RESUMO
To investigate the putative stem cell/tumor stem cell (SC/TSC) niche contribution to hyperplasic/adenomatous pituitary lesions, we analyzed variation in the pituitary stem cell population during the development of experimental pituitary tumors. Pituitary tumors were induced in female F344 rats with estradiol benzoate for 5, 10, 20 and 30 days. Cells positive for GFRa2, Sox2, Sox9, Nestin, CD133 and CD44 were identified in the marginal zone and in the adenoparenchyma in both control and 30D groups, with predominant adenoparenchyma localization of GRFa2 and SOX9 found in tumoral pituitaries. GFRa2, Nestin, CD133 and CD44 were upregulated at the initial stages of tumor growth, whereas Sox9 significantly decreased at 5D, with Sox2 remaining invariable during the hyperplasic/adenomatous development. In addition, isolated pituispheres from normal and tumoral pituitary glands enriched in SC/TSC were characterized. Pituispheres from the 30D glands were positive for the above-mentioned markers and showed a significant increase in the proliferation. In conclusion, our data revealed pituitary SC pool fluctuations during hyperplastic/adenomatous development, with differential localization of the SC/TSC niche in this process. These findings may help to provide a better understanding of these cell populations, which is crucial for achieving advancements in the field of pituitary tumor biology.
Assuntos
Adenoma/patologia , Neoplasias Hipofisárias/patologia , Nicho de Células-Tronco/fisiologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Feminino , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/fisiologia , Hipófise/patologia , Hipófise/fisiologia , Ratos , Ratos Endogâmicos F344 , Microambiente Tumoral/fisiologiaRESUMO
The anterior pituitary gland is comprised of specialized cell-types that produce and secrete polypeptide hormones in response to hypothalamic input and feedback from target organs. These specialized cells arise during embryonic development, from stem cells that express SOX2 and the pituitary transcription factor PROP1, which is necessary to establish the stem cell pool and promote an epithelial to mesenchymal-like transition, releasing progenitors from the niche. Human and mouse embryonic stem cells can differentiate into all major hormone-producing cell types of the anterior lobe in a highly plastic and dynamic manner. More recently human induced pluripotent stem cells (iPSCs) emerged as a viable alternative due to their plasticity and high proliferative capacity. This mini-review gives an overview of the major advances that have been achieved to develop protocols to generate pituitary hormone-producing cell types from stem cells and how these mechanisms are regulated. We also discuss their application in pituitary diseases, such as pituitary hormone deficiencies.
Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Células-Tronco Pluripotentes Induzidas/transplante , Hipófise/fisiologia , Hipófise/transplante , Medicina Regenerativa/métodos , Animais , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Doenças da Hipófise/patologia , Doenças da Hipófise/terapia , Hipófise/citologia , Medicina Regenerativa/tendênciasRESUMO
During the female reproductive cycle, estradiol exerts negative and positive feedback at both the central level to alter gonadotropin-releasing hormone (GnRH) release and at the pituitary to affect response to GnRH. Many studies of the neurobiologic mechanisms underlying estradiol feedback have been done on ovariectomized, estradiol-replaced (OVX+E) mice. In this model, GnRH neuron activity depends on estradiol and time of day, increasing in estradiol-treated mice in the late afternoon, coincident with a daily luteinizing hormone (LH) surge. Amplitude of this surge appears lower than in proestrous mice, perhaps because other ovarian factors are not replaced. We hypothesized GnRH neuron activity is greater during the proestrous-preovulatory surge than the estradiol-induced surge. GnRH neuron activity was monitored by extracellular recordings from fluorescently tagged GnRH neurons in brain slices in the late afternoon from diestrous, proestrous, and OVX+E mice. Mean GnRH neuron firing rate was low on diestrus; firing rate was similarly increased in proestrous and OVX+E mice. Bursts of action potentials have been associated with hormone release in neuroendocrine systems. Examination of the patterning of action potentials revealed a shift toward longer burst duration in proestrous mice, whereas intervals between spikes were shorter in OVX+E mice. LH response to an early afternoon injection of GnRH was greater in proestrous than diestrous or OVX+E mice. These observations suggest the lower LH surge amplitude observed in the OVX+E model is likely not attributable to altered mean GnRH neuron activity, but because of reduced pituitary sensitivity, subtle shifts in action potential pattern, and/or excitation-secretion coupling in GnRH neurons.
Assuntos
Estradiol/fisiologia , Hormônio Liberador de Gonadotropina/fisiologia , Hormônio Luteinizante/sangue , Hipófise/fisiologia , Proestro/fisiologia , Potenciais de Ação , Animais , Feminino , Camundongos Endogâmicos C57BL , Neurônios/metabolismoRESUMO
OBJECTIVES: Melatonin and androgens are involved in the regulation of cell proliferation. However, effects of these hormones on pituitary pars distalis (PD) of male viscachas is not fully understood. In the present study, we analysed melatonin and gonadal androgens' effects on proliferating cell nuclear antigen (PCNA) expression. MATERIALS AND METHODS: Pituitary glands from foetuses, immature individuals, prepubertal individuals and adult viscachas during their reproductive cycle, after melatonin administration and after castration, were used. PCNA-ir cells were detected by immunocytochemistry and morphometrically quantified using image analysis. RESULTS: Total percentage of PCNA-ir cells varied seasonally in the adult pituitary, with maximum values during the reproductive period and minima during gonadal regression periods. Percentages of PCNA-ir cells increased after melatonin administration, whereas it decreased after castration. Caudal end and ventral regions were the PD zones which were most affected by seasonal variations and castration. PCNA expression was highest in foetal pituitary from midpregnancy. Numbers of PCNA-ir cells decreased during sexual maturity. CONCLUSIONS: Our results demonstrate the effect of gonadal androgens on cell proliferation during the reproductive period and sexual maturity of these animals. Exogenous melatonin increased PD cell proliferation in adults. Thus, these hormones seem to be involved in different mechanisms that regulate cell renewal of PD in this seasonally breeding rodent.
Assuntos
Androgênios/farmacologia , Proliferação de Células/efeitos dos fármacos , Chinchila/fisiologia , Melatonina/farmacologia , Hipófise/citologia , Hipófise/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Animais , Castração , Masculino , Hipófise/fisiologia , Hipófise/ultraestrutura , Antígeno Nuclear de Célula em Proliferação/análise , Reprodução , Estações do AnoRESUMO
OBJECTIVE: To compare stimulation requirements and ICSI outcome when agonist treatment is started in the early follicular phase or in mid luteal phase of the cycle. METHODS: 181 infertile patients were randomly assigned to: group A (N=66) and group B (N=115). GnRH-a (Triptorelin) subcutaneous daily injections started on day 20-22 of the previous cycle till pituitary suppression is achieved where gonadotropins stimulation commenced. In group A, agonist treatment was started on the first or second days of the cycle, in group B it was started on day 20-22 of the cycle. The agonist treatment was continued till the day of (hCG) administration. RESULTS: The stimulation requirements were similar in the two groups. The days of t agonist treatment required to reach pituitary suppression were higher in group A: 12.5±6.4 than in group B, 11±4.5. Days of stimulation (10.4±1.7 and 10.3±1.6) and number of gonadotropin vials (40.1±8.7and 39.3±9.5) did not differ between both groups. The mean number of oocytes retrieved, mean number of embryos produced (11.7±7.4 and 13.3±9.3) (5.9±4.2and 6±5.2) were similar in both groups. The rates of fertilization and cleavage were similar in the two groups. Pregnancy rates were similar in both groups. The clinical pregnancy rates per cycle was 31.8% and 33%, while pregnancy rates per embryo transfer was 36.2 % and 36.5% in groups A and B respectively. CONCLUSION: Starting pituitary suppression with GnRH agonist in the early follicular phase or mid luteal phase were comparable regarding stimulation requirements and final outcomes.
Assuntos
Fármacos para a Fertilidade Feminina/administração & dosagem , Fármacos para a Fertilidade Feminina/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Gravidez/estatística & dados numéricos , Técnicas de Reprodução Assistida/estatística & dados numéricos , Adulto , Feminino , Humanos , Fase Luteal , Recuperação de Oócitos/estatística & dados numéricos , Hipófise/fisiologia , Estudos Prospectivos , Injeções de Esperma Intracitoplásmicas/estatística & dados numéricosRESUMO
ABSTRACT Objective To evaluate melatonin secretion in adult hypopituitary patients with Growth Hormone deficiency (AGHD) on and off replacement therapy. Subjects and methods We studied 48 subjects: 12 (6 males) untreated AGHD (AGHDnt), 20 (10 males) treated AGHD (AGHDt) and 16 healthy subjects (8 males) as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24 h samples), nocturnal (6-SMn): 1800-0800 and diurnal samples (6-SMd): 0800-1800. Results Significant differences were observed among the 3 groups of male subjects, in total 6-SM (p < 0.05), nocturnal 6-SM (p < 0.02) and nighttime-daytime delta values (p < 0.003). CG had significantly higher values than the AGHDnt in total 6-SM (p < 0.01), nocturnal 6-SM (p < 0.05) and nighttime-daytime delta values (p < 0.01). AGHDt patients showed significantly higher levels in nighttime-daytime delta values than AGHDnt patients (p < 0.05). In females, no significant differences were found among the 3 groups studied in total, nocturnal, diurnal or nighttime-daytime delta values. In males, significant correlations were found among total 6-SM (r = 0.58; p = 0.029), nocturnal 6-SM (r = 0.70; p = 0.006) and nighttime-daytime delta values (r = 0.71; p = 0.004) vs. serum IGF-1 levels in subjects evaluated. In females, significant correlations were found among total 6-SM (r = 0.57; p = 0.02) vs. serum IGF-1 levels in subjects evaluated. A tendency towards a significant correlation was found in diurnal 6-SM (r = 0.48; p = 0.07). Conclusions Our findings show a sexual dimorphism in 6-SM excretion in AGHD patients and provide an interesting approach to a further understanding of some chronobiological disorders involved in GH deficiency.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Fatores Sexuais , Ritmo Circadiano/fisiologia , Hormônio do Crescimento Humano/deficiência , Melatonina/análogos & derivados , Hipófise/fisiologia , Fator de Crescimento Insulin-Like I , Estudos de Casos e Controles , Estudos Prospectivos , Hipopituitarismo/fisiopatologia , Melatonina/metabolismo , Melatonina/urinaRESUMO
OBJECTIVE: To evaluate melatonin secretion in adult hypopituitary patients with Growth Hormone deficiency (AGHD) on and off replacement therapy. SUBJECTS AND METHODS: We studied 48 subjects: 12 (6 males) untreated AGHD (AGHDnt), 20 (10 males) treated AGHD (AGHDt) and 16 healthy subjects (8 males) as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24 h samples), nocturnal (6-SMn): 1800-0800 and diurnal samples (6-SMd): 0800-1800. RESULTS: Significant differences were observed among the 3 groups of male subjects, in total 6-SM (p < 0.05), nocturnal 6-SM (p < 0.02) and nighttime-daytime delta values (p < 0.003). CG had significantly higher values than the AGHDnt in total 6-SM (p < 0.01), nocturnal 6-SM (p < 0.05) and nighttime-daytime delta values (p < 0.01). AGHDt patients showed significantly higher levels in nighttime-daytime delta values than AGHDnt patients (p < 0.05). In females, no significant differences were found among the 3 groups studied in total, nocturnal, diurnal or nighttime-daytime delta values. In males, significant correlations were found among total 6-SM (r = 0.58; p = 0.029), nocturnal 6-SM (r = 0.70; p = 0.006) and nighttime-daytime delta values (r = 0.71; p = 0.004) vs. serum IGF-1 levels in subjects evaluated. In females, significant correlations were found among total 6-SM (r = 0.57; p = 0.02) vs. serum IGF-1 levels in subjects evaluated. A tendency towards a significant correlation was found in diurnal 6-SM (r = 0.48; p = 0.07). CONCLUSIONS: Our findings show a sexual dimorphism in 6-SM excretion in AGHD patients and provide an interesting approach to a further understanding of some chronobiological disorders involved in GH deficiency.
Assuntos
Ritmo Circadiano/fisiologia , Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/fisiopatologia , Melatonina/análogos & derivados , Fatores Sexuais , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Fator de Crescimento Insulin-Like I , Masculino , Melatonina/metabolismo , Melatonina/urina , Pessoa de Meia-Idade , Hipófise/fisiologia , Estudos Prospectivos , Adulto JovemRESUMO
It is well known that sex hormones play an important role during Taenia solium infection; however, to our knowledge no studies exist concerning the immune response following complete or lobe-specific removal of the pituitary gland during T. solium infection. Thus, the aim of this work was to analyze in hamsters, the effects of lack of pituitary hormones on the duodenal immune response, and their impact on T. solium establishment and development. Thus, in order to achieve this goal, we perform anterior pituitary lobectomy (AL, n = 9), neurointermediate pituitary lobectomy (NIL, n = 9) and total hypophysectomy (HYPOX, n = 8), and related to the gut establishment and growth of T. solium, hematoxylin-eosin staining of duodenal tissue and immunofluorescence of duodenal cytokine expression and compared these results to the control intact (n = 8) and control infected group (n = 8). Our results indicate that 15 days post-infection, HYPOX reduces the number and size of intestinally recovered T. solium adults. Using semiquantitative immunofluorescent laser confocal microscopy, we observed that the mean intensity of duodenal IFN-γ and IL-12 Th1 cytokines was mildly expressed in the infected controls, in contrast with the high level of expression of these cytokines in the NIL infected hamsters. Likewise, the duodenum of HYPOX animals showed an increase in the expression of Th2 cytokines IL-5 and IL-6, when compared to control hamsters. Histological analysis of duodenal mucosa from HYPOX hamsters revealed an exacerbated inflammatory infiltrate located along the lamina propria and related to the presence of the parasite. We conclude that lobe-specific pituitary hormones affect differentially the T. solium development and the gut immune response.
Assuntos
Citocinas/metabolismo , Duodeno/parasitologia , Hipófise/fisiologia , Taenia solium/fisiologia , Teníase/imunologia , Teníase/metabolismo , Animais , Cricetinae , Duodeno/imunologia , Duodeno/patologia , Feminino , Hipofisectomia , Imuno-Histoquímica , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-5/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/parasitologia , Mucosa Intestinal/patologia , Mesocricetus , Hipófise/cirurgia , Taenia solium/imunologiaRESUMO
OBJECTIVE: To determine the value of acromegaly screening in adult patients not reporting enlargement of the extremities, but who present arterial hypertension associated with at least one other comorbidity of the disease. SUBJECTS AND METHODS: Patients seen by general practitioners at primary health care units were evaluated. Among the patients without extremity enlargement, those with recently diagnosed arterial hypertension associated with at least one other comorbidity were selected. RESULTS: A total of 1,209 patients were submitted to laboratory investigation. Elevated IGF-1 was observed in 22 patients. Eighteen patients had adequate suppression of growth hormone (GH). No GH suppression was observed in four women with confirmed elevated IGF-1. In the latter, IGF-1 and nadir GH were only slightly elevated, magnetic resonance showed a normal pituitary, and chest and abdominal computed tomography revealed no tumor, and no intervention was performed. CONCLUSION: In patients with arterial hypertension without known pituitary disease, acromegaly is unlikely in the absence of enlargement of the extremities.
Assuntos
Acromegalia/diagnóstico , Diabetes Mellitus/epidemiologia , Extremidades/anatomia & histologia , Transtornos da Cefaleia/epidemiologia , Hipertensão/diagnóstico , Fator de Crescimento Insulin-Like I/análise , Acromegalia/sangue , Adulto , Idoso , Biomarcadores/sangue , Brasil , Comorbidade , Extremidades/fisiologia , Feminino , Teste de Tolerância a Glucose , Hormônio do Crescimento/sangue , Humanos , Imageamento por Ressonância Magnética , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Hipófise/fisiologia , Atenção Primária à Saúde , Inquéritos e Questionários , Adulto JovemRESUMO
Objective To determine the value of acromegaly screening in adult patients not reporting enlargement of the extremities, but who present arterial hypertension associated with at least one other comorbidity of the disease. Subjects and methods Patients seen by general practitioners at primary health care units were evaluated. Among the patients without extremity enlargement, those with recently diagnosed arterial hypertension associated with at least one other comorbidity were selected. Results A total of 1,209 patients were submitted to laboratory investigation. Elevated IGF‐1 was observed in 22 patients. Eighteen patients had adequate suppression of growth hormone (GH). No GH suppression was observed in four women with confirmed elevated IGF‐1. In the latter, IGF‐1 and nadir GH were only slightly elevated, magnetic resonance showed a normal pituitary, and chest and abdominal computed tomography revealed no tumor, and no intervention was performed. Conclusion In patients with arterial hypertension without known pituitary disease, acromegaly is unlikely in the absence of enlargement of the extremities. .
Objetivo Determinar o valor do rastreamento de acromegalia em pacientes adultos sem aumento de extremidades, mas com hipertensão arterial associada a pelo menos uma outra comorbidade da doença. Sujeitos e métodos Pacientes vistos por clínicos em unidades primárias de saúde foram avaliados. Entre pacientes sem aumento de extremidades, aqueles com hipertensão arterial diagnosticada recentemente e associada a pelo menos uma outra comorbidade foram selecionados. Resultados Um total de 1.209 pacientes foi submetido à investigação laboratorial. IGF‐1 foi elevado em 22 pacientes. Dezoito pacientes apresentavam supressão adequada do hormônio do crescimento (GH). Ausência de supressão do GH foi vista em quatro mulheres com IGF‐1 repetidamente elevado. Nestas, IGF‐1 e nadir do GH foram apenas discretamente aumentados, ressonância magnética revelou hipófise normal, tomografia computadorizada de tórax e abdome não revelaram tumor, e nenhuma intervenção foi realizada. Conclusão Em pacientes com hipertensão arterial sem doença hipofisária conhecida, acromegalia é improvável na ausência de aumento de extremidades. .