Research Progress of Androgen/Androgen Receptor Signaling Pathway in Hepatocellular Carcinoma / 肿瘤防治研究

Hepatocellular carcinoma (HCC) is a kind of primary liver cancer with a high mortality rate. In China, the incidence ratio in males to females with HCC is 2:1–5:1. The difference in sex hormone pathways between males and females and the interaction between androgen/androgen receptors and HBV can lead to an incidence difference between males and females with HCC. Hence, the androgen/androgen receptor oncogenic pathway in hepatocellular carcinoma has received considerable attention. This review mainly summarizes the recent research progress on the androgen/androgen receptor oncogenic pathway in hepatocellular carcinoma.

Research Progress in Androgen Receptor and Triple Negative Breast Cancer / 中国医学科学院学报

The research on androgen receptor (AR) in breast cancer is advancing.Although the prognostic value of AR in triple negative breast cancer (TNBC) is controversial,a variety of studies have demonstrated that the lack of AR expression exacerbates disease progression.Moreover,the TNBC subtype of AR(-) is more aggressive than that of AR(+) due to the lack of prognostic biomarkers and therapeutic targets.With the discovery and deepening research of novel therapeutic targets such as phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin and S-phase kinase-associated protein 2 signaling pathways,as well as the emerging of immunotherapies,the treatment options for TNBC are increasing.Regarding the role of AR in TNBC,the studies about the tumor biology of AR(-)TNBC and novel biomarkers for improved management of the disease remain insufficient.In this review,we summarize the research progress of AR in TNBC,put forward avenues for future research on TNBC,and propose potential biomarkers and therapeutic strategies that warrant investigation.

Investigation of androgen receptor-dependent alternative splicing has identified a unique subtype of lethal prostate cancer / 亚洲男科学杂志(英文版)

A complete proteomics study characterizing active androgen receptor (AR) complexes in prostate cancer (PCa) cells identified a diversity of protein interactors with tumorigenic annotations, including known RNA splicing factors. Thus, we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression. We selected two AR-interacting RNA splicing factors, Src associated in mitosis of 68 kDa (SAM68) and DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5) to examine their associative roles in AR-dependent alternative RNA splicing. To assess the true physiological role of AR in alternative RNA splicing, we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets. As a result, we were able to highlight alternative splicing events of clinical significance. Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression. The physiological significance in PCa was investigated through the application of clinical exon array analysis, where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria. Using a clinical dataset with patients categorized as prostate cancer-specific death (PCSD), these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes. Overall, these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa. Moreover, AR-mediated alternative spicing contributes to aggressive PCa progression, where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.

FOXA1 in prostate cancer / 亚洲男科学杂志(英文版)

Most prostate cancers initially respond to androgen deprivation therapy (ADT). With the long-term application of ADT, localized prostate cancer will progress to castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), and neuroendocrine prostate cancer (NEPC), and the transcriptional network shifted. Forkhead box protein A1 (FOXA1) may play a key role in this process through multiple mechanisms. To better understand the role of FOXA1 in prostate cancer, we review the interplay among FOXA1-targeted genes, modulators of FOXA1, and FOXA1 with a particular emphasis on androgen receptor (AR) function. Furthermore, we discuss the distinct role of FOXA1 mutations in prostate cancer and clinical significance of FOXA1. We summarize possible regulation pathways of FOXA1 in different stages of prostate cancer. We focus on links between FOXA1 and AR, which may play different roles in various types of prostate cancer. Finally, we discuss FOXA1 mutation and its clinical significance in prostate cancer. FOXA1 regulates the development of prostate cancer through various pathways, and it could be a biomarker for mCRPC and NEPC. Future efforts need to focus on mechanisms underlying mutation of FOXA1 in advanced prostate cancer. We believe that FOXA1 would be a prognostic marker and therapeutic target in prostate cancer.

Core Needle Biopsy Accuracy for Androgen Receptor Expression in Invasive Breast Cancer / Precisão da biópsia com agulha de grande calibre para expressão de receptores androgênicos no câncer de mama invasivo

Abstract Objective Breast cancer (BC) biomarkers, such as hormone receptors expression, are crucial to guide therapy in BC patients. Antiandrogens have been studied in BC; however, limited data are available on androgen receptor (AR) expression test methodology. We aim to report the core needle biopsy (CNB) accuracy for AR expression in BC. Methods Patients diagnosed with stage I-III invasive BC from a single institution were included. Androgen receptor expression was evaluated by immunohistochemistry (IHC) using 1 and 10% cutoff and the AR expression in surgical specimens (SS) was the gold standard. Kappa coefficients were used to evaluate the intraprocedural agreement. Results A total of 72 patients were included, with a mean age of 61 years old and 84% were Luminal A or B tumors. The prevalence of AR expression in all BC samples was 87.5% using a cutoff ≥ 10% in SS. With a cutoff value ≥ 1%, CNB had an accuracy of 95.8% (Kappa value = 0.645; 95% confidence interval [CI]: 0.272-1.000; p< 0.001) and 86.1% (Kappa value = 0.365; 95% CI: 0.052-0.679; p< 0.001) when ≥ 10% cutoff was used for AR positivity. Androgen receptor expression in CNB (cutoff ≥ 1%) had a sensitivity of 98.5%, specificity of 60%, positive predictive value of 97.0%, and a negative predictive value of 76.9% in the detection of AR expression in SS. Conclusion Core needle biopsy has good accuracy in evaluating AR expression in BC. The accuracy of CNB decreases with higher cutoff values for AR positivity.

Resumo Objetivo Biomarcadores, como a expressão de receptores hormonais, são cruciais para guiar a terapia de pacientes com câncer de mama. Apesar de ter sido estudado, poucos dados estão disponíveis sobre o método de testagem. Buscamos avaliar a precisão da biópsia com agulha de grande calibre (CNB, na sigla em inglês) para a expressão de receptores androgênicos (AR, na sigla em inglês) no câncer de mama. Métodos Foram incluídos pacientes de uma única instituição diagnosticados com câncer de mama invasivo estágio I-III. A expressão de AR foi avaliada por imunohistoquímica, com valores de cutoff de 1 e 10%. A expressão de AR em espécimes cirúrgicos foi o padrão ouro. O coeficiente Kappa foi usado para avaliar a concordância entre procedimentos. Resultados Foi incluído um total de 72 pacientes, com idade média de 61 anos; 84% eram tumores luminais A ou B. A prevalência da expressão de AR em todas as amostras foi de 87.5%, com cutoff ≥ 10%. Com um valor de cutoff ≥ 1%, a CNB teve precisão de 95.8% (Kappa = 0.64; intervalo de confiança [IC] 95%: 0.272-1.000; p< 0.001) e 86.1% (Kappa = 0.365; CI95%: 0.052-0.679]; p< 0.001) quando um cutoff ≥ 10% foi usado para AR positivo. A expressão de AR na CNB (cutoff ≥ 1%) teve a sensibilidade de 98.5%, especificidade de 60%, valor preditivo positivo de 97.0% e valor preditivo negativo de 76.9% na detecção. Conclusão -Biópsia com agulha de grande calibre tem uma boa precisão em avaliar a expressão de AR no câncer de mama. A precisão do método cai com valores elevados de cutoff para AR positivo.

Expressions and clinical significance of ZEB1, AR, E-Ca and N-Ca in prostate cancer / 现代泌尿外科杂志

【Objective】 To analyze the correlation between the expressions of ZEB1, androgen receptor (AR), E-cadherin (E-Ca), N-cadherin (N-Ca) and clinicopathological features of prostate cancer patients with different risk levels, and to explore their significance. 【Methods】 The clinical data of 47 patients with prostate cancer treated during Nov.2013 and Jun.2021 were retrospectively analzyed. The patients were divided into medium-low risk group and high-risk group. The expressions of ZEB1, AR, E-Ca and N-Ca in the prostate cancer tissues of the two groups were detected with immunohistochemical staining. The relationship between the expressions and Gleason grade, prostate-specific antigen (PSA) level and TNM stage was analyzed. 【Results】 The positive expression rate of ZEB1 increased with higher risk, Gleason score, and PSA level (P<0.01); the strong positive expression rate of AR decreased with higher risk and Gleason score (P<0.05); the positive expression rate of E-Ca decreased with increased risk, Gleason score, and PSA level (P<0.05); the positive expression rate of N-Ca increased with the increased risk and Gleason score (P<0.01); the positive expression rate of ZEB1 increased with higher tumor stage and TNM stage (all P<0.01); the strong positive expression rate of AR decreased only with increased TNM stage (P<0.05). Patients whose first surgical specimen showing a higher expression level of ZEB1 were more likely to develop into castration-resistant prostate cancer CRPC (P<0.05). 【Conclusion】 ZEB1 and N-Ca levels increase with increased tumor aggressiveness, while AR and E-Ca levels decrease. ZEB1, AR, E-Ca and N-Ca play important roles in prostate cancer progression. ZEB1 can not only affect prostate cancer through epithelial stromal transformation (EMT), but also through AR. ZEB1 may also be related to the development of CRPC.

Role of androgen receptors in the development of hepatocellular carcinoma / 上海预防医学

Hepatocellular carcinoma （HCC） has emerged as a significant public health concern， posing a serious threat to the lives and health of residents in China. Furthermore， the incidence and mortality rates of HCC are notably higher in males than in females. Androgen receptors （AR） can contribute to the occurrence of male-specific cancers such as prostate cancer， suggesting a potential link to the increased susceptibility of males to HCC. Elucidating the cancer-promoting mechanism of AR and developing specific targeted interventions are effective ways to advance tertiary prevention of HCC and improve patient prognosis. This paper reviews the relevant evidence of AR’s role in promoting the occurrence and development of HCC， summarizes relevant mechanisms discovered to date， including promoting the stemness of HCC cells， altering the immune microenvironment， regulating key signaling pathways， inducing glycolysis in hepatocellular carcinoma， and synergizing with hepatitis B virus to promote HCC. Additionally， research directions for targeted interventions in HCC through AR-related signaling pathways are discussed.

Potential mechanism of Sophora flavescens against breast cancer via network pharmacology and molecular docking / 药学实践杂志

Objective To analyze the main active components and potential molecular mechanism of Sophora flavescens against breast cancer based on network pharmacology and molecular docking. Methods The chemical constituents were collected and screened by TCMSP, ETCM database and literature review. The targets of active ingredients were predicted by Swiss Target Prediction database. Breast cancer-related targets were collected by GeneCards, TTD, Drugbank and OMIM. The anti-breast cancer targets of Sophora flavescens were screened by Venny 2.1.0 software. Cytoscape software was used to construct the network diagram of Sophora flavescens-key active ingredients-targets. STRING database was used to analyze the common targets, and PPI network diagram was constructed. GO function enrichment analysis and KEGG pathway enrichment analysis of key target proteins were performed by DAVID database and Hiplot online platform. Schrodinger software was used to calculate the molecular docking between the active ingredients and targets. Molecular biological methods were used to verify the key targets. Results A total of 36 active components with clear structures were screened from Sophora flavescens. 70 anti-breast cancer targets of Sophora flavescens were screened out. 12 core targets including EGFR, AKT1, ESR1, SRC, CYP19A1, AR and ABCB1 participate in endocrine resistance, EGFR tyrosine kinase inhibitors and estrogen signaling pathways in breast cancer. Moreover, the docking score between the core component and the key target AR is the highest. In vitro experiments showed that the extract of Sophora flavescens can inhibit the proliferation of breast cancer cells, induce cell apoptosis and up-regulate AR protein expression. Conclusion It was revealed that Sophora flavescens plays an anti-breast cancer role by regulating complex biological processes through multiple components acting on multiple targets and signaling pathways. The upregulation of AR protein by Sophora flavescens may become a new therapeutic strategy for the treatment of breast cancer.

Function and regulatory mechanism of androgen receptor variant 7 in castration resistant prostate cancer / 中华泌尿外科杂志

Androgen receptor (AR) plays a key regulatory role in the development of castration resistant prostate cancer (CRPC), and the level of constitutive active variants represented by androgen receptor variant 7 (AR-V7) is increasing during the progress of CRPC, which can be used as a molecular marker of disease progress and prognosis of patients with CRPC. It is an important target to overcome castration resistance and improve the quality of life and survival of patients. In this paper, the function of AR-V7 and its molecular regulation mechanism in CRPC are reviewed. The research shows that the generation of AR-V7 is related to the structural rearrangement of AR gene, gene amplification and the selective splicing of AR gene transcripts, and it is affected by the coordinated regulation of multiple signal pathway molecules such as TGF-β; AR-V7 changes the transport and nuclear localization mechanism of AR protein, and further affects the transcriptional expression of downstream target genes. AR-V7 antagonizes AR activity and blocks the differentiation process driven by AR and androgen, and inhibits the expression of tumor suppressor genes to stimulate the proliferation of tumor cells, thus promoting the progress of Pca. Related targeting studies have revealed AR-V7 targets and CRPC treatment strategies. Currently, they mainly focus on AR-V7 protein degradation, mRNA expression inhibition and N-terminal domain targeting intervention. With the development of in-depth research, the molecular mechanism of AR-V7 in the progress of Pca will be gradually clarified, which will certainly play a greater role in the prevention and treatment of CRPC.

PROSTATE CANCER AND DIABETES BIOLOGY OR DETECTION BIAS

Prostate cancer and diabetes are the two highly prevalent health problems in men worldwide and have a high mortality rates but their association is quite complex and contradictory. This review reported several population based studies which tried to establish a possible association and explains the mechanism by which diabetes exhibits its effect on prostate cancer progression. It also explores the literature around the expression of various receptors and genes which enlightens the possible molecular basis of association and the effect of current antidiabetic drugs like metformin and insulin on the growth and advancement of prostate cancer in diabetic men. Masking of early tumor detection by diabetes might be the possible explanation for the reported inverse association with worse prognosis and shorter survival rate in diabetic prostate cancer patients.

Research progress of androgen receptor signaling pathway in castration-resistant prostate cancer / 国际生物医学工程杂志

Prostate cancer is the most common male malignant tumor in the world, and its death toll is second only to lung cancer. Androgen deprivation therapy (ADT) is a major treatment for prostate cancer besides radical surgery. ADT treatment will lead to the inevitable progression of prostate cancer patients to castration-resistant prostate cancer (CRPC). The current research results have confirmed that the transformation from androgen deprivation prostate cancer (ADPC) to CRP is related to the reactivation of the androgen receptor signal pathway. In this review, the research progress on the mechanism of the androgen receptor signaling pathway in CRPC was reviewed in order to provide a scientific basis and new ideas for the diagnosis and treatment of CRP.

Expression of androgen receptor and Ki67 in cancer tissues of patients with triple-negative breast cancer and their relationship with prognosis / 中国综合临床

Objective:To investigate the expression of androgen receptor (AR) and Ki67 in cancer tissues of patients with triple-negative breast cancer (TNBC) and its relationship with prognosis.Methods:The clinical data of 41 patients with TNBC treated in Beijing Chuiyangliu Hospital from January 2010 to December 2017 were collected and analyzed retrospectively. In a retrospective case-control study, 186 patients with non TNBC diagnosed by surgery and pathology in Beijing Chuiyangliu Hospital in the same period were selected as the control group. The expression of AR and Ki67 in cancer tissues of the two groups was detected by immunohistochemical method. and the relationship between the different expression of AR and Ki67 and the clinicopathological features and prognosis of TNBC patients was analyzed. In the statistical analysis of this study, the measurement data with normal distribution were compared between the two groups by t-test. Chi square test was used for counting data. The survival rate was analyzed by Kaplan Meier method and compared between groups by long rank method.Results:The positive expression of AR in cancer tissues in TNBC group was lower than that in control group (46.3%(19/41) and 81.2%(151/186)) and the difference between the two groups was statistically significant (χ 2=21.69, P<0.001). The positive expression of Ki67 in TNBC group was higher than that in the control group (75.6%(31/41) and 58.6%(109/186)) and the difference between the two groups was statistically significant (χ 2=4.11, P=0.040). Among 41 patients with TNBC, there was no significant difference in age, menopausal status and tumor diameter between AR negative group and AR positive group (all P>0.05). There were significant differences in TNM stage, histological grade and lymph node metastasis between the two groups(χ 2 values were 9.34, 5.71 and 6.60, respectively; P values were <0.001, 0.020 and 0.010, respectively). Among 41 patients with TNBC, there was no significant difference in age, menopausal status, tumor diameter and histological grade between Ki67 negative group and Ki67 positive group (all P>0.05). There were significant differences in TNM stage and lymph node metastasis between the two groups (χ 2 values were 6.03 and 4.03; P values were 0.010 and 0.040). The 3-year disease-free survival rate of TNBC patients with AR positive expression was higher than that of patients with AR negative expression (80.1% and 67.2%), but there was no significant difference between them (χ 2=3.75, P=0.056). The 3-year survival rate of TNBC patients with AR positive expression was higher than that of patients with AR negative expression (94.1% and 78.0%), but there was no significant difference between the two groups (χ 2=3.35, P=0.068). The 3-year disease-free survival rate of TNBC patients with Ki67 positive expression was lower than that of patients with Ki67 negative expression (61.0% and 89.2%) (χ 2=6.53, P=0.038). The 3-year survival rate of TNBC patients with Ki67 positive expression was lower than that of patients with Ki67 negative expression (76.1% and 96.7%) (χ 2=4.01, P=0.045). Conclusion:Compared with non TNBC patients, the expression of AR decreased and the expression of Ki67 increased in TNBC patients. The higher the expression level of AR and the lower the positive expression of Ki67 in TNBC patients, the better prognosis. It can be used as an indicator to evaluate the prognosis of breast cancer patients.

The extract of Celtis choseniana Nakai alleviates testosterone-induced benign prostatic hyperplasia through inhibiting 5α reductase type 2 and the Akt/NF-κB/AR pathway / 中国天然药物

Benign prostatic hyperplasia (BPH) is a chronic male disease characterized by the enlarged prostate. Celtis chosenianaNakai (C. choseniana) is medicinally used to alleviate pain, gastric disease, and lung abscess. In this study, the effect of C. choseniana extract on BPH was investigated using testosterone-induced rats. Sprague Dawley rats were divided into five groups: control, BPH (testosterone 5 mg·kg-1), Fina (finasteride 2 mg·kg-1), and C. choseniana (50 and 100 mg·kg-1). After four weeks of TP treatment with finasteride or C. choseniana, prostate weights and DHT levels were measured. In addition, the prostates were histopathologically examined and measured for protein kinase B (Akt)/nuclear factor-κB (NF-κB)/AR signaling, proliferation, apoptosis, and autophagy. Prostate weight and epithelial thickness were reduced in the C. choseniana groups compared with that in the BPH group. The extract of C. choseniana acted as a 5α reductase inhibitor, reducing DHT levels in the prostate. Furthermore, the extract of C. choseniana blocked the activation of p-Akt, nuclear NF-κB activation and reduced the expression of AR and PSA compared with BPH. Moreover, the expression of Bax, PARP-1, and p53 increased, while the expression of bcl-2 decreased. The present study demonstrated that C. choseniana extract alleviated testosterone-induced BPH by suppressing 5α reductase and Akt/NF-κB activation, reducing AR signaling and inducing apoptosis and autophagy in the prostate. These results suggested that C. choseniana probably contain potential herbal agents to alleviate BPH.

Up-regulation of androgen receptor by heat shock protein 27 and miR-1 induces pathogenesis of androgenic alopecia / 中南大学学报(医学版)

OBJECTIVES@#The pathogenesis of androgenetic alopecia (AGA) is related to the level of androgen and its metabolic pathways. The binding of androgen and androgen receptor (AR) depends on the assistance of heat shock protein 27 (HSP27). HSP27 combined with microRNAs (miR)-1 can regulate AR levels. However, it is not clear whether HSP27 and miR-1 jointly participate in the pathogenesis of AGA. This study aims to investigate the role of AR up-regulation in the pathogenesis of AGA and underlying mechanisms.@*METHODS@#A total of 46 male AGA patients (AGA group), who admitted to the First Affiliated Hospital of Guangzhou Medical University from September 2019 to February 2020, and 52 healthy controls admitted to the same period were enrolled in this study. Serum levels of dihydrotestosterone (DHT) and HSP27 in patients and healthy controls were measured by ELISA. Western blotting was used to detect the protein expression of HSP27 and AR in scalp tissues of patients and the healthy controls. The levels of HSP27, AR, and miR-1 were analyzed using real-time PCR. Human dermal papilla cells were transfected with HSP27 siRNA to inhibit the expression of HSP27. MiR-1 and miR-1 inhibitors were transfected simultaneously or separately into cells and then the changes in AR protein expression were detected.@*RESULTS@#The levels of DHT and HSP27 in the AGA group were (361.4±187.7) pg/mL and (89.4±21.8) ng/mL, respectively, which were higher than those in the control group [(281.8±176.6) pg/mL and (41.2±13.7) ng/mL, both P<0.05]. However, there was no significant difference in serum HSP27 and AR levels among AGA patients with different degrees of hair loss (P>0.05). Correlation analysis showed that there was a positive correlation between HSP27 level and DHT level in the AGA patients (P<0.05). The level of HSP27 mRNA in scalp tissue was negatively correlated with that of miR-1 mRNA (P<0.05). Compared with the control group, the levels of HSP27 protein, AR protein, HSP27 mRNA, and AR mRNA in scalp tissues of AGA group were significantly increased (P<0.05). The up-regulation of HSP27 in scalp tissues of AGA patients was closely related to the increased levels of AR. However, the level of miR-1 in scalp tissues of AGA patients was significantly down-regulated, contrary to the expression of AR (P<0.05). Further in cell studies showed that inhibition of HSP27 or miR-1 expression in human dermal papilla cells could inhibit the expression of AR, and inhibition of both HSP27 and miR-1 expression was found to have an accumulative effect on AR, with statistically significant differences (all P<0.05).@*CONCLUSIONS@#HSP27 could combine with miR-1 to up-regulate AR levels, which is closely related to the development of AGA.

Complete Androgen Insensitivity Syndrome: A Rare Case of Prenatal Diagnosis / Síndrome de insensibilidade completa aos androgênios: um caso raro de diagnóstico pré-natal

Abstract With the widespread uptake of noninvasive prenatal testing (NIPT), a larger cohort of women has access to fetal chromosomal sex, which increases the potential to identify prenatal sex discordance. The prenatal diagnosis of androgen insensitivity syndrome (AIS) is an incidental and rare finding. We wish to present the diagnosis of a prenatal index case after NIPT of cell-free fetal DNA and mismatch between fetal sex and ultrasound phenotype. In this particular case, the molecular analysis of the androgen receptor (AR) gene showed the presence of a pathogenic mutation, not previously reported, consistent with complete androgen insensitivity syndrome. Carrier testing for the mother revealed the presence of the same variant, confirming maternal hemizygous inheritance. Identification of the molecular basis of these genetic conditions enables the preimplantation or prenatal diagnosis in future pregnancies.

Resumo Com a utilização generalizada de testes pré-natais não invasivos (TPNIs), uma crescente porção de mulheres tem acesso ao sexo cromossômico fetal, o que aumenta o potencial para identificar discordância sexual pré-natal. O diagnóstico pré-natal da síndrome de insensibilidade androgénica é um achado incidental e raro. Pretendemos apresentar um caso índice de diagnóstico pré-natal por meio de DNA fetal livre e incompatibilidade entre sexo fetal e fenótipo ecográfico. Neste caso particular, a análise molecular do gene do receptor de andrógenios (RA) revelou a presença de uma mutação patogênica, não relatada anteriormente, consistente com a síndrome de insensibilidade completa aos androgênios. A mãe revelou ser portadora da mesma variante, confirmando a hereditariedade hemizigótica. A identificação da base genética permite o diagnóstico pré-implantação ou pré-natal em futuras gestações.

Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy

BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake­via AMP-activated protein kinase (AMPK)­after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.

Síndrome de insensibilidad a andrógenos: revisión bibliográfica a propósito de 5 casos / Androgen insensitivity syndrome: literature review about 5 cases

El síndrome de insensibilidad a andrógenos (AIS en la sigla inglesa) es una entidad muy poco frecuente en endocrinología. Se caracteriza por la mutación del receptor de andrógenos de magnitud variable, por medio del cual individuos 46,XY no se virilizan normalmente, a pesar de conservar sus testículos y tener concentraciones de testosterona en rango masculino. El cuadro clínico es variable y depende la profundidad de la alteración del receptor. En un extremo, hay casos de insensibilidad androgénica completa (CAIS) con fenotipo femenino. En el otro extremo hay insensibilidad parcial (PAIS) que se extiende desde el fenotipo femenino, con o sin ambigüedad genital, hasta los casos de hombres infértiles o con subvirilización, que presentan insensibilidad androgénica más leve. En los fenotipos femeninos, los testículos suelen estar en posición ectópica y aquellos ubicados dentro del abdomen tienen riesgo de malignizarse, por lo que suelen extirparse. Estos son los casos de más difícil manejo, pues aparte de la necesidad de gonadectomía seguida de terapia hormonal femenina, existe una vagina estrecha y en fondo de saco ciego y que suele requerir corrección quirúrgica para permitir la actividad sexual. En este trabajo presentamos 5 casos de AIS vistos recientemente en 2 centros clínicos de Santiago y que ilustran la heterogeneidad de presentación. Además, hacemos una revisión actualizada de los criterios diagnósticos, los tratamientos más adecuados y el manejo global de esta condición.

The Androgen insensitivity syndrome (AIS, in its English acronym) is a very rare entity in endocrinology. It is characterized by a variable magnitude androgen receptor mutation, whereby 46, XY individuals are not normally virilized, despite retaining their testicles and having testosterone concentrations in the male range. The clinical picture is variable and depends on the depth of the receptor alteration. At one extreme, there are cases of complete androgenic insensitivity (CAIS) with a female phenotype. At the other extreme, there is partial insensitivity (PAIS) that extends from the female phenotype, with or without genital ambiguity, to cases of infertile or undervirilized men, who have milder androgenic insensitivity. In female phenotypes, the testes are usually in an ectopic position and those located within the abdomen are at risk of malignancy, and therefore are usually removed. These are the most difficult cases to manage because apart from the need for gonadectomy followed by female hormonal therapy, there is a narrow vagina and a deep blind pouch that usually requires surgical correction to allow sexual activity. In this work, we present 5 cases of AIS recently seen in 2 clinical centers in Santiago and that illustrate the heterogeneity of presentation. In addition, we make an updated review of the diagnostic criteria, the most appropriate treatments, and the overall management of this condition.

Abiraterone acetate rechallenge for mCRPC patients with AR mutant / 中华泌尿外科杂志

A 75-year-old patient was admitted with "progressive dysuria for more than 2 months" in January 2017. The tPSA level was 498 ng/ml and then diagnosed as metastatic prostate cancer (cT 3bN xM 1). For the resistance of abiraterone, gene mutation was detected during the endocrine therapy. After 5 months of endocrine therapy, the serum tPSA was decreased to a minimum of 12.5 ng/ml. Since July, the serum PSA level gradually rebounded, and the endocrine therapy was altered to androgen deprivation therapy (ADT). The level of tPSA was maintained at 104 ng/ml in October 2017, and ADT was discontinued. After 1 year of discontinuation, the re-examination of PSA was 3 205 ng/ml. As the first-line regimen for mCRPC, abiratone and prednisone combined with goserelin was used. After 5 months of treatment, the level of tPSA still showed progression. The drug resistance of abiraterone was considered, so the treatment was discontinued. Next-generation sequencing technology (NGS) revealed the presence of AR, FGFR3 and RIT1 mutations, while no HRR germline mutation was detected. Docetaxel combined with ADT was performed. It was changed to comprehensive treatment of goserelin + docetaxel in March 2019. During chemotherapy CT images indicated significant reduction of pelvic lymph nodes and left inguinal lymph nodes, while bone metastasis showed stable condition. In April 2020, the chemotherapy was terminated for the lower extremity edema, joint pain and other related discomfort. The level of tPSA was 289 ng/ml after the last chemotherapy. DNA sequencing testing were performed again, and the mutation of AR and AR-V7 was negative. According to the results of genetic testing, the tPSA continued to decrease to 23 ng/ml after 6 months of abiraterone rechallenge, the imagings suggested that no disease progression. After AR mutation turns negative after chemotherapy, patients with refractory CRPC can still obtain a good PSA response such as tumor control and other clinical benefits from abiraterone. Abiraterone rechallenge is probably a new attempt for AR mutant patients with refractory CRPC.

The progress of novel androgen receptor inhibitors for non-metastatic castration-resistant prostate cancer / 中华泌尿外科杂志

Prostate cancer is one of the most common cancers threatening the health of males. The incidence of prostate cancer in China is on the rise. Non-metastatic castration-resistant stage is a special disease stage during the progression of prostate cancer, early identification of nmCRPC and prompt intervention can help delay disease progression and prolong patient survival. In recent years, many studies demonstrated the efficacy of novel androgen receptor inhibitors such as apalutamide, in prolonging metastasis-free survival and time to symptomatic progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). This article reviews the recent progress of novel androgen receptor inhibitors for nmCRPC.

An expert review of novel hormone therapy in metastatic prostate cancer / 中华泌尿外科杂志

Prostate cancer is one of the most common male malignancies all over the world. Patients with metastatic prostate cancer (mPCa) have a poor prognosis compared to those with local disease. In China, most newly diagnosed patients are initially found with distant metastasis. Novel hormone therapies (NHT) develop rapidly in recent years. The randomized clinical trials have demonstrated significant benefits in prolonging overall survival and improving the quality of life. It is essential to choose and optimize regimens following the development of NHT. The article focuses on reviewing current and developing strategies, treatment selection, sequence, and combination in mPCa.