Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous TXNRD2 splice variant.

OBJECTIVE: Adrenal cortisol production occurs through a biosynthetic pathway which depend on NADH and NADPH for energy supply. The mitochondrial respiratory chain and the reactive oxygen species (ROS) detoxification system are therefore important for steroidogenesis. Mitochondrial dysfunction leading to oxidative stress has been implicated in the pathogenesis of several adrenal conditions. Nonetheless, only very few patients with variants in one gene of the ROS detoxification system, Thioredoxin Reductase 2 (TXNRD2), have been described with variable phenotypes. DESIGN: Clinical, genetic, structural, and functional characterization of a novel, biallelic TXNRD2 splice variant. METHODS: On human biomaterial, we performed whole exome sequencing to identify and RNA analysis to characterize the specific TXNRD2 splice variant. Amino acid conservation analysis and protein structure modeling were performed in silico. Using patient's fibroblast-derived human induced pluripotent stem cells, we generated adrenal-like cells (iALC) to study the impact of wild-type (WT) and mutant TXNRD2 on adrenal steroidogenesis and ROS production. RESULTS: The patient had a complex phenotype of primary adrenal insufficiency (PAI), combined with genital, ophthalmological, and neurological features. He carried a homozygous splice variant c.1348-1G > T in TXNRD2 which leads to a shorter protein lacking the C-terminus and thereby affecting homodimerization and flavin adenine dinucleotide binding. Patient-derived iALC showed a loss of cortisol production with overall diminished adrenal steroidogenesis, while ROS production was significantly increased. CONCLUSION: Lack of TXNRD2 activity for mitochondrial ROS detoxification affects adrenal steroidogenesis and predominantly cortisol production.

Estudio Descriptivo: Estrés y Calidad de Vida en Estudiantes de Medicina de la Universidad del Azuay / Descriptive Research: Stress and Life Quality of Medicine Career Students.

OBJETIVO: Determinar los niveles de estrés y calidad de vida de estudiantes de primero y quinto ciclo de la carrera de medicina para compararlos y determinar la influencia de estos factores en su rendimiento académico. MÉTODO: Se realizó un estudio observacional, desarrollado en un modelo longitudinal y comparativo. Incluyó a los estudiantes de primero y quinto ciclo de la facultad de Medicina. Se realizó una medición del cortisol plasmático durante el periodo de clases regulares y en la semana de exámenes finales para comparar los resultados, así como se aplicó el cuestionario Q LES Q para determinar calidad de vida. RESULTADOS: Se evaluaron 78 estudiantes, 43 fueron de primer ciclo y 35 de quinto ciclo. La calidad de vida fue catalogada como buena en un 27 % de estudiantes. La media de cortisol inicial fue 9.88 ±3.35 µg/dl en alumnos de primer ciclo y 14.88 ±7.09 µg/dl en los alumnos de quinto (p: ˂0.05). Luego del periodo de exámenes, la media de cortisol llegó a 14.36 ±5.43 µg/dl en alumnos de primer ciclo y 18.23 ±5.83 µg/dl en los alumnos de quinto (p: ˂0.05). Dos personas reprobaron primer ciclo, sin embargo ninguno de ellos tuvo valores de cortisol para determinar la existencia de estrés. Se encontraron diferencias significativas entre los valores de cortisol obtenidos antes y después del período de exámenes. No se demostró asociación entre el desenlace académico y los resultados del cuestionario Q LES Q en relación a los niveles plasmáticos de cortisol (Fisher ˃0.05). CONCLUSIÓN: Existieron diferencias significativas entre los niveles plasmáticos de cortisol de los alumnos de primero y quinto ciclo así como al comparar los valores en los dos periodos examinados. No se demostró que una calidad de vida regular se relacione con un desempeño académico negativo ni con los niveles plasmáticos de cortisol.(au)

OBJECTIVE: To determine stress level and quality of life of students from first and fifth cycle of Medicine, compareand determine the influence of these factors on their academic performance. METHODS: A longitudinal observational and comparative study was performed. It included students from first and fifth cycle of Medicine career. Cortisol serum levels were measured during regular classes and final examination period to compare results; Q LES Q was also applied to determine life quality. RESULTS: 78 students were part of the study, 43 from first and 35 from fifth cycle. Life quality was rated as «good¼ in 27 % of them. Initial cortisol means were 9.88 ±3.35 µg/dl in first cycle students and 14.88 ±7.09 µg/dl in fifth cycle students (p: ˂0.05). After examination period it reached 14.36 ±5.43 µg/dl for the first cycle students and 18.23 ±5.83 µg/dl in fifth cycle students (p: ˂0.05). Two students reproved and none of them had high cortisol levels. Significant differences were found between cortisol levels before and after examination period. There was no association among academic outcome and Q LES Q results compared with cortisol serum levels (Fisher: ˃0.05). CONCLUSIONS: Significant differences were found between cortisol levels in first and fifth cycle students and also before and after examination period. A relation was not established between cortisol levels, life quality and a negative academic outcome.(au)

La melatonina reduce la respuesta de cortisol al ACTH en humanos / Melatonin reduces cortisol response to ACTH in humans

Background: Melatonin receptors are widely distributed in human tissues but they have not been reported in human adrenal gland. Aim: To assess if the human adrenal gland expresses melatonin receptors and if melatonin affeets cortisol response to ACTH in dexamethasone suppressed volunteers. Material and methods: Adrenal glands were obtained from 4 patients undergoing unilateral nephrectomy-adrenalectomy for renal cáncer. Expression of mRNA MT1 and MT2 melatonin receptors was measured by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). The effect of melatonin on the response to intravenous (i.v.) ACTH was tested (randomized cross-over, double-blind, placebo-controlled tríal) in eight young healthy males pretreated with dexamethasone (1 mg) at 23:00 h. On the next day at 08:00 h, an i.v. Une was inserted, at 08:30 h, and after a blood sample, subjeets ingested 6 mg melatonin or placebo. At 09:00 h, 1-24 ACTH (Cortrosyn, 1µg/1.73 m² body surface área) was injected, drawing samples at 0, 15, 30, 45 and 60 minutes after. Melatonin, cortisol, cortisone, progesterone, aldosterone, DHEA-S, testosterone and prolactin were measured by immunoassay. Results: The four adrenal glands expressed only MT1 receptor mRNA. Melatonin ingestión reduced the cortisol response to ACTH from 14.6+1.45µg/dl at 60 min in the placebo group to 10.8+1.2µg/dl in the melatonin group (p <0.01 mixed model test). It did not affect other steroid hormone levels and abolished the morningphysiological decline of prolactin. Conclusions: The expression ofMTl melatonin receptor in the human adrenal, and the melatonin reduction of ACTH-stimulated cortisol production suggest a direct melatonin action on the adrenal gland .

Hiperplasia adrenal congénita e hipertensión arterial / Congenital adrenal hyperplasia and arterial hypertension

El fenotipo asociado a Hiperplasia Adrenal Congénita (HAC) fue descripto por primera vez en 1865 pero la naturaleza de este desorden permaneció obscura hasta mediados del siglo XX. Se denomina HAC a un conjunto de enfermedades hereditarias que producen un trastorno en la esteroideogénesis suprarrenal. Dado que dicho trastorno afecta siempre la síntesis de cortisol condiciona una hipersecreción de adrenocorticotrofina (ACTH), que implicará, una hipertrofia de la glándula suprarrenal dando origen al nombre de ésta patología. Actualmente, mediante técnicas de biología molecular se pueden identificar mutaciones específicas que afectan a los genes de las proteínas involucradas en la biosíntesis de cortisol; estas permiten su diagnóstico precoz y la aplicación de un tratamiento adecuado. El déficit de 11Bhidroxilasa (11BOH) es la segunda causa más frecuente de HAC, apróximadamente 2/3 de los pacientes con este desorden tienen hipertensión arterial, por otra parte, en el déficit de 17 alfahidroxilasa (17OH), encontramos mujeres hipogonádicas y varones con genitales ambiguos e hipertensión arterial.