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1.
World J Surg Oncol ; 19(1): 122, 2021 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-33865422

RESUMEN

BACKGROUND AND OBJECTIVES: Long non-coding RNA (lncRNA) prostate androgen-regulated transcript 1 (PART1) was previously shown to exert an oncogenic role in several human cancers. However, whether PART1 is associated with the malignant progression of pancreatic cancer remains unclear. In the current study, we aimed to identify the role and potential mechanism of PART1 in pancreatic cancer. METHODS: qRT-PCR was applied to detect PART1 expression in 45 cases of pancreatic cancer patients. The chi-square test was performed to assess the association between PART1 expression and clinicopathologic features, and Kaplan-Meier method was applied to evaluate overall survival. In vitro CCK-8, transwell invasion, and flow cytometry assays were applied to detect the effects of PART1 on cell proliferation, invasion, and apoptosis, respectively. Luciferase reporter and RNA immunoprecipitation assays were used to identify the regulatory mechanism between PART1 and miR-122. RESULTS: PART1 expression was upregulated in pancreatic cancer tissues and cell lines. High PART1 expression was closely correlated with tumor size, T classification, clinical stage, and vascular invasion, and predicted a poor overall survival. PART1 knockdown significantly suppressed cell proliferation and invasion abilities of pancreatic cancer but promoted cell apoptosis. PART1 was found to serve as a molecular sponge of miR-122, and miR-122 inhibition partially reversed the inhibitory phenotypes of PART1 knockdown on pancreatic cancer cells. CONCLUSIONS: PART1 promotes the malignant progression of pancreatic cancer by sponging miR-122. The PART1/miR-122 axis might be a promising target for anticancer therapy in patients with pancreatic cancer.


Asunto(s)
Proliferación Celular/genética , MicroARNs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN no Traducido/genética , Andrógenos , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico
2.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808818

RESUMEN

Dichlorodiphenyltrichloroethane (DDT) is the most widespread, persistent pollutant and endocrine disruptor on the planet. Although DDT has been found to block androgen receptors, the effects of its low-dose exposure in different periods of ontogeny on the male reproductive system remain unclear. We evaluate sex steroid hormone production in the pubertal period and after maturation in male Wistar rats exposed to low doses of o,p'-DDT, either during prenatal and postnatal development or postnatal development alone. Prenatally and postnatally exposed rats exhibit lower testosterone production and increased estradiol and estriol serum levels after maturation, associated with the delayed growth of gonads. Postnatally exposed rats demonstrate accelerated growth of gonads and higher testosterone production in the pubertal period. In contrast to the previous group, they do not present raised estradiol production. All of the exposed animals exhibit a reduced conversion of progesterone to 17OH-progesterone after sexual maturation, which indicates putative attenuation of sex steroid production. Thus, the study reveals age-dependent outcomes of low-dose exposure to DDT. Prenatal onset of exposure results in the later onset of androgen production and the enhanced conversion of androgens to estrogens after puberty, while postnatal exposure induces the earlier onset of androgen secretion.


Asunto(s)
Andrógenos/biosíntesis , DDT/farmacología , Disruptores Endocrinos/farmacología , Exposición a Riesgos Ambientales/efectos adversos , Estrógenos/biosíntesis , Animales , DDT/administración & dosificación , Disruptores Endocrinos/administración & dosificación , Femenino , Genitales Masculinos/efectos de los fármacos , Genitales Masculinos/metabolismo , Hormonas Esteroides Gonadales/biosíntesis , Gónadas/efectos de los fármacos , Gónadas/metabolismo , Masculino , Ratas
3.
Environ Sci Technol ; 55(6): 3827-3835, 2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33646749

RESUMEN

Iodoacetic acid (IAA) is the most genotoxic iodinated disinfection byproduct known in drinking water. Previous studies have shown that IAA may be an endocrine disruptor. However, whether IAA has reproductive and developmental toxicity remains unclear. In this study, the reproductive and developmental toxicity of IAA was evaluated using a battery of in vitro and in vivo reproductive/developmental toxicity screening tests. The results of E-Screen, uterotrophic, and H295R steroidogenesis assays were negative. The Hershberger bioassay revealed that IAA could induce significant increases in absolute and relative weights of paired Cowper's glands. Moreover, there was an increasing trend in the relative weights of the ventral prostate. The micromass test showed that IAA could inhibit the differentiation of midbrain and limb bud cells. A reproductive/developmental toxicity screening test showed that IAA resulted in significantly increased relative weights of testis and seminal vesicles plus coagulating glands in parental male rats, with a dose-response relationship. IAA could not only induce head congestion in offspring but also decrease litter weight, viability index, and anogenital distance index of male pups on postnatal day 4. All these results indicated that IAA had reproductive and developmental toxicity.


Asunto(s)
Agua Potable , Andrógenos , Animales , Desinfección , Agua Potable/análisis , Ácido Yodoacético , Masculino , Tamaño de los Órganos , Ratas , Testículo
5.
Environ Int ; 151: 106459, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33684682

RESUMEN

BACKGROUND: Several in vitro and in vivo studies have demonstrated the effects of phthalates on androgen synthesis, and the adverse outcomes of phthalate exposure on male reproductive function have been reported. However, the direct relationship among these three factors remains unknown. OBJECTIVE: To explore the potential roles of steroids involved in androgen synthesis in the association between phthalate exposure and semen quality. METHODS: Eighteen phthalate metabolites (mPAEs) and nine steroids were analyzed in semen samples of 403 male participants aged 18-54 years from a hospital in Shenzhen, China. The associations across phthalate metabolites, steroids, and eleven semen quality parameters were evaluated by multivariate linear regression and logistical regression models. The potential contributions of steroids to the associations between phthalate metabolites and semen quality outcomes were explored by mediation effect analysis. RESULTS: In this cross-sectional study, mono-n-butyl phthalate (MnBP) was inversely associated with nine continuous semen quality parameters in a dose-dependent manner (all p for trend < 0.05). Positive associations were observed between MnBP tertiles and androstenedione (ADD) and pregnenolone (PGL), of which only ADD was significantly associated with sperm quality (i.e., motility, p < 0.05). The estimated average mediated effects of seminal ADD on the associations between MnBP and lower sperm motility parameters (i.e., total motility, TR; progressive motility, PR; curvi-linear velocity, VCL) were 6.4-11.9% (all p < 0.05). The potential mediated effects of ADD on the increasing risks of TR (9.8%) and PR (8.5%) abnormalities induced by MnBP exposure were also observed in logistical regression analysis. CONCLUSION: Our results indicated that androgen synthesis in reproductive system may be potentially affected by phthalate exposure, thereby resulting in reduced sperm motility in adult men. Further studies are needed to understand the actual roles and underlying mechanism of action of androstenedione on these associations.


Asunto(s)
Andrógenos , Ácidos Ftálicos , Adolescente , Adulto , China , Estudios Transversales , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Humanos , Masculino , Persona de Mediana Edad , Ácidos Ftálicos/toxicidad , Semen , Análisis de Semen , Motilidad Espermática , Espermatozoides , Adulto Joven
6.
Adv Exp Med Biol ; 1321: 261-264, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33656731

RESUMEN

Identification of the causal risk factors of COVID-19 would allow better risk stratification and designing effective therapies. Epidemiological data have shown a higher incidence and mortality of COVID-19 in males compared to females. Here, we have used logistic regression analysis modeling to determine the association between gender and COVID-19 mortality in the Iranian population. The records of 2293 patients with COVID-19 infection were analyzed. The odds of death due to COVID-19 were 1.7 times higher in males compared to females after adjustment for age and background diseases. The gender difference was mainly observed at higher ages, suggesting an adjusted 2.32-fold higher risk of mortality in males aged >59.5 years old compared to females within the same age group. This finding suggests the male gender is a potential predisposing factor for mortality due to COVID-19 infection. The potential role of male hormones, particularly testosterone, as therapeutic targets deserves further investigation.


Asunto(s)
Andrógenos , Anciano , Femenino , Humanos , Irán/epidemiología , Masculino , Persona de Mediana Edad , Factores Sexuales
7.
Georgian Med News ; (310): 7-11, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33658401

RESUMEN

We present a case of androgen and glucocorticoid secreting adrenocortical carcinoma with concomitant myelolipoma. A giant adrenal tumor which was initially nonfunctional was reassessed four years later due to the patient's refusal to treat. The patient was a 48-year-old woman with hypertension and acne lesions on the face. Laboratory findings were consistent with glucocorticoid and androgen hypersecretion. Computed tomography revealed a heterogeneously contrasting mass of 145x118x100 mm with lobular contour and soft tissue areas. The patient underwent left laparoscopic transperitoneal adrenalectomy with three port technique. There were no complications in the perioperative period. The resected specimen weighed 850 grams. Pathological findings showed a combination of myelolipoma-adrenal cortical cancer. In the postoperative period, hypertension improved and the hormone panel was normalized. Postoperative computed tomography and PET-CT showed no residual mass and metastasis. Although imaging is compatible with benign masses such as myelolipoma, coexistence of ACC-myelolipoma should be kept in mind and functional evaluation should be performed.


Asunto(s)
Neoplasias de la Corteza Suprarrenal , Neoplasias de las Glándulas Suprarrenales , Carcinoma Corticosuprarrenal , Mielolipoma , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/cirugía , Neoplasias de las Glándulas Suprarrenales/cirugía , Carcinoma Corticosuprarrenal/complicaciones , Carcinoma Corticosuprarrenal/diagnóstico por imagen , Carcinoma Corticosuprarrenal/cirugía , Andrógenos , Femenino , Glucocorticoides , Humanos , Persona de Mediana Edad , Mielolipoma/complicaciones , Mielolipoma/diagnóstico , Mielolipoma/cirugía , Tomografía Computarizada por Tomografía de Emisión de Positrones
8.
Sci Total Environ ; 771: 144514, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33736142

RESUMEN

Every year thousands of chemicals get discharged into the waterbodies of the world. These chemicals cause endocrine disruption and induce adverse health effects in human and aquatic life. Global environmental protection agencies emphasise the need to develop rapid and specific tests for identification of these endocrine disruptive chemicals (EDCs) in water. Detection of chemicals that disrupt androgen signaling is especially important because androgen input at specific phases of life is critical for proper male development. Effect-based methods such as reporter assays are suitable tools for identification of EDCs in mixtures of unknown composition. The current study describes a stable, secreted alkaline protease (SEAP)-based reporter assay system, for visual detection of androgenic/antiandrogenic activity present in water samples. A novel feature of this system is the inclusion of coactivators, GRIP1, CARM1, p300 and mZac1b, in addition to an optimal combination of androgen response element (3× HRE), androgen receptor (AR) and the SEAP reporter gene. Incorporation of the coactivators resulted in a transcriptional fold change of 162 folds, enabling visual detection at much lower concentrations of androgen (1 picomolar) within 1 h of addition of test sample. Also, non-androgenic steroids such as estrogen, progesterone and Dexamethasone did not induce significant reporter activity, except at very high concentrations. This reporter assay can be readily converted into a high throughput format for investigation in multiple samples simultaneously, and reflects the changes that can be expected to occur inside a mammalian cell. The androgenic activity in six different water sources was evaluated using this assay. The results reveal significant androgenic activity in rivers and lakes close to Industrial areas, whereas the highest androgenic activity was observed in water containing paper and pulp mill effluents. This bioassay therefore provides a rapid, visual detection tool for effect-directed analysis of androgenic/antiandrogenic compounds in water. IMPACT STATEMENT: The current SEAP-based assay allows visual detection of androgens/antiandrogens in water, at concentrations as low as 1 picomolar, within a 1 h time period, in a high throughput format, providing a very useful technique for field users and regulatory bodies.


Asunto(s)
Antagonistas de Andrógenos , Andrógenos , Antagonistas de Andrógenos/toxicidad , Animales , Proteínas Bacterianas , Bioensayo , Endopeptidasas , Genes Reporteros , Humanos , Masculino , Agua
9.
Sci Total Environ ; 775: 145671, 2021 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-33621872

RESUMEN

Fenitrothion is an organophosphorus insecticide usually found in aquatic ecosystems at concentrations in the range of low ng/L. In this manuscript we show that 24 h exposure to environmental concentrations of fenitrothion, from ng/L to low µg/L, altered basal locomotor activity, visual-motor response and acoustic/vibrational escape response of zebrafish larvae. Furthermore, fenitrothion and expression of gap43a, gfap, atp2b1a, and mbp exhibited a significant non-monotonic concentration-response relationship. Once determined that environmental concentrations of fenitrothion were neurotoxic for zebrafish larvae, a computational analysis identified potential protein targets of this compound. Some of the predictions, including interactions with acetylcholinesterase, monoamine-oxidases and androgen receptor (AR), were experimentally validated. Binding to AR was the most suitable candidate for molecular initiating event, as indicated by both the up-regulation of cyp19a1b and sult2st3 and the non-monotonic relationship found between fenitrothion and the observed responses. Finally, when the integrity of the monoaminergic system was evaluated, altered levels of L-DOPA, DOPAC, HVA and 5-HIAA were found, as well as a significant up-regulation of slc18a2 expression at the lowest concentrations of fenitrothion. These data strongly suggest that concentrations of fenitrothion commonly found in aquatic ecosystems present a significant environmental risk for fish communities.


Asunto(s)
Fenitrotión , Insecticidas , Andrógenos , Animales , Ecosistema , Fenitrotión/toxicidad , Insecticidas/toxicidad , Larva , Pez Cebra
10.
Nat Commun ; 12(1): 1117, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602919

RESUMEN

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.


Asunto(s)
Modelos Biológicos , Organoides/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Andrógenos/metabolismo , Antineoplásicos/uso terapéutico , Genoma Humano , Humanos , Masculino , Mutación/genética , Metástasis de la Neoplasia , Neoplasias de la Próstata/genética , Transcriptoma/genética
11.
Ecotoxicol Environ Saf ; 214: 112086, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33640727

RESUMEN

Production of polychlorinated biphenyls (PCBs) was banned a long time ago because of their harmful health effects but humans continue to be exposed to residual PCBs in the environment. In this study, the susceptibility of human nuclear receptors to binding by PCBs was investigated using molecular docking simulation. Findings revealed that PCBs belonging to ortho-substituted, mono-ortho-substituted and non-ortho-substituted congeners could bind to agonistic conformations of androgen (AR), estrogen (ER α and ER ß), glucocorticoid (GR) and thyroid hormone (TR α and TR ß) receptors as well as antagonistic conformation of androgen receptor (AR an) but only ortho-substituted and mono-ortho-substituted PCBs could bind to estrogen receptors in their antagonistic conformations (ER α an and ER ß an). Further molecular docking analyses showed that PCBs mimic the modes of interaction observed for the co-crystallized ligands in the crystal structures of the affected receptors, utilizing 81%, 83%, 78%, 60%, 75%, 60%, 86%, 100% and 75% of the amino acid residues utilized by the co-crystallized ligands for binding in AR, AR an, ER α, ER α an, ER ß, ER ß an, GR, TR α and TR ß respectively. This computational study suggests that PCBs may cause endocrine disruption via formation of non-covalent interactions with androgen, estrogen, glucocorticoid and thyroid hormone receptors.


Asunto(s)
Disruptores Endocrinos/toxicidad , Bifenilos Policlorados/toxicidad , Andrógenos , Disruptores Endocrinos/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno , Humanos , Enlace de Hidrógeno , Ligandos , Conformación Molecular , Simulación del Acoplamiento Molecular , Bifenilos Policlorados/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Hormonas Tiroideas
12.
J Chromatogr A ; 1640: 461933, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33588275

RESUMEN

Liquid Chromatography tandem mass spectrometry (LC-MS/MS) is the gold-standard approach for androgen analysis in biological fluids, superseding immunoassays in selectivity, particularly at low concentrations. While LC-MS/MS is established for analysis of testosterone and androstenedione, 5α-dihydrotestosterone (DHT) presents greater analytical challenges. DHT circulates at low nanomolar concentrations in men and lower in women, ionizing inefficiently and suffering from isobaric interference from other androgens. Even using current LC-MS/MS technology, large plasma volumes (>0.5 mL) are required for detection, undesirable clinically and unsuitable for animals. This study investigated derivatization approaches using hydrazine-based reagents to enhance ionization efficiency and sensitivity of analysis of DHT by LC-MS/MS. Derivatization of DHT using 2-hydrazino-1-methylpyridine (HMP) and 2-hydrazino-4-(trifluoromethyl)-pyrimidine (HTP) were compared. A method was validated using an UHPLC interfaced by electrospray with a triple quadruple mass spectrometer , analyzing human plasma (male and post-menopausal women) following solid-phase extraction. HMP derivatives were selected for validation affording greater sensitivity than those formed with HTP. HMP derivatives were detected by selected reaction monitoring (DHT-HMP m/z 396→108; testosterone-HMP m/z 394→108; androstenedione-HMP m/z 392→108). Chromatographic separation of androgen derivatives was optimized, carefully separating isobaric interferents and acceptable outputs for precision and trueness achieved following injection of 0.4 pg on column (approximately 34 pmol/L). HMP derivatives of all androgens tested could be detected in low plasma volumes: male (100 µL) and post-menopausal female (200 µL), and derivatives were stable over 30 days at -20°C. In conclusion, HMP derivatization, in conjunction with LC-MS/MS, is suitable for quantitative analysis of DHT, testosterone and androstenedione in low plasma volumes, offering advantages in sensitivity over current methodologies.


Asunto(s)
Dihidrotestosterona/sangre , Hidrazinas/química , Piridinas/química , Espectrometría de Masas en Tándem/métodos , Adulto , Andrógenos/sangre , Androstenodiona/sangre , Bioensayo , Calibración , Cromatografía Liquida , Femenino , Humanos , Hidrazinas/síntesis química , Masculino , Piridinas/síntesis química , Estándares de Referencia , Reproducibilidad de los Resultados , Testosterona/sangre
13.
Eur J Endocrinol ; 184(4): 487-501, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33524003

RESUMEN

Objective: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH). Design: Combined cross-sectional and retrospective clinical study. Methods: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. Results: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. Conclusions: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.


Asunto(s)
Corticoesteroides/uso terapéutico , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Tumor de Resto Suprarrenal/epidemiología , Terapia de Reemplazo de Hormonas/métodos , Análisis de Semen , Neoplasias Testiculares/epidemiología , Adolescente , Glándulas Suprarrenales/patología , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/fisiopatología , Tumor de Resto Suprarrenal/patología , Adulto , Andrógenos/sangre , Humanos , Estudios Longitudinales , Masculino , Mutación , Pubertad , Espermatogénesis , Neoplasias Testiculares/patología , Ultrasonografía , Adulto Joven
15.
Maturitas ; 145: 78-85, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33541567

RESUMEN

BACKGROUND: Androgen deficiency of aging males (ADAM) largely manifests as sexual symptoms. Erectile dysfunction is one of the most common symptoms of ADAM. AIM: To ascertain the effect of concurrent training and supplementation with Eurycoma longifolia on erectile function and testosterone levels in men with ADAM, and the association of erectile function with levels of total testosterone. METHODS: 6-month, randomized, double-blind, placebo-controlled four-arm clinical. 45 men (47.38 ± 5.03 years) were randomized into 4 groups (G1: control + placebo; G2: control + Eurycoma longifolia; G3: concurrent training + placebo; G4: concurrent training + Eurycoma longifolia). 22 received a 200 mg supplement of Eurycoma longifolia and 23 underwent the intervention with concurrent training, 3 times a week for 60 min at progressive intensity. OUTCOMES: International Index of Erectile Function (IIEF-5), Aging Male Scale (AMS) and total testosterone. RESULTS: Erectile function demonstrated improvements in both interventions; however, the most significant results were obtained by men allocated to concurrent training + Eurycoma longifolia. CLINICAL IMPLICATIONS: A 200 mg supplement of Eurycoma longifolia and the practice of concurrent training for 6 months significantly improved the erectile function of men with ADAM. STRENGTHS & LIMITATIONS: The study's design stands out as a strength, in addition to the six-month intervention. The main limitation is the study not having groups that used only Eurycoma longifolia and only concurrent training. CONCLUSION: The combination of Eurycoma longifolia and concurrent training improved erectile function and increased total testosterone levels in men with ADAM.


Asunto(s)
Disfunción Eréctil/terapia , Eurycoma , Ejercicio Físico , Extractos Vegetales/uso terapéutico , Adulto , Envejecimiento/sangre , Envejecimiento/fisiología , Andrógenos/sangre , Andrógenos/deficiencia , Método Doble Ciego , Disfunción Eréctil/sangre , Humanos , Masculino , Persona de Mediana Edad , Fitoterapia , Testosterona/sangre , Testosterona/deficiencia
16.
Am J Epidemiol ; 190(4): 600-610, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33521821

RESUMEN

Fetal exposure to elevated androgens is thought to contribute to autism spectrum disorder (ASD) risk. However, data rely heavily on in utero androgens measurements, which also reflect fetal secretions. Thus, in utero hyperandrogenemia might indicate adverse autism-related neurogenesis that has already occurred affecting fetal androgen homeostasis, rather than being a cause of the disorder. Associations between maternal androgen-related conditions and ASD could more directly implicate androgens' etiological role. We examined the association between maternal hyperandrogenemia-related conditions, focusing primarily on polycystic ovarian syndrome (PCOS), and progeny ASD, in an Israeli cohort of 437,222 children born in 1999-2013. Odds ratios and 95% confidence intervals were estimated using generalized estimating equations. Multiple mediation analyses using natural effect models were conducted to evaluate combined mediation of the PCOS effect by androgen-related cardiovascular, metabolic, and fertility factors. Results indicated that children of mothers with PCOS had higher ASD odds compared with children of mothers without PCOS (odds ratio = 1.42, 95% confidence interval: 1.24,1.64), and this effect was only partly mediated by the factors considered. Elevated odds were also observed for other hyperandrogenemia-related conditions. Findings provide support for direct involvement of maternal hyperandrogenemia in ASD etiology. Alternatively, findings might reflect shared genetic and/or environmental factors independently affecting maternal androgen homeostasis and fetal neurodevelopment.


Asunto(s)
Andrógenos/sangre , Trastorno del Espectro Autista/epidemiología , Enfermedades Cardiovasculares/complicaciones , Fertilidad/fisiología , Enfermedades Metabólicas/complicaciones , Madres/estadística & datos numéricos , Efectos Tardíos de la Exposición Prenatal , Adulto , Trastorno del Espectro Autista/sangre , Trastorno del Espectro Autista/etiología , Enfermedades Cardiovasculares/epidemiología , Preescolar , Femenino , Humanos , Incidencia , Masculino , Enfermedades Metabólicas/epidemiología , Oportunidad Relativa , Embarazo , Estudios Retrospectivos , Medición de Riesgo/métodos , Estados Unidos/epidemiología , Adulto Joven
17.
Artículo en Inglés | MEDLINE | ID: mdl-33557243

RESUMEN

Increasing contamination of the environment by toxic compounds such as endocrine disrupting chemicals (EDCs) is one of the major causes of reproductive defects in both sexes. Estrogen/androgen pathways are of utmost importance in gonadal development, determination of secondary sex characteristics and gametogenesis. Most of the EDCs mediate their action through respective receptors and/or downstream signaling. The purpose of this review is to highlight the mechanism by which EDCs can trigger antagonistic or agonistic response, acting through estrogen/androgen receptors causing reproductive defects that lead to infertility. In vitro, in vivo and in silico studies focusing on the impact of EDCs on estrogen/androgen pathways and related proteins published in the last decade were considered for the review. PUBMED and PUBCHEM were used for literature search. EDCs can bind to estrogen receptors (ERα and ERß) and androgen receptors or activate alternative receptors such as G protein-coupled receptors (GPCR), GPR30, estrogen-related receptor (ERRγ) to activate estrogen signaling via downstream kinases. Bisphenol A, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethylene, polychlorinated biphenyls and phthalates are major toxicants that interfere with the normal estrogen/androgen pathways leading to infertility in both sexes through many ways, including DNA damage in spermatozoids, altered methylation pattern, histone modifications and miRNA expression.


Asunto(s)
Disruptores Endocrinos , Andrógenos/toxicidad , Disruptores Endocrinos/toxicidad , Estrógenos/toxicidad , Femenino , Masculino , Receptores Androgénicos , Receptores Estrogénicos
18.
Int J Clin Oncol ; 26(4): 753-763, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33575828

RESUMEN

BACKGROUND: Based on results from Japanese post-marketing surveillance, exploratory analyses were performed to investigate real-world outcomes of radium-223 for metastatic CRPC (mCRPC) according to patient characteristics. METHODS: This non-interventional, prospective study enrolled mCRPC patients selected for radium-223 treatment in clinical practice. Six-month safety and effectiveness were evaluated in subgroups who had/had not received prior chemotherapy (prior-chemo/no prior-chemo groups), and a subgroup who had not received concomitant androgen-receptor axis-targeted agents (ARATs). RESULTS: In the overall population (n = 296), the prior-chemo group (n = 126) tended to have more bone metastases, more analgesic use, and higher prostate-specific antigen values than the no prior-chemo group (n = 170). Incidences of treatment-emergent adverse events (TEAEs), drug-related TEAEs, and ≥ grade 3 drug-related hematological TEAEs were 47% vs. 53%, 25% vs. 29%, and 4% vs. 7% in the no prior-chemo and prior-chemo groups, respectively. Incidences of TEAEs (61%), drug-related TEAEs (36%), and ≥ grade 3 drug-related hematological events (12%) were numerically higher in 33 patients who had received two lines of prior chemotherapy. Multivariate analysis showed that two lines of prior chemotherapy, and hemoglobin, platelet, and lactate dehydrogenase values were baseline factors significantly related to ≥ grade 2 platelet count decreased. Safety and effectiveness in patients without concomitant ARATs (n = 201) were similar to those in the overall population. CONCLUSION: In a real-life setting, radium-223 was well tolerated irrespective of prior chemotherapy, but relatively higher incidences of TEAEs and hematotoxicities were suggested in patients with two lines of prior chemotherapy, possibly reflecting more advanced disease. Radium-223 safety and effectiveness in patients without concomitant ARATs were favorable.


Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata Resistentes a la Castración , Andrógenos , Neoplasias Óseas/tratamiento farmacológico , Humanos , Japón , Masculino , Vigilancia de Productos Comercializados , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radioisótopos , Radio (Elemento) , Resultado del Tratamiento
19.
Chemistry ; 27(19): 6044-6049, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33556193

RESUMEN

The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidation has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids. In addition, simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of saturated androgens.


Asunto(s)
Andrógenos , Androstanos , Hidrogenación , Esteroides
20.
Sensors (Basel) ; 21(3)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33572727

RESUMEN

In recent years, there has been an increasing demand for predictive and sensitive in vitro tools for drug discovery. Split complementation assays have the potential to enlarge the arsenal of in vitro tools for compound screening, with most of them relying on well-established reporter gene assays. In particular, ligand-induced complementation of split luciferases is emerging as a suitable approach for monitoring protein-protein interactions. We hereby report an intracellular nanosensor for the screening of compounds with androgenic activity based on a split NanoLuc reporter. We also confirm the suitability of using 3D spheroids of Human Embryonic Kidney (HEK-293) cells for upgrading the 2D cell-based assay. A limit of detection of 4 pM and a half maximal effective concentration (EC50) of 1.7 ± 0.3 nM were obtained for testosterone with HEK293 spheroids. This genetically encoded nanosensor also represents a new tool for real time imaging of the activation state of the androgen receptor, thus being suitable for analysing molecules with androgenic activity, including new drugs or endocrine disrupting molecules.


Asunto(s)
Andrógenos , Mediciones Luminiscentes , Nanotecnología , Receptores Androgénicos , Genes Reporteros , Células HEK293 , Humanos , Luciferasas/genética , Receptores Androgénicos/genética
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