RESUMEN
Purpose: To evaluate the association of Life's Essential 8 (LE8) and its subscales with male biochemical androgen deficiency (MBAD) and total testosterone based on the data from the national health and nutrition examination survey (NHANES) database. Methods: Data of males aged 20 years or older from NHANES of 2013-2016 were extracted. LE8 score was calculated based on American Heart Association definitions. Total testosterone (TT) values were measured in NHANES using precise isotope dilution liquid chromatography. MBAD was defined as serum TT of <300 ng/dL. Univariate and multivariable analyses were conducted. Propensity score matching (PSM) and weighted regression after matching were added as sensitivity analyses. The generalized additive model, smooth curve fitting, and the recursive algorithm were used to determine the potential inflection points. Piecewise regression models with log-likelihood ratio test were used to quantify nonlinear effects. Results: A total of 3094 participants who were males and aged 20 years or above were included. Out of them, 805 males were diagnosed with MBAD. After adjusting the confounders in the multivariable model, LE8 was independently associated with MBAD (OR 0.96, P < 0.001) and TT (ß 2.7, P < 0.001). The association remained robust even after PSM. The non-linear relationship of LE8 behaviors score with MBAD and TT was revealed. Conclusion: LE8 was an independent protective factor of MBAD and a feasible approach to promote male endocrine sexual function.
Asunto(s)
Encuestas Nutricionales , Testosterona , Humanos , Masculino , Adulto , Testosterona/sangre , Testosterona/deficiencia , Persona de Mediana Edad , Adulto Joven , Andrógenos/sangre , Andrógenos/deficiencia , Anciano , Hipogonadismo/epidemiología , Hipogonadismo/sangreRESUMEN
OBJECTIVE: Assessment of Androgen Deficiency in Aging Males (ADAM) questionnaire in predicting serum testosterone levels in type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A single centre, prospective, cross-sectional epidemiological study in 250 male individuals with T2DM. ADAM questionnaire and serum total testosterone (TT) levels were analyzed for correlation using a Chi-squared test. Jaccard analysis to evaluate the concordance and dissimilarity between ADAM score and TT levels, providing insights into ADAM's predictive ability for testosterone levels. RESULTS: The mean age of the study population was 49.1 ± 7.8 years. The mean duration of diabetes was 6.2 ± 5.1 years. 27.6% were diagnosed with hypogonadism, while 72.4% were eugonadal. The mean age was 51.1 and 48.4 years in the hypogonadal and eugonadal cohorts, respectively (p < 0.02). The mean TT in the hypogonadal cohort was 220.6 ± 61.3 ng/dL, and in the eugonadal cohort was 475.4 ± 152.9 ng/dL (p < 0.001). The mean body mass index (BMI) in the hypogonadal cohort was 26.5 ± 4.0 kg/m2, and in the eugonadal group was 25.2 ± 3.6 kg/m2 (p < 0.02). Chi-square analysis established a strong positive correlation between the positive ADAM score and hypogonadism (p < 0.011). Of the 69 hypogonadal subjects, 84.05% had a positive ADAM score, yielding a sensitivity of 84.05% in detecting hypogonadism with a specificity of 32.04%. CONCLUSION: The ADAM questionnaire is a practical and cost-effective initial screening tool for identifying symptoms suggestive of testosterone deficiency. It has high sensitivity in identifying men with hypogonadism, while caution must be in place as it has a very low specificity. In resource-poor settings, ADAM score could be a clinical marker of hypogonadism.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hipogonadismo , Testosterona , Humanos , Masculino , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Testosterona/sangre , Testosterona/deficiencia , Estudios Transversales , Persona de Mediana Edad , Estudios Prospectivos , Hipogonadismo/sangre , Hipogonadismo/diagnóstico , Hipogonadismo/epidemiología , Encuestas y Cuestionarios , Adulto , Andrógenos/sangre , Andrógenos/deficienciaRESUMEN
INTRODUCTION: Androgens play important roles in regulating the growth and development of the male reproductive system and maintaining libido and erectile function. The specific mechanisms by which androgen deficiency leads to erectile dysfunction (ED) are not yet fully understood. OBJECTIVES: To understand the mechanisms and treatment of androgen deficiency-related ED. METHODS: A literature search in the past 10 years was conducted in PubMed and Google Scholar to determine the effects of androgen deficiency on erectile function and the treatment of androgen deficiency. RESULTS: Androgen deficiency can be caused by hypothalamic-pituitary lesions and injuries, testicular-related diseases and injuries, endocrine and metabolic disorders, the side effects of medication, and age. Androgen deficiency can lead to ED by inhibiting the NOS/NO/cGMP pathway (nitric oxide synthase/nitric oxide/cyclic guanosine monophosphate) and altering the expression of ion channel proteins, as well as by inducing oxidative stress, death, and fibrosis in penile corpus cavernosum cells. Testosterone replacement therapy is effective at improving the serum testosterone levels and erectile function in patients with androgen deficiency. For patients who need to maintain a low androgenic state, erectile function can be improved by lifestyle changes, treatment with phosphodiesterase type 5 inhibitors, low-intensity extracorporeal shock wave therapy, and stem cell therapy. CONCLUSIONS: Androgen deficiency can affect the structure and function of the penile corpus cavernosum, leading to ED. Areas of further study include how androgen replacement therapy can improve erectile function and how to improve the maintenance of erectile function in patients with hypoandrogenic status.
Asunto(s)
Andrógenos , Disfunción Eréctil , Terapia de Reemplazo de Hormonas , Humanos , Disfunción Eréctil/etiología , Disfunción Eréctil/terapia , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/fisiopatología , Masculino , Andrógenos/uso terapéutico , Andrógenos/deficiencia , Testosterona/deficiencia , Testosterona/uso terapéutico , Inhibidores de Fosfodiesterasa 5/uso terapéuticoRESUMEN
Syndromic autism spectrum conditions (ASC), such as Klinefelter syndrome, also manifest hypogonadism. Compared to the popular Extreme Male Brain theory, the Enhanced Perceptual Functioning model explains the connection between ASC, savant traits, and giftedness more seamlessly, and their co-emergence with atypical sexual differentiation. Overexcitability of primary sensory inputs generates a relative enhancement of local to global processing of stimuli, hindering the abstraction of communication signals, in contrast to the extraordinary local information processing skills in some individuals. Weaker inhibitory function through gamma-aminobutyric acid type A (GABAA) receptors and the atypicality of synapse formation lead to this difference, and the formation of unique neural circuits that process external information. Additionally, deficiency in monitoring inner sensory information leads to alexithymia (inability to distinguish one's own emotions), which can be caused by hypoactivity of estrogen and oxytocin in the interoceptive neural circuits, comprising the anterior insular and cingulate gyri. These areas are also part of the Salience Network, which switches between the Central Executive Network for external tasks and the Default Mode Network for self-referential mind wandering. Exploring the possibility that estrogen deficiency since early development interrupts GABA shift, causing sensory processing atypicality, it helps to evaluate the co-occurrence of ASC with attention deficit hyperactivity disorder, dyslexia, and schizophrenia based on phenotypic and physiological bases. It also provides clues for understanding the common underpinnings of these neurodevelopmental disorders and gifted populations.
Asunto(s)
Andrógenos , Trastorno del Espectro Autista , Estrógenos , Humanos , Andrógenos/deficiencia , Andrógenos/metabolismo , Estrógenos/metabolismo , Estrógenos/deficiencia , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Masculino , Diferenciación Sexual/fisiología , Síndrome de Klinefelter/fisiopatología , Síndrome de Klinefelter/metabolismo , Percepción/fisiología , Encéfalo/metabolismoRESUMEN
BACKGROUND: It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK-positive cancer and in murine models. METHODS: In this study, three groups, including an experimental group of male patients with ALK-positive, advanced non-small cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK-positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK-negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. RESULTS: Ninety-five patients were consecutively enrolled onto the study. Among sixty-eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p = .0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p = .0002) were significantly lower in ALK-positive ANSCLC patients in cohort A compared with ALK-negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p = .0059) and LH levels (4.72 vs. 7.49 mUI/ml; p = .0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK-positive male patients (74.3 vs. 44.24 pg/ml; p = .0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. CONCLUSIONS: Symptoms of androgen deficiency should be tracked in male patients with ALK-positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate.
Asunto(s)
Quinasa de Linfoma Anaplásico , Carbazoles , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Piperidinas , Testosterona , Humanos , Masculino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Carbazoles/uso terapéutico , Carbazoles/efectos adversos , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Anciano , Adulto , Testosterona/sangre , Testosterona/deficiencia , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Disfunciones Sexuales Fisiológicas/inducido químicamente , Femenino , Andrógenos/deficiencia , Estudios Prospectivos , Hipogonadismo/inducido químicamente , Hipogonadismo/tratamiento farmacológico , Proteínas Tirosina Quinasas ReceptorasRESUMEN
Women with hypopituitarism have various degrees of androgen deficiency, which is marked among those with combined hypogonadotrophic hypogonadism and secondary adrenal insufficiency. The consequences of androgen deficiency and the effects of androgen replacement therapy have not been fully elucidated. While an impact of androgen deficiency on outcomes such as bone mineral density, quality of life, and sexual function is plausible, the available evidence is limited. There is currently no consensus on the definition of androgen deficiency in women and it is still controversial whether androgen substitution should be used in women with hypopituitarism and coexisting androgen deficiency. Some studies suggest beneficial clinical effects of androgen replacement but data on long-term benefits and risk are not available. Transdermal testosterone replacement therapy in hypopituitary women has shown some positive effects on bone metabolism and body composition. Studies of treatment with oral dehydroepiandrosterone have yielded mixed results, with some studies suggesting improvements in quality of life and sexual function. Further research is required to elucidate the impact of androgen deficiency and its replacement treatment on long-term outcomes in women with hypopituitarism. The lack of transdermal androgens for replacement in this patient population and limited outcome data limit its use. A cautious and personalized treatment approach in the clinical management of androgen deficiency in women with hypopituitarism is recommended while awaiting more efficacy and safety data.
Asunto(s)
Andrógenos , Terapia de Reemplazo de Hormonas , Hipopituitarismo , Humanos , Andrógenos/deficiencia , Andrógenos/uso terapéutico , Andrógenos/administración & dosificación , Femenino , Hipopituitarismo/tratamiento farmacológico , Terapia de Reemplazo de Hormonas/métodos , Hipogonadismo/tratamiento farmacológico , Testosterona/deficiencia , Testosterona/uso terapéutico , Testosterona/administración & dosificación , Calidad de VidaRESUMEN
BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases. METHODS: We administered orchiectomy, GnRH agonist, or GnRH antagonist in male ApoE-/- mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms. RESULTS: Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist-treated mice, blocking of short FSH surge by anti-FSHß antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist-treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA (protein kinase A)/CREB (cAMP response element-binding protein)/c-Jun and PI3K (phosphatidylinositol 3 kinase)/AKT (protein kinase B)/GSK-3ß (glycogen synthase kinase 3 beta)/GATA-6 (GATA-binding protein 6) pathways. In monocytes, FSH upregulated CD29 (cluster of differentiation 29) expression via the PI3K/AKT/GSK-3ß/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist-induced endothelial inflammation and atherosclerosis in mice. CONCLUSIONS: FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Neoplasias de la Próstata , Animales , Masculino , Ratones , Antagonistas de Andrógenos/efectos adversos , Andrógenos/deficiencia , Aterosclerosis/patología , Endotelio/metabolismo , Hormona Folículo Estimulante/genética , Hormona Folículo Estimulante/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/fisiología , Inflamación/etiología , Monocitos/metabolismo , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , TestosteronaRESUMEN
Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene-conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.
Asunto(s)
Antagonistas de Andrógenos , Andrógenos , Monoterpenos Bicíclicos , Resistencia a Antineoplásicos , Lipocalinas , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/deficiencia , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos , Microambiente Tumoral , Monoterpenos Bicíclicos/uso terapéutico , Lipocalinas/genética , Lipocalinas/metabolismo , Línea Celular Tumoral , Animales , Ratones , Anticuerpos/uso terapéutico , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
CONTEXT: Women with Turner syndrome (TS) suffer from hypergonadotropic hypogonadism, causing a deficit in gonadal hormone secretion. As a consequence, these women are treated with estrogen from the age of 12 years, and later in combination with progesterone. However, androgens have been given less attention. OBJECTIVE: To assess sex hormone levels in women with TS, both those treated and those nontreated with hormone replacement therapy (HRT), and investigate the impact of HRT on sex hormone levels. METHODS: At Aarhus University Hospital, 99 women with TS were followed 3 times from August 2003 to February 2010. Seventeen were lost during follow-up. Control group 1 consisted of 68 healthy age-matched control women seen once during this period. Control group 2 consisted of 28 young, eumenorrheic women sampled 9 times throughout the same menstrual cycle. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17ß-estradiol, estrone sulfate, DHEAS, testosterone, free androgen index, androstenedione, 17-OH progesterone, and sex hormone-binding globulin (SHBG) were analyzed. RESULTS: All androgens, 17-OH progesterone, and sex hormone-binding globulin (SHBG) were 30% to 50% lower in TS compared with controls (P < 0.01). FSH, LH, and estrone sulfate were more than doubled in women with TS compared with controls (P < 0.02). Using principal component analysis, we describe a positive correlation between women with TS receiving HRT, elevated levels of SHBG, and decreased levels of androgens. CONCLUSION: The sex hormone profile in TS reveals a picture of androgen deficiency, aggravated further by HRT. Conventional HRT does not normalize estradiol levels in TS.
Asunto(s)
Andrógenos , Estrógenos , Terapia de Reemplazo de Hormonas , Síndrome de Turner , Andrógenos/deficiencia , Estradiol , Estrógenos/deficiencia , Femenino , Hormona Folículo Estimulante , Hormonas Esteroides Gonadales/uso terapéutico , Humanos , Hormona Luteinizante , Progesterona/uso terapéutico , Globulina de Unión a Hormona Sexual/análisis , Testosterona , Síndrome de Turner/tratamiento farmacológicoRESUMEN
This study addresses the roles of nuclear receptor corepressor 2 (NCOR2) in prostate cancer (PC) progression in response to androgen deprivation therapy (ADT). Reduced NCOR2 expression significantly associates with shorter disease-free survival in patients with PC receiving adjuvant ADT. Utilizing the CWR22 xenograft model, we demonstrate that stably reduced NCOR2 expression accelerates disease recurrence following ADT, associates with gene expression patterns that include neuroendocrine features, and induces DNA hypermethylation. Stably reduced NCOR2 expression in isogenic LNCaP (androgen-sensitive) and LNCaP-C4-2 (androgen-independent) cells revealed that NCOR2 reduction phenocopies the impact of androgen treatment and induces global DNA hypermethylation patterns. NCOR2 genomic binding is greatest in LNCaP-C4-2 cells and most clearly associates with forkhead box (FOX) transcription factor FOXA1 binding. NCOR2 binding significantly associates with transcriptional regulation most when in active enhancer regions. These studies reveal robust roles for NCOR2 in regulating the PC transcriptome and epigenome and underscore recent mutational studies linking NCOR2 loss of function to PC disease progression.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Andrógenos/deficiencia , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Recurrencia Local de Neoplasia/patología , Co-Represor 2 de Receptor Nuclear/antagonistas & inhibidores , Neoplasias de la Próstata/patología , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Humanos , Masculino , Ratones , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Co-Represor 2 de Receptor Nuclear/genética , Co-Represor 2 de Receptor Nuclear/metabolismo , Pronóstico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Castration-resistant prostate cancer (CRPC) is a clinical challenge in treatment because of its aggressive nature and resistance to androgen deprivation therapy. Topoisomerase II catalytic inhibitors have been suggested as a strategy to overcome these issues. We previously reported AK-I-190 as a novel topoisomerase II inhibitor. In this study, the mechanism of AK-I-190 was clarified using various types of spectroscopic and biological evaluations. AK-I-190 showed potent topoisomerase II inhibitory activity through intercalating into DNA without stabilizing the DNA-enzyme cleavage complex, resulting in significantly less DNA toxicity than etoposide, a clinically used topoisomerase II poison. AK-I-190 induced G1 arrest and effectively inhibited cell proliferation and colony formation in combination with paclitaxel in an androgen receptor-negative CRPC cell line. Our results confirmed that topoisomerase II catalytic inhibition inhibited proliferation and induced apoptosis of AR-independently growing prostate cancer cells. These findings indicate the clinical relevance of topoisomerase II catalytic inhibitors in androgen receptor-negative prostate cancer.
Asunto(s)
Andrógenos/deficiencia , Apoptosis , Proliferación Celular , ADN-Topoisomerasas de Tipo II/química , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Inhibidores de Topoisomerasa II/farmacología , Ciclo Celular , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/enzimología , Neoplasias de la Próstata Resistentes a la Castración/patología , Células Tumorales CultivadasRESUMEN
In mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age and identifying novel factors influencing the aging rate using only DNA methylation data. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), which can predict chronological age with a median absolute error of 5.1 months. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens. Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Comparable sex-specific methylation differences in MKLN1 also exist in bat skin and a range of mouse tissues that have high androgen receptor expression, indicating that it may drive androgen-dependent hypomethylation in divergent mammalian species. In characterizing these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.
Asunto(s)
Envejecimiento/genética , Andrógenos/deficiencia , Metilación de ADN , Epigénesis Genética , Feminización/veterinaria , Orquiectomía/veterinaria , Oveja Doméstica/fisiología , Animales , Relojes Biológicos , Femenino , Feminización/metabolismo , Masculino , Oveja Doméstica/cirugíaRESUMEN
BACKGROUND: Androgen deficiency is common among prostate cancer survivors, but many guidelines consider history of prostate cancer a contraindication for testosterone replacement. We determined the safety and efficacy of a selective androgen receptor modulator (OPK-88004) in symptomatic, testosterone-deficient men who had undergone radical prostatectomy for low-grade, organ-confined prostate cancer. METHODS: In this placebo-controlled, randomized, double-blind trial, 114 men, ≥19 years of age, who had undergone radical prostatectomy for low-grade, organ-localized prostate cancer, undetectable PSA (<0.1 ng/mL) for ≥2 years after radical prostatectomy and testosterone deficiency were randomized in stages to placebo or 1, 5, or 15 mg OPK-88004 daily for 12 weeks. Outcomes included PSA recurrence, sexual activity, sexual desire, erectile function, body composition, muscle strength and physical function measures, mood, fatigue, and bone markers. RESULTS: Participants were on average 67.5 years of age and had severe sexual dysfunction (mean erectile function and sexual desire domain scores 7.3 and 14.6, respectively). No participant experienced PSA recurrence or erythrocytosis. OPK-88004 was associated with a dose-related increase in whole-body (P < 0.001) and appendicular (P < 0.001) lean mass and a significantly greater decrease in percent body fat (P < 0.001) and serum alkaline phosphatase (P < 0.001) than placebo. Changes in sexual activity, sexual desire, erectile function, mood, fatigue, physical performance, and bone markers did not differ among groups (P = 0.73). CONCLUSIONS: Administration of OPK-88004 was safe and not associated with PSA recurrence in androgen-deficient men who had undergone radical prostatectomy for organ-confined prostate cancer. OPK-88004 increased lean body mass and decreased fat mass but did not improve sexual symptoms or physical performance.
Asunto(s)
Andrógenos/deficiencia , Supervivientes de Cáncer , Prostatectomía/efectos adversos , Neoplasias de la Próstata/cirugía , Receptores Androgénicos/metabolismo , Anciano , Andrógenos/sangre , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangreRESUMEN
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/deficienciaRESUMEN
Upregulation of androgen receptor splice variants (AR-Vs), especially AR-V7, is associated with castration resistance of prostate cancer. At the RNA level, AR-V7 upregulation is generally coupled with increased full-length AR (AR-FL); consequently, AR-V7 and AR-Vs collectively constitute a minority of the AR population. However, Western blotting showed that the relative abundance of AR-V proteins is much higher in many castration-resistant prostate cancers (CRPCs). To address the mechanism underlying this discrepancy, we analyzed RNA-seq data from ~350 CRPC samples and found a positive correlation between all canonical and alternative AR splicing. This indicates that increased alternative splicing is not at the expense of canonical splicing. Instead, androgen deprivation releases AR-FL from repressing the transcription of the AR gene to induce coordinated increase of AR-FL and AR-V mRNAs. At the protein level, however, androgen deprivation induces AR-FL, but not AR-V, degradation. Moreover, AR-V7 is translated much faster than AR-FL. Thus, androgen-deprivation-induced AR-gene transcription and AR-FL protein decay, together with efficient AR-V7 translation, explain the discrepancy between the relative AR-V mRNA and protein abundances in many CRPCs, highlighting the inevitability of AR-V induction after endocrine therapy.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Andrógenos/deficiencia , Biosíntesis de Proteínas , Empalme del ARN , Receptores Androgénicos/genética , Transcripción Genética , Humanos , Masculino , ARN Mensajero/genéticaRESUMEN
Hypogonadism contributes to limb skeletal muscle atrophy by increasing rates of muscle protein breakdown. Androgen depletion increases markers of the autophagy protein breakdown pathway in the limb muscle that persist throughout the diurnal cycle. However, the regulatory signals underpinning the increase in autophagy markers remain ill-defined. The purpose of this study was to characterize changes to autophagy regulatory signals in the limb skeletal muscle following androgen depletion. Male mice were subjected to a castration surgery or a sham surgery as a control. Seven weeks post-surgery, a subset of mice from each group was sacrificed every 4 hr over a 24 hr period. Protein and mRNA from the Tibialis Anterior (TA) were subjected to Western blot and RT-PCR. Consistent with an overall increase in autophagy, the phosphorylation pattern of Uncoordinated Like Kinase 1 (ULK1) (Ser555) was elevated throughout the diurnal cycle in the TA of castrated mice. Factors that induce the progression of autophagy were also increased in the TA following androgen depletion including an increase in the phosphorylation of c-Jun N-terminal Kinase (JNK) (Thr183/Tyr185) and an increase in the ratio of BCL-2 Associated X (BAX) to B-cell lymphoma 2 (BCL-2). Moreover, we observed an increase in the protein expression pattern of p53 and the mRNA of the p53 target genes Cyclin-Dependent Kinase Inhibitor 1A (p21) and Growth Arrest and DNA Damage Alpha (Gadd45a), which are known to increase autophagy and induce muscle atrophy. These data characterize novel changes to autophagy regulatory signals in the limb skeletal muscle following androgen deprivation.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Andrógenos/deficiencia , Ritmo Circadiano/fisiología , Músculo Esquelético/metabolismo , Animales , Autofagia/fisiología , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Modelos Animales de Enfermedad , Extremidades/patología , Masculino , Ratones , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Fosforilación , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
AIM: The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. METHODS: Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed. RESULTS: For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%). CONCLUSIONS: Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance.
Asunto(s)
Acetato de Abiraterona/efectos adversos , Acetato de Abiraterona/uso terapéutico , Andrógenos/deficiencia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Prednisolona/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Prednisolona/administración & dosificación , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
Androgen deficiency is known to cause both osteoporosis and sarcopenia. Myokines, humoral factors secreted from the skeletal muscles, have recently been getting attention as the key factors related to the interactions between muscle and bone. Dickkopf (Dkk) 2 is known as an inhibitor of canonical Wnt/ß-catenin signaling, and Wnt/ß-catenin signaling is crucial for the maintenance of muscle and bone. The present study was therefore performed to investigate the roles of Dkk2 in the alterations of muscle and bone of androgen-deficient mice with orchidectomy (ORX). ORX significantly enhanced Dkk2 mRNA levels, but not other Dkks and secreted frizzled related proteins, in the soleus muscles of mice. Moreover, ORX enhanced serum Dkk2 levels, but not Dkk2 mRNA levels in the tibial bone tissues, the white adipose tissues and liver of mice. In simple regression analyses, serum Dkk2 levels were negatively related to trabecular bone mineral density at the tibias in mice employed in the experiments. In vitro experiments, testosterone suppressed Dkk2 mRNA levels in mouse muscle C2C12 cells. In conclusion, we showed that androgen deficiency enhances Dkk2 expression and secretion in the muscles of mice. Dkk2 might be involved in androgen deficiency-induced muscle wasting and osteopenia as a myokine linking muscle to bone.
Asunto(s)
Andrógenos/deficiencia , Enfermedades Óseas Metabólicas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Sarcopenia/metabolismo , Animales , Enfermedades Óseas Metabólicas/sangre , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intercelular/sangre , Masculino , Ratones , Orquiectomía , Sarcopenia/sangreRESUMEN
Androgens are some of the most important sex hormones in men, and they maintain important physiological activities in the human body. Cognitive impairment is one of the most common manifestations of aging in the elderly population and an important factor affecting the quality of life of elderly individuals. The levels of sex hormones in elderly people decrease with age, and low levels of androgens in older male individuals have been closely linked to the development of cognitive impairment. Basic studies have shown that androgens have neuroprotective effects and that androgen deficiency impairs cognitive function by increasing oxidative stress and decreasing synaptic plasticity, among other effects. Additionally, clinical studies have also shown that androgen deficiency is closely related to cognitive impairment. This article reviews the relationship between low androgen levels and cognitive impairment, their potential mechanisms, and the effects of testosterone supplementation in improving cognition.