-
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Some epidemiological studies have shown that pregnant women who develop preeclampsia (PE) have elevated levels of testosterone in their maternal plasma compared to women...
OBJECTIVE
Some epidemiological studies have shown that pregnant women who develop preeclampsia (PE) have elevated levels of testosterone in their maternal plasma compared to women with normal blood pressure during pregnancy, revealing a potential association between hyperandrogenism in women and PE. To explore the causal relationship between hyperandrogenism and PE, this study selected total testosterone (TT), bioavailable testosterone (BIOT), and sex hormone binding globulin (SHBG) as exposure factors and PE and chronic hypertension with superimposed PE as disease outcomes. Two-sample Mendelian randomization (MR) analyses were used to genetically dissect the causal relationships between the three exposure factors (TT, BIOT, and SHBG) and the outcomes of PE and chronic hypertension with superimposed PE.
METHODS
Two independent genome-wide association study (GWAS) databases were used for the two-sample MR analysis. In the GWAS data of female participants from the UK Biobank cohort, single nucleotide polymorphisms (SNPs) associated with TT, BIOT, and SHBG were analyzed, involving 230454, 188507, and 188908 samples, respectively. GWAS data on PE and chronic hypertension with superimposed PE from the Finnish database were used to calculate SNP, involving 3556 PE cases and 114735 controls, as well as 38 cases of chronic hypertension with superimposed PE and 114735 controls. To meet the assumptions of instrumental relevance and independence in MR analysis, SNPs associated with exposure were identified at the genome-wide level (<5.0×10), and those in linkage disequilibrium interference were excluded based on clustering thresholds of <0.001 and an allele distance greater than 10000 kb. Known confounding factors, including previous PE, chronic kidney disease, chronic hypertension, diabetes, systemic lupus erythematosus, or antiphospholipid syndrome, were also identified and the relevant SNPs were removed. Finally, we extracted the outcome data based on the exposure-related SNPs in the outcome GWAS, integrating exposure and outcome data, and removing palindromic sequences. Five genetic causal analysis methods, including inverse variance-weighted method (IVW), MR-Egger regression, weighted median method, simple mode method, and weighted mode method, were used to infer causal relationships. In the IVW, it was assumed that the selected SNPs satisfied the three assumptions and provided the most ideal estimate of the effect. IVW was consequently used as the primary analysis method in this study. Considering the potential heterogeneity among the instrumental variables, random-effects IVW was used for MR analysis. The results were interpreted using odds ratios (OR) and the corresponding 95% confidence interval (CI) to explain the impact of exposure factors on PE and chronic hypertension with superimposed PE. If the CI did not include 1 and had a value less than 0.05, the difference was considered statistically significant. Sensitivity analysis was conducted to assess heterogeneity and pleiotropy. Heterogeneity was examined using Cochran's test, and pleiotropy was assessed using MR-Egger intercept analysis. Additionally, leave-one-out analysis was conducted to examine whether individual SNPs were driving the causal associations. To further validate the findings, MR analyses were performed using the same methods and outcome variables, but with different exposure factors, including waist-to-hip ratio adjusted for BMI (WHRadjBMI) and 25-hydroxyvitamin D levels, with MR results for WHRadjBMI and PE serving as the positive controls and MR results for 25-hydroxyvitamin D levels and PE as the negative controls.
RESULTS
According to the criteria for selecting genetic instrumental variables, 186, 127, and 262 SNPs were identified as genetic instrumental variables significantly associated with testosterone indicators TT, BIOT, and SHBG. MR analysis did not find a causal relationship between the TT, BIOT, and SHBG levels and the risk of developing PE and chronic hypertension with superimposed PE. The IVW method predicted that genetically predicted TT (OR [95% CI]=1.018 [0.897-1.156], =0.78), BIOT (OR [95% CI]=1.11 [0.874-1.408], =0.392), and SHBG (OR [95% CI]=0.855 [0.659-1.109], =0.239) were not associated with PE. Similarly, genetically predicted TT (OR [95% CI]=1.222 [0.548-2.722], =0.624), BIOT (OR [95% CI]=1.066 [0.242-4.695], =0.933), and SHBG (OR [95% CI]=0.529 [0.119-2.343], =0.402) were not significantly associated with chronic hypertension with superimposed PE. Additionally, MR analysis using the MR-Egger method, weighted median method, simple mode method, and weighted mode method yielded consistent results, indicating no significant causal relationship between elevated testosterone levels and PE or chronic hypertension with superimposed PE. Heterogeneity was observed for SHBG in the analysis with PE (Cochran's test, =0.01), and pleiotropy was detected for BIOT in the analysis with PE (MR-Egger intercept analysis, =0.014), suggesting that the instrumental variables did not affect PE through BIOT. Other instrumental variables did not show significant heterogeneity or pleiotropy. Leave-one-out analysis confirmed that the results of the MR analysis were not driven by individual instrumental variables. Consistent with previous MR studies, the results of the control MR analyses using WHRadjBMI and 25-hydroxyvitamin D levels supported the accuracy of the MR analysis approach and the methods used in this study.
CONCLUSION
The MR analysis results suggest that current genetic evidence does not support a causal relationship between TT, BIOT, and SHBG levels and the development of PE and chronic hypertension with superimposed PE. This study suggests that elevated testosterone may be a risk factor for PE but not a direct cause.
Topics: Humans; Female; Polymorphism, Single Nucleotide; Pregnancy; Pre-Eclampsia; Genome-Wide Association Study; Hyperandrogenism; Sex Hormone-Binding Globulin; Mendelian Randomization Analysis; Testosterone; Hypertension
PubMed: 38948277
DOI: 10.12182/20240560106 -
MethodsX Jun 2024Chromatography combined with mass spectrometry is a gold standard technique for steroid measurement, however the type of sample preparation, the dynamic range and...
Chromatography combined with mass spectrometry is a gold standard technique for steroid measurement, however the type of sample preparation, the dynamic range and reliability of the calibration curve, the chromatographic separation and mass spectrometry settings ultimately determine the success of the method. The steroid biosynthetic pathway is conserved in higher mammals and literature demonstrates that the concentration ranges of different steroid groups are relatively comparable across species. We sought to develop a robust and reliable multi steroid targeted analysis method for blood that would have wide application across higher mammals. The method was developed following bioanalytical method validation guidelines to standards typically applied to human clinical studies, including isotopically labelled internal standards where at all possible. Here we describe the practical approach to a 96-well supported liquid extraction (SLE) method of extraction from plasma (200 µL) using an Extrahera liquid handling robot (Biotage, Sweden), including quality control samples, followed by a comprehensive separation and targeted LC-MS/MS analysis of 18 steroids in plasma (pregnenolone, progesterone, 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycortisol, 21-deoxycortisol, cortisol, cortisone, androstenedione, testosterone, 5α-dihydrotestosterone, dehydroepiandrosterone, estrone, 17β-estradiol and estriol). •SLE in a 96-well format of up to 74 biological plasma samples, enriched with multiple isotopically labelled internal standards, a 12-point aqueous calibration curve, and 6 serum quality controls, designed to monitor long-term performance of the method•Chromatographic separation of multiple steroids along the gradient, with ammonium fluoride mobile phase additive to improve sensitivity, followed by electrospray ionisation and constant polarity switching•Aqueous calibration standards that cover physiologically relevant ranges - high nanomolar glucocorticoids, low nanomolar androgens and picomolar ranges for estrogens and steroid intermediates.
PubMed: 38948242
DOI: 10.1016/j.mex.2024.102728 -
World Journal of Clinical Pediatrics Jun 2024Microphallus/Micropenis is a rare condition with significant physical and psychological implications for affected individuals. This article comprehensively reviews... (Review)
Review
Microphallus/Micropenis is a rare condition with significant physical and psychological implications for affected individuals. This article comprehensively reviews micropenis, its etiology, epidemiology, and various treatment options. We conducted a thorough literature review to collect relevant information on micropenis and microphallus, as well as related disorders. Our primary databases were PubMed, Medline, and Google Scholar. We searched for articles published in English between 2000 and 2023. Our analysis included 67 review articles, 56 research studies, 11 case reports, one guideline, and one editorial. Our search terms included "microphallus", "micropenis", "congenital hypogonadotropic hypogonadism", "androgen insensitivity syndrome", "pediatric management of micropenis", "testosterone therapy", and "psychosocial implications of micropenis". We focused on diagnosing micropenis and related conditions, including hormonal assessments, medical and surgical treatment options, psychosocial and psychological well-being, sexual development of adolescents, and sociocultural influences on men's perceptions of penile size. Additionally, we explored parenting and family dynamics in cases of micropenis and disorders of sex development, implications of hormonal treatment in neonates, and studies related to penile augmentation procedures and their effectiveness. The article highlights the importance of early diagnosis and intervention in addressing the physical and psychological well-being of individuals with micropenis. Surgical procedures, such as penile lengthening and girth enhancement, and non-surgical approaches like hormonal therapy are explored. The significance of psychological support, education, and lifestyle modifications is emphasized. Early management and comprehensive care are crucial for individuals with micropenis, from infancy to adolescence and beyond. A multidisciplinary approach involving urologists, endocrinologists, and mental health professionals is recommended. Regular assessment of treatment effectiveness and the need for updated guidelines are essential to provide the best possible care. Healthcare professionals should prioritize early diagnosis, and neonatologists should measure stretched penile length in neonates. A collaborative effort is needed among professionals, parents, and affected individuals to create a supportive environment that recognizes worth beyond physical differences. Continuous research and evidence-based updates are crucial for improving care standards.
PubMed: 38947989
DOI: 10.5409/wjcp.v13.i2.89224 -
Frontiers in Oncology 2024Treatment intensification with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPi) have led to improved survival in advanced prostate...
Treatment intensification with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPi) have led to improved survival in advanced prostate cancer. However, ADT is linked to significant cardiovascular toxicity, and ARPi also negatively impacts cardiovascular health. Together with a higher prevalence of baseline cardiovascular risk factors reported among prostate cancer survivors at diagnosis, there is a pressing need to prioritise and optimise cardiovascular health in this population. Firstly, While no dedicated cardiovascular toxicity risk calculators are available, other tools such as SCORE2 can be used for baseline cardiovascular risk assessment. Next, selected patients on combination therapy may benefit from de-escalation of ADT to minimise its toxicities while maintaining cancer control. These patients can be characterised by an exceptional PSA response to hormonal treatment, favourable disease characteristics and competing comorbidities that warrant a less aggressive treatment regime. In addition, emerging molecular and genomic biomarkers hold the potential to identify patients who are suited for a de-escalated treatment approach either with ADT or with ARPi. One such biomarker is AR-V7 splice variant that predicts resistance to ARPi. Lastly, optimization of modifiable cardiovascular risk factors for patients through a coherent framework (ABCDE) and exercise therapy is equally important. This article aims to comprehensively review the cardiovascular impact of hormonal manipulation in metastatic hormone-sensitive prostate cancer, propose overarching strategies to mitigate cardiovascular toxicity associated with hormonal treatment, and, most importantly, raise awareness about the detrimental cardiovascular effects inherent in our current management strategies involving hormonal agents.
PubMed: 38947889
DOI: 10.3389/fonc.2024.1386597 -
ACS Omega Jun 2024Prostate cancer (PCa) is the second most common cancer in males worldwide. Androgen deprivation therapy (ADT) is the primary treatment method used for PCa. Although more... (Review)
Review
Prostate cancer (PCa) is the second most common cancer in males worldwide. Androgen deprivation therapy (ADT) is the primary treatment method used for PCa. Although more effective androgen synthesis and antiandrogen inhibitors have been developed for clinical practice, hormone resistance increases the incidence of ADT-insensitive prostate cancer and poor prognoses. The tumor microenvironment (TME) has become a research hotspot with efforts to identify treatment targets based on the characteristics of the TME to improve prognosis. Herein, we introduce the basic characteristics of the PCa TME and the side effects of traditional prostate cancer treatments. We further highlight the emergence of novel nanotherapy strategies, their therapeutic mechanisms, and their effects on the PCa microenvironment. With further research, clinical applications of nanotherapy for PCa are expected in the near future. Collectively, this Review provides a valuable resource regarding the various nanotherapy types, demonstrating their broad clinical prospects to improve the quality of life in patients with PCa.
PubMed: 38947792
DOI: 10.1021/acsomega.4c03055 -
Global Health & Medicine Jun 2024In recent years, randomized controlled trials have demonstrated that upfront androgen receptor signaling inhibitors (ARSIs) prolong overall survival (OS) compared with...
Comparison of oncological outcomes of upfront androgen receptor signaling inhibitors and combined androgen blockade in Japanese patients with metastatic castration-sensitive prostate cancer.
In recent years, randomized controlled trials have demonstrated that upfront androgen receptor signaling inhibitors (ARSIs) prolong overall survival (OS) compared with androgen deprivation therapy (ADT) alone or combined androgen blockade (CAB) in patients with metastatic castration-sensitive prostate cancer (mCSPC). However, it remains unclear whether upfront ARSI is superior to CAB in Asian populations, among which the efficacy of ADT/CAB is considered relatively high. In this study, we compared the oncological outcomes of upfront ARSI and CAB in Japanese patients with mCSPC. Patients with mCSPC who underwent systemic therapy between May 2009 and October 2023 were enrolled retrospectively. Propensity score matching (PSM) was performed to compare the castration-resistant prostate cancer-free survival (CRPC-FS), cancer-specific survival (CSS), and OS between patients treated with upfront ARSI (ARSI group) and those treated with CAB (CAB group). In total, 30 and 142 patients were enrolled in the ARSI and CAB groups, respectively. After PSM (25 patients in each group), CRPC-FS was significantly longer in the ARSI group than in the CAB group (median: 36.7 12.3 months, hazard ratio: 0.44, 95% confidence interval: 0.20-0.97, = 0.035). No significant differences were observed in CSS or OS between the two groups. In conclusion, when compared to CAB, upfront ARSI might have the potential to extend CRPC-FS among individuals in the Japanese population.
PubMed: 38947410
DOI: 10.35772/ghm.2024.01019 -
Cancer Innovation Apr 2024Cancer remains a major cause of mortality worldwide, and urological cancers are the most common cancers among men. Several therapeutic agents have been used to treat... (Review)
Review
Cancer remains a major cause of mortality worldwide, and urological cancers are the most common cancers among men. Several therapeutic agents have been used to treat urological cancer, leading to improved survival for patients. However, this has been accompanied by an increase in the frequency of survivors with cardiovascular complications caused by anticancer medications. Here, we propose the novel discipline of uro-cardio-oncology, an evolving subspecialty focused on the complex interactions between cardiovascular disease and urological cancer. In this comprehensive review, we discuss the various cardiovascular toxicities induced by different classes of antineoplastic agents used to treat urological cancers, including androgen deprivation therapy, vascular endothelial growth factor receptor tyrosine kinase inhibitors, immune checkpoint inhibitors, and chemotherapeutics. In addition, we discuss possible mechanisms underlying the cardiovascular toxicity associated with anticancer therapy and outline strategies for the surveillance, diagnosis, and effective management of cardiovascular complications. Finally, we provide an analysis of future perspectives in this emerging specialty, identifying areas in need of further research.
PubMed: 38946935
DOI: 10.1002/cai2.108 -
Advanced Science (Weinheim,... Jul 2024Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to...
Genetically Engineered Membrane-Coated Nanoparticles for Enhanced Prostate-Specific Membrane Antigen Targeting and Ferroptosis Treatment of Castration-Resistant Prostate Cancer.
Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration-resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron-dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate-specific membrane antigen (PSMA)-targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane-coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M-gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA-specific, CRPC-targeting platform for ferroptosis induction with increased efficacy and safety.
PubMed: 38946578
DOI: 10.1002/advs.202401095 -
Organic & Biomolecular Chemistry Jul 2024A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic...
A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic combination of synthetic methods, including CBS reduction, Evans' aldol reaction, Keck-Maruoka allylation, and enzymatic resolution, enabled the selective introduction of these stereocenters. Furthermore, the pivotal coupling of key fragments is successfully executed through a Julia-Kocienski olefination reaction, connecting the C8-C14 and C15-C23 subunits.
PubMed: 38946203
DOI: 10.1039/d4ob00852a -
Radiation Oncology Journal Jun 2024This study aimed to analyze the treatment outcomes of combined definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for clinically node-positive...
PURPOSE
This study aimed to analyze the treatment outcomes of combined definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for clinically node-positive prostate cancer.
MATERIALS AND METHODS
Medical records of 60 patients with clinically suspected metastatic lymph nodes on radiological examination were retrospectively analyzed. Eight patients (13.3%) were suspected to have metastatic common iliac or para-aortic lymph nodes. All patients underwent definitive RT with a dose fractionation of 70 Gy in 28 fractions. ADT was initiated 2-3 months before RT and continued for at least 2 years. Biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS), and prostate cancer-specific survival (PCSS) were calculated, and genitourinary and gastrointestinal adverse events were recorded.
RESULTS
The median follow-up period was 5.47 years. The 5-year BFR, CFR, OS, and PCSS rates were 19.1%, 11.3%, 89.0%, and 98.2%, respectively. The median duration of ADT was 2.30 years. BFR and CFR increased after 3 years, and 11 out of 14 biochemical failures occurred after the cessation of ADT. Grade 2 and beyond late genitourinary and gastrointestinal toxicity rates were 5.0% and 13.3%, respectively. However, only two grade 3 adverse events were reported, and no grade 4-5 adverse events were reported. Patients with non-regional lymph node metastases did not have worse BFR, CFR, or adverse event rates.
CONCLUSION
This study reported the efficacy and tolerable toxicity of hypofractionated definitive RT combined with ADT for clinically node-positive prostate cancer. Additionally, selected patients with adjacent non-regional lymph node metastases might be able to undergo definitive RT combined with ADT.
PubMed: 38946076
DOI: 10.3857/roj.2024.00080