G PRL in hyperprolactinemic patients with no menstrual alterations or galactorrhea. L PRL, B PRL, and BB PRL were identified by gel filtration chromatography on Sephadex G-100; G PRL and NG PRL were identified by chromatography on Concanavalin A Sepharose. PRL was measured by IRMA DPC. Eleven women, aged 22-50 yrs, were studied for: breast dysplasia (1), controlled hypothyroidism (3), dysmenorrhea (3), microadenoma follow-up (2), and gynecological control (2). Pituitary MRI was normal in all but one patient, who had a microadenoma discovered by Magnetic Resonance Imaging. Six patients had normal L PRL levels, and their hyper PRL was due to excess BPRL or BB PRL. Five patients had increased L PRL levels, but excess G PRL. Patients harboring molecular PRL variants do not present the symptoms typical of the hyperprolactinemic syndrome. Furthermore in patients with clinically controlled prolactinomas the presence of PRL variants should be ruled out to avoid an unnecessary increase of dopamine agonist dosage.
Assuntos
Hiperprolactinemia/genética , Prolactina/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Adulto , Bioensaio , Cromatografia de Afinidade , Cromatografia em Gel , Feminino , Glicosilação , Humanos , Linfoma/metabolismo , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Peso Molecular , Prolactina/biossíntese , Células Tumorais CultivadasRESUMO
We have demonstrated the selective secretion of high mol wt PRL series (big big PRL) in women with hyperprolactinemia and normal ovarian function. This observation suggests that big big PRL is immunologically similar, but biologically less active, than monomeric or little PRL. In this study we determined the molecular size heterogeneity of immunoreactive PRL in the serum from two ovulatory hyperprolactinemic women (subjects A and B) who had large amounts of serum big big PRL during a menstrual cycle and/or gestation. Serum samples obtained throughout the menstrual cycle (days 6, 10, 14, 17, 23, and 28, taking as day 1 the first day of bleeding) and pregnancy (weeks 7, 9, 11, 15, 20, 25, 30, 34, and 38) were fractionated by gel filtration chromatography. PRL was identified in column eluates by specific RIA. Two additional pregnant women, one with a bromocriptine-treated PRL-secreting adenoma (subject C), and a normal woman (subject D) were studied. Big big PRL was the predominant species throughout the different phases of the menstrual cycle in subject B, comprising 70-80% of the total immunoreactive PRL. Most of the remainder was big PRL, and little PRL was present in only small amounts (6-12%) during the luteal phase. During their pregnancies, the serum PRL in subjects A and B initially was mostly big big PRL, but later in gestation the PRL composition shifted from the high mol wt variants to little PRL. The infant's cord (subject A) and peripheral (subject B) serum at birth contained appreciable quantities of big big and big PRL, respectively. These results indicate that structural changes in PRL occur during pregnancy and the menstrual cycle which are probably influenced by the hormonal environment. In addition, the occurrence of larger mol wt PRL species in the serum of the infant of a hyperprolactinemic mother suggests that the presence of high proportions of big big PRL in the serum is genetically determined.