Riesgo cardiovascular en el síndrome de Cushing / Cardiovascular risk found in Cushing syndrome

El síndrome de Cushing se caracteriza por un estado de hipercortisolismo endógeno, que produce múltiples y variadas alteraciones metabólicas que aumentan el riesgo cardiovascular en la fase activa de la enfermedad y aún después de la curación. La presencia de la obesidad central, la dislipidemia, la hipertensión arterial, la resistencia a la insulina y los trastornos en la tolerancia a la glucosa (componentes del síndrome metabólico), aceleran el proceso de la aterosclerosis sistémica. El exceso de glucocorticoides genera además, un estado protrombótico que se acompaña de disfunción endotelial. Esto se traduce en un mayor riesgo de infarto del miocardio, insuficiencia cardiaca, ictus y eventos tromboembólicos venosos. Se ha estimado un incremento de la mortalidad hasta 4 veces mayor cuando se compara a estos pacientes con la población general, de ahí que pueda considerarse una enfermedad potencialmente letal. Asociado a la necesidad de eliminar la causa del exceso de glucocorticoides, se recomienda la evaluación del riesgo cardiovascular global y el tratamiento intensivo de cada uno de los factores de riesgo durante la fase activa, en el periodo de remisión y luego de la curación. Teniendo en cuenta lo mencionado anteriormente y la importancia del tema, se realiza una actualización de la repercusión cardiovascular del hipercortislismo en los pacientes que lo padecen(AU)

Cushing's syndrome is characterized by endogenous hypercortisolism that causes many different metabolic alterations increasing the cardiovascular risk at the active phase of disease and even after recovery. Central obesity, dyslipidemia, blood hypertension, insulin resistance, and glucose tolerance disorders (components of the metabolic syndrome) accelerate the process of systemic atherosclerosis. Excessive glucocorticoids also generate a prothrombotic condition with endothelial dysfunction. This leads to higher risk of myocardial infarction, heart failure, ictus and vein thromboembolic events. A fourfold increase of mortality has been estimated in these patients when compared to the general population; hence this disease may be considered a lethal one. In addition to the need of eliminating the cause of excessive glucocorticoids, it is recommended to evaluate the global cardiovascular risk and the intensive treatment for each of the risk factors during the active phase, in the remission period and after recovery. Taking into account the above-mentioned and the importance of this topic, an update on the cardiovascular impact of hypercortisolism was presented(AU)

Changes in prolactin secretion in the short- and long-term after adrenalectomy / Efeito da evolução temporal da adrenalectomia na secreção de prolactina

OBJECTIVE: To evaluate the modulation of the hypothalamus-pituitary-adrenal axis (HPA) on prolactin secretion in rats after adrenalectomy (ADX). MATERIALS AND METHODS: Plasma corticosterone, ACTH, and prolactin concentrations were measured by radioimmunoassay in rats after bilateral ADX in the short- (3 hours and 1day) and long-term (3, 7, and 14 days). RESULTS: Animals that underwent ADX showed undetectable corticosterone levels and a triphasic ACTH response with a transient increase (3h), a decrease (1d), and further increase in the long-term after ADX. Sham animals showed a marked increase in corticosterone and ACTH levels three hours after surgery, with a decrease to basal levels thereafter. Plasma prolactin levels were not changed after ADX. CONCLUSION: There are different points of equilibrium in the HPA axis after the glucocorticoid negative feedback is removed. Prolactin plasma secretion is not altered in the short or long- term after ADX, suggesting that the peptidergic neurons essential for prolactin release are not activated after ADX.

OBJETIVO: Avaliar a modulação do eixo hipotálamo-hipófise-adrenal (HHA) sobre a secreção de prolactina após adrenalectomia (ADX). MATERIAIS E MÉTODOS: Quantificamos por RIE corticosterona, ACTH e prolactina plasmáticos em ratos após curtos (3 horas e 1 dia) e longos (3, 7 e 14 dias) períodos de ADX bilateral. RESULTADOS: Animais ADX mostraram níveis indetectáveis de corticosterona. As concentrações plasmáticas de ACTH apresentaram resposta trifásica: aumento transitório (3h), diminuição (1d) e novo aumento após longos períodos de ADX. Animais Sham mostraram aumento de corticosterona/ACTH após três horas de cirurgia, diminuindo posteriormente aos níveis basais. As concentrações plasmáticas de prolactina não se alteraram após ADX. CONCLUSÃO: Existem diferentes pontos de equilíbrio do eixo HHA após a remoção da retroalimentação negativa exercida pelos glicocorticoides. A secreção de prolactina não se alterou após curtos/longos períodos de ADX, sugerindo que os neurônios peptidérgicos essenciais para a liberação de prolactina não estão ativados durante os diferentes períodos de ADX.

Neural regulation of the stress response: glucocorticoid feedback mechanisms

The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback ‘switch’, control of the stress response requires a wide-reaching feedback ‘network’ that coordinates HPA activity to suit the overall needs of multiple body systems.

El papel del receptor de glucocorticoide en el estrés temprano: [revisión] / The relevance of glucocorticoid receptor in early stress: [review]

En estudios previos se han relacionado las alteraciones funcionales del eje hipotálamohipofisario-adrenal y el estrés temprano; por ejemplo, el aumento en la producción de corticotropina (ACTH) y glucocorticoide como factor clave en la fisiopatología de trastornos del estrés como la depresión. En este artículo se presentan los resultados de estudios en epigenética en busca del posible nexo entre el estrés temprano, la disminución en la expresión del receptor de glucocorticoide y la hiperactividad del eje hipotálamo-hipofisario-adrenal. De esta manera, se identifica al estrés temprano como modulador del neurodesarrollo de las estructuras cerebrales implicadas en la respuesta frente al estrés, así como el papel del receptor de glucocorticoide en dicho proceso.

Previous studies have shown how Hypothalamic-Pituitary-adrenal Axis dysfunction is related to early life stress; several works show that Hypothalamic-Pituitary-adrenal Axishyperactivity increases production of ACTH and glucocorticoids, indicating a pathophysiological key factor in stress related diseases like depression. This review will discuss results of some epigenetical studies linking early life stress, decreased production of the glucocorticoid receptor and Hypothalamic-Pituitary-adrenal Axis hyperactivity. We conclude how early life stress modulates the expression of the glucocorticoid receptor affecting the development of several brain structures involved in the stress response.

Localización extra nuclear de receptores esteroides y activación de mecanismos no genómicos / Extra nuclear localization of steroid receptors and non genomic activation mechanisms

Los receptores de hormonas esteroides han sido considerados históricamente como factores de transcripción nucleares. Sin embargo, en los últimos años surgieron evidencias que indican que su activación desencadena eventos rápidos, independientes de la transcripción y que involucran a diferentes segundos mensajeros; muchos de estos receptores han sido localizados en la membrana celular. Por otra parte, se han caracterizado varios receptores de hormonas esteroides noveles, de estructura molecular diferente al receptor clásico, localizados principalmente en la membrana celular. Esta revisión enfoca los diferentes efectos iniciados por los glucocorticoides, mineralocorticoides, andrógenos, estrógenos y progesterona, y los posibles receptores involucrados en los mismos.

Steroid hormone receptors have been historically considered as nuclear transcription factors. Nevertheless, in the last years, many of them have been detected in the cellular membrane. It has been postulated that their activation can induce transcription independent rapid events involving different second messengers. In addition, several novel steroid hormone receptors, showing a different molecular structure than the classical ones, have also been characterized and most of them are also located in the plasmatic membrane. This review focuses on the variety of effects initiated by glucocorticoids, mineralocorticoids, androgens, estrogens and progesterone, and the possible receptors involved mediating these effects.

Central actions of glucocorticoids in the control of body fluid homeostasis: review

The involvement of the hypothalamic-pituitary-adrenal axis in the control of body fluid homeostasis has been extensively investigated in the past few years. In the present study, we reviewed the recent results obtained using different approaches to investigate the effects of glucocorticoids on the mechanisms of oxytocin and vasopressin synthesis and secretion in response to acute and chronic plasma volume and osmolality changes. The data presented here suggest that glucocorticoids are not only involved in the mechanisms underlying the fast release but also in the transcriptional events that lead to decreased synthesis and secretion of these neuropeptides, particularly oxytocin, under diverse experimental conditions of altered fluid volume and tonicity. The endocannabinoid system, through its effects on glutamatergic neurotransmission within the hypothalamus and the nuclear factor κB-mediated transcriptional activity, seems to be also involved in the specific mechanisms by which glucocorticoids exert their central effects on neurohypophyseal hormone synthesis and secretion.

Aspectos moleculares da sensibilidade aos glicocorticóides / Molecular aspects of glucocorticoid sensitivity / Molecular aspects of glucocorticoid sensitivity

Os glicocorticóides exercem um papel importante na regulação fisiológica e na adaptação a situações de stress, sendo a maioria dos efeitos destes hormônios mediada pela interação com os receptores glicocorticóides. A sensibilidade ao glicocorticóide depende da densidade celular de receptores expressos, bem como da eficiência da transdução do sinal mediada pelo complexo hormônio-receptor. Os estados de resistência ou de hipersensibilidade ao glicocorticóide, observados, respectivamente, nas doenças inflamatórias auto-imunes e na síndrome metabólica, podem representar a variabilidade dos fatores que influenciam a cascata de sinalização do glicocorticóide. O reconhecimento destes fatores contribui para uma melhor compreensão tanto do fenótipo clínico e da evolução destas doenças quanto da resposta terapêutica com glicocorticóide. A compreensão destes mecanismos fisiopatológicos também pode contribuir para a escolha de intervenções terapêuticas. Neste artigo de revisão, descrevemos os múltiplos fatores envolvidos nesta cascata de sinalização, os quais são capazes de influenciar a sensibilidade ao glicocorticóide.

Glucocorticoids play an essential role in maintaining basal and stress-related homeostasis. Most known effects of glucocorticoids are mediated by the intracellular glucocorticoid receptors. The glucocorticoid sensitivity seems to depend on the amount of receptors expressed and the efficiency of glucocorticoid receptor-mediated signal transduction. Glucocorticoid resistance or hypersensitivity, seen in autoimmune-inflammatory diseases and in metabolic syndrome respectively, can represent the variability of several steps that influence the signaling cascade of glucocorticoid action. The recognition of these steps could provide the understanding of the clinical phenotype and course of such diseases as well as their responsiveness to glucocorticoid therapy. The comprehension of these pathophysiological mechanisms can also improve the possible therapeutic interventions. In this review, we have summarized the multiple factors that have been shown to be involved in this signaling cascade and, thus, to influence glucocorticoid sensitivity.

Causas raras de pseudo-hermafroditismo feminino: quando suspeitar? / Rare forms of female pseudohermaphroditism: when to investigate?

Neste artigo discutiremos as causas raras de pseudo-hermafroditismo feminino. Hiperplasia congênita adrenal é a causa mais comum da ambigüidade da genitalia externa no nascimento, em fetos 46,XX, devido principalmente à forma clássica de deficiência de 21-hidroxilase. São apresentadas aqui as deficiências de 11beta-hidroxilase e de 3beta-hidroxiesteroide desidrogenase, além da resistência familial aos glicocorticóides, caracterizada pela secreção aumentada de cortisol sem evidência clínica de hipercortisolismo, mas com manifestations de excesso de andrógenos e de mineralocorticóides, decorrente de mutações no gene do receptor do glucocorticóide. Também são discutidas a deficiência de aromatase placentária, caracterizada por masculinização do feto feminino, acompanhada de virilização materna durante a gestação, e deve ser considerada na ausência da hiperplasia adrenal fetal e de tumores maternos produtores de andrógenos e a deficiência da P450-oxidorredutase, além das causas maternas e de quadros dismórficos complexos que levam ao pseudo-hermafroditismo feminino. A investigação requer a análise do cariótipo, dosagens séricas iniciais de 17OH progesterona, 11 desoxicortisol, 17-pregnenolone e andrógenos para avaliar o diagnóstico das diferentes causas de hiperplasia adrenal congênita. Após este diagnóstico ser afastado, dados clínicos e laboratoriais devem ser coletados para afastar as causas ainda mais raras de pseudo-hermafroditismo feminino.

Rol fisiológico del eje somatotrófico GH-IGF y otras hormonas en el crecimiento de los animales domésticos. Influencia del estado nutricional / Physiologic role of the somatotrophic GH-IGF and others hormones in the domestic animals growth. Influence of the nutritional status

En esta revisión se describen las principales hormonas invlolucradas en el desarrollo y crecimiento muscular, haciendo especial énfasis en la hormona de cricimiento (GH) y los factores del crecimiento semejante a insulina (IGF). Se recopila la composición química, el lugar de síntesis y los principales mecanismos de acción de estas hormonas. Se observó que la GH, IGF, las hormonas tiroideas, la insulina, los glucocorticoides y los esteroides sexuales actuán en una forma compleja y coordinada para producir una respuesta productiva a diferentes estrategias nutricionales.

comparison between the effects of hypophysectomy and cyproterone acetate on the adrenal medulla chromaffin cells of the mouse

The effects of reduction in the glucocorticoid secretion on the adrenomedullary chromaffin cells of the mouse were studied through hypophysectomy and cyproterone acetate [CA] administration. The latter drug is reported to have a pronounced ACTH suppressive effect and to interfere with steroid biosynthesis. There was no evidence of a change in the proportion of epinephrine - storing [E] and nonepinephrine storing [NE] cells in the adrenal medulla of hypophysectomized mice or CA-treated animals. In hypophysectomized animals, the norepinephrine [NE] showed a significant Increase in content and proportion. This was attributed - to a significant decrease in the epinephrine [E] content of these animals. The adrenal glands of CA-treated animals did not show any significant change in NE content, although a significant increase in the NE proportion of the total catecholamine was observed. This was again attributed to the significant decrease in the E content of CA animals. The ultrastructural changes showed the presence of both E and NE granules in the same cell. In addition, many cells showed marked reduction in their secretory granules and appear similar to sympathetic neurons. The reversibility of these changes following cessation of CA - treatment suggests that they represented temporary metabolic changes rather than a process of dedifferentiation of these cells

Síndrome de hipoaldosteronismo hiporreninémico / Hyporrheninemic hypoaldosteronism syndrome

El hipoaldosteronismo hiporreninémico es un síndrome que no es infrecuente en la práctica clínica, pero que indudablemente es subdiagnosticado. Constituye la mitad de los casos de hiperkalemia inexplicada, por lo que es un diagnóstico que siempre debe tenerse presente, sobre todo en pacientes diabéticos con algún grado de insuficiencia renal. El diagnóstico se confirma con la medición de aldosterona plasmática y la actividad de renina plasmática, en presencia de una función glucocorticoidea normal. Se presenta un caso clínico de hipoaldosteronismo hiporreninémico, cuyo diagnóstico fue sospechado a través de una hiperkalemia asintomática de etiología inexplicada, el que fue confirmado por los exámenes pertinentes y cuyo tratamiento con diuréticos resultó exitoso

Interacciones inmuno neuro endocrinas / Immune neuroendocrine interactions

El estudio de las relaciones entre el sistema inmunológico y los sistemas nervioso y endocrino ha sido motivo de gran interés en años recientes. Se ha establecido claramente la inervación autonómica de algunos órganos del sistema inmunológico, la presencia de receptores para hormonas o neuropéptidos en los inmunocitos y la acción de ciertas citokinas sobre órganos del sistema neuroendocrino. Varias leukinas y monokinas son activas sobre glándulas endocrinas y diversas hormonas regulan la producción de citokinas y la proliferación y distribución de los inmunocitos. Por otra parte, se han encontrado pequeñas cantidades de ciertas hormonas en inmunocitos y secreción de citokinas en algunas células endocrinas, lo que sugiere la existencia de una compleja variedad de efectoa paracrinos entre ambos sistemas. De este modo, tal vez, el sistema inmunológico participa como sistema integrador junto al sistema neuroendocrino, aportando estímulos frente a la presencia de bacterias, virus, tumores, antígenos, etc., dando como resultado de ello a los cambios fisiológicos; sus vinculaciones con el sistema nervioso parece contribuir a dilucidar algunos procesos por los cuales factores psicosociales influencian la salud

Induccion de Anilina Hidroxilasa por la Hormona Adrenocorticotropica y la Dexametasona / Induction of Aniline Hydroxilase by the Adenocorticotropic Hormone and Dexametasone

La administracion in vivo de la hormona adrenocorticotropica (ACTH) produce induccion de las oxidasas de funcion mixta (OFM) microsomales en el higado de raton si se utiliza anilina como sustrato. El comportamiento inductivo semeja el patron natural, pues muestra una induccion temprana con disminucion posterior como respuesta a una sola dosis de hormona, a diferencia de lo observado comunmente para otro tipo de inductores. El suministro progresivo y creciente de la hormona presenta un efecto de saturacion. La administracion del glucocorticoide dexametasona reproduce los resultados obtenidos con ACTH, lo cual esta de acuerdo con la hipotesis de que el efecto es mediado por la corteza suprarrenal. La inhibicion del efecto inductivo por cicloheximida sugiere la sintesis de novo de proteina enzimatica