Lower Urinary Tract Symptoms (LUTS) as a New Clinical Presentation of Histamine Intolerance: A Prevalence Study of Genetic Diamine Oxidase Deficiency.

Lower urinary tract symptoms (LUTS) are highly prevalent, and their treatment is mainly focused on the control of symptoms. Histamine intolerance (HIT) has been related to a variety of systemic symptoms. DAO deficiency has been identified as a significant factor contributing to histamine intolerance (HIT). Preclinical evidence indicates the involvement of histamine in the lower urinary tract. This study aimed to assess the prevalence of diamine oxidase deficiency (DAO) in a prospective cohort of 100 patients with at least moderate LUTS. A genetic study of four single nucleotide polymorphisms (SNPs) (c.-691G>T, c.47C>T, c.995C>T, and c.1990C>G) was performed. HIT was found in 85.9% of patients. The prevalence of at least one minor allele in the SNPs analyzed was 88%, without gender differences. Storage symptoms were more intense in the presence of HIT as well as asthenia and neurological and musculoskeletal symptoms. The presence of minor alleles of the AOC1 gene was associated with a higher intensity of symptoms. Minor alleles from c.-691G>T and c.47C>T SNPs were also associated with a greater severity of obstructive symptoms. Thirty-one percent of patients presented the four SNPS with at least one associated minor allele. The relationship between HIT and LUTS in a mixed population of men and women found in this study supports further investigations to define the pathophysiology of histamine in LUTS.

[Castration resistance mechanisms in prostate cancer.] / Mecanismos de resistencia a la castración.

The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients.

Mecanismos de resistencia a la castración / Castration resistance mechanisms in prostate cancer

El eje de señalización de andrógenos desempeña un papel fundamental en la patogénesis del cáncer de próstata. Desde el descubrimiento histórico de Huggins y Hodges, la depleción androgénica permanece como la piedra angular en el tratamiento de la enfermedad avanzada. Sin embargo, de forma invariable, la progresión a cáncer de próstata resistente a la castración se produce dentro de los 2-3 años posteriores al inicio de la terapia de deprivación androgénica (TDA). Múltiples mecanismos de resistencia ayudan a la progresión a la enfermedad resistente a la castración, y el receptor de andrógenos (RA) sigue siendo un impulsor importante en esta progresión. Los mecanismos moleculares que subyacen a la reactivación del RA en el cáncer de próstata resistente a la castración (CPRC) incluyen la amplificación y sobreexpresión del RA, mutaciones del RA, expresión de variantes constitutivamente activas del RA, síntesis de andrógenos intratumorales y suprarrenales y activación promiscua del RA por otros factores. También se discuten otros mecanismos de resistencia independientes del RA, que incluyen la activación del receptor de glucocorticoides, la alteración de las vías de reparación del ADN, la resistencia mediada por mecanismos inmunes, la diferenciación neuroendocrina y la expresión de microARN. El cáncer de próstata resistente a la castración es una enfermedad compleja, se caracteriza por múltiples mecanismos de resistencia al tratamiento de deprivación de andrógenos, y sigue siendo una enfermedad incurable. La comprensión de los mecanismos que subyacen a esta resistencia es necesaria para identificar objetivos terapéuticos futuros, así como la identificación y validación de nuevos biomarcadores predictivos de resistencia, lo que puede conducir a una mejora terapéutica para pacientes con CPRC

The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients

[Testosterone deficit syndrome in the old male]. / Síndrome de deficit de testosterona en el anciano.

Epidemiological studies have demonstrated that prevalence of hypogonadism in old males increases with every additional decade of life. These males present various symptoms including decrease of sexual function, decrease of cognitive function, altered lipid profile, increased visceral adiposity, changes in bone density and muscular strength secondary to atrophy. Currently, testosterone injections and gel preparations are the most used. Testosterone replacement therapy provides significant symptomatic improvements for men with late start hypogonadism. Long-term benefits and risks of testosterone replacement therapy will be more evident when testosterone effects are studied on all health related parameters over a prolonged period of time. There is a large ongoing multicentric randomized clinical trial sponsored by NIH for testosterone control in old men with low testosterone levels. Its results may give answers to the possible benefits and risks of testosterone replacement in aging males. If an aging male is diagnosed as late-start hypogonadism, the urologist should discuss with the patient potential benefits and risks of testosterone therapy. Aging males with significant erythrocytosis, untreated sleep apnea, prostate cancer and high risk of cardiovascular events must be excluded from testosterone replacement therapy. Currently, there are not enough evidences to clearly state that the benefits of testosterone replacement therapy in aging males are better than the risks of this treatment. A general recommendation cannot be given that testosterone replacement therapy may be applied to all aging males with low testosterone levels independently of significant signs or symptoms.

Síndrome de déficit de testosterona en el anciano / Testosterone deficit syndrome in the old male

Los estudios epidemiológicos han demostrado que la prevalencia de hipogonadismo en los hombres de edad avanzada aumenta con cada década adicional de vida. Estos hombres presentan diversos síntomas que incluyen la disminución de la función sexual, disminución de la función cognitiva, perfil lipídico alterado, aumento de la adiposidad visceral, cambios en la densidad ósea y en la fuerza muscular secundaria a la atrofia. En la actualidad, las inyecciones de testosterona y preparaciones en forma de gel son las más usadas. La terapia de reemplazo de testosterona proporciona mejoras significativas en los síntomas para hombres con hipogonadismo de inicio tardío. Los beneficios a largo plazo y los riesgos del tratamiento con testosterona de reemplazo se harán más evidentes cuando los efectos de la testosterona se estudian en todos los parámetros relacionados con la salud durante un período prolongado de tiempo. Está en curso un gran ensayo multicéntrico aleatorizado patrocinado por NIH para el control de la testosterona en hombres de edad avanzada con niveles bajos de testosterona. Sus resultados pueden dar respuestas a los posibles beneficios y riesgos de reemplazo de testosterona en los hombres que envejecen. Si se produce un envejecimiento masculino se diagnostica como hipogonadismo de inicio tardío, el urólogo debe consensuar con el paciente los beneficios y riesgos potenciales de la terapia con testosterona (AU)

Los hombres ancianos que tienen eritrocitosis significativa, apnea del sueño no tratada, cáncer de próstata, y alto riesgo de eventos cardiovasculares deben ser excluidos de la terapia de reemplazo de testosterona. En la actualidad, no hay pruebas suficientes para afirmar claramente que los beneficios de la terapia de reemplazo de testosterona es mejor que los riesgos de este tratamiento de reemplazo en los hombres que envejecen. No se puede hacer una recomendación generalizada de que esta terapia de reemplazo de testosterona puede ser aplicada a todos los varones ancianos con niveles bajos de testosterona independientes de los signos o síntomas significativos (AU)

Epidemiological studies have demonstrated that prevalence of hypogonadism in old males increases with every additional decade of life. These males present various symptoms including decrease of sexual function, decrease of cognitive function, altered lipid profile, increased visceral adiposity, changes in bone density and muscular strength secondary to atrophy. Currently, testosterone injections and gel preparations are the most used. Testosterone replacement therapy provides significant symptomatic improvements for men with late start hypogonadism. Long-term benefits and risks of testosterone replacement therapy will be more evident when testosterone effects are studied on all health related parameters over a prolonged period of time. There is a large ongoing multicentric randomized clinical trial sponsored by NIH for testosterone control in old men with low testosterone levels. Its results may give answers to the possible benefits and risks of testosterone replacement in aging males. If an aging male is diagnosed as late-start hypogonadism, the urologist should discuss with the patient potential benefits and risks of testosterone therapy. Aging males with significant erythrocytosis, untreated sleep apnea, prostate cancer and high risk of cardiovascular events must be excluded from testosterone replacement therapy. Currently, there are not enough evidences to clearly state that the benefits of testosterone replacement therapy in aging males are better than the risks of this treatment. A general recommendation cannot be given that testosterone replacement therapy may be applied to al aging males with low testosterone levels independently of significant signs or symptoms (AU)