Androgen signalling is the primary driver of male sexual differentiation in mammals, directing masculinization during a crucial fetal window. In male fetuses, high levels of fetal androgens, mainly from the testes, promo...Androgen signalling is the primary driver of male sexual differentiation in mammals, directing masculinization during a crucial fetal window. In male fetuses, high levels of fetal androgens, mainly from the testes, promote male reproductive tract development through androgen receptor activation, whereas low levels of androgens in female fetuses enable the development along the female pathway. This androgen-centric view of reproductive development has long dominated the field, casting oestrogens as passive bystanders. However, both historical and emerging evidence challenges this narrative, pointing to an active role of oestrogens in shaping reproductive development through complex, tissue-specific interactions with androgen pathways. Oestrogen receptors are expressed in developing reproductive tissues of both sexes, and disruptions in oestrogen signalling - shown in genetic and pharmacological models - can lead to reproductive abnormalities. Oestrogens might counteract androgen action at the tissue level and modulate androgen receptor expression, independently of effects on androgen production. Moreover, combined exposure to anti-androgens and oestrogenic compounds can amplify developmental disruptions, underscoring the importance of hormonal crosstalk. These findings question the adequacy of an androgen-only model, especially when assessing endocrine disruptors. Understanding the role of oestrogens is essential for interpreting normal development and chemical risks. Reproductive differentiation seems to depend on the integrated balance between androgen and oestrogen pathways, rather than on isolated signals.
John PP, Mike L, Mysorekar IU
… +11 more, Ruiz-Rosado JD, Clatworthy M, Schwartz L, Ching C, Kimbrough D, Shaikh N, Braga L, Rajadhyaksha E, Hains D, Watson J, Becknell B
Bacterial urinary tract infections (UTIs) are prevalent in childhood and adolescence. Paediatric UTIs present unique challenges with respect to diagnosis, prevention and management, and the potential for adverse sequelae...Bacterial urinary tract infections (UTIs) are prevalent in childhood and adolescence. Paediatric UTIs present unique challenges with respect to diagnosis, prevention and management, and the potential for adverse sequelae. Uropathogenic Escherichia coli (UPEC) accounts for the majority of UTIs and is the best studied uropathogen. Novel discoveries have advanced our understanding of host-pathogen interactions, cellular and molecular mechanisms of host defence, and risk factors for UTI recurrence. Emerging evidence also highlights an association of the gut, vaginal and urinary microbiota in influencing UTI risk and recurrence. Yet, key knowledge gaps persist regarding UTI pathogenesis, host susceptibility, optimal diagnostic and management strategies and prevention of UTI recurrence and sequelae, especially in paediatric populations. The development of standardized clinical pathways offers an opportunity to improve care consistency and outcomes by integrating evidence-based practices into routine management. As technologies evolve and understanding deepens, future efforts must integrate host, microbial and clinical insights to optimize UTI prevention and treatment in paediatric populations.
Prostate cancer remains the most frequently diagnosed malignancy in men worldwide. Most primary prostate cancer cells express the androgen receptor (AR) and rely on androgens for oncogenic growth and progression. Thus, a...Prostate cancer remains the most frequently diagnosed malignancy in men worldwide. Most primary prostate cancer cells express the androgen receptor (AR) and rely on androgens for oncogenic growth and progression. Thus, androgen deprivation therapy (ADT) that directly targets AR-expressing prostate cancer cells has been the frontline treatment for advanced prostate cancer. However, ADT inevitably fails in most patients, resulting in castration-resistant prostate cancer development. To inhibit reactivation of AR-promoted tumour progression via residual androgens and altered AR activation, next-generation AR antagonists and inhibitors of androgen biosynthesis were developed to improve clinical outcomes. However, these therapeutic advances also induce heterogeneous resistance phenotypes. Among them, double-null prostate cancer, featuring AR-null and neuroendocrine-null cell properties, occurs in patients treated with abiraterone and enzalutamide. Emerging clinical and experimental evidence demonstrates that current ADT induces HGF and canonical WNT signalling activation, which further elevates nuclear exporting and ribosomal biogenesis to foster tumour lineage plasticity and promote diverse castration-resistant prostate cancer phenotypes and double-null prostate cancer development. These mechanistic insights remain under active investigation, but they provide therapeutic prospects for co-targeting nuclear exporting, ribosomal biosynthesis and other oncogenic pathways in combination with current ADT to forestall the lethal disease.
Radical cystectomy is the gold-standard treatment for patients with muscle-invasive and very high-risk non-muscle-invasive bladder cancer. In female patients, radical cystectomy has traditionally included removal of the...Radical cystectomy is the gold-standard treatment for patients with muscle-invasive and very high-risk non-muscle-invasive bladder cancer. In female patients, radical cystectomy has traditionally included removal of the uterus, ovaries, fallopian tubes and anterior vaginal wall. The majority of female patients undergoing radical cystectomy are postmenopausal, but a subset of patients are premenopausal and experience surgical menopause as a result of bilateral oophorectomy. Surgical menopause results from an abrupt loss of sex steroid hormones, resulting in symptoms such as vasomotor instability and sexual dysfunction, while also increasing the long-term risk of osteoporosis, cardiovascular disease and cognitive decline. The importance of ovarian preservation during radical cystectomy is increasingly recognized; however, oophorectomy might still be indicated in selected premenopausal patients for oncological control. In these individuals, awareness and management of surgical menopause among urologists is often limited, resulting in avoidable morbidity. Thus, when surgical menopause is unavoidable, patients should be counselled regarding symptom management, cardiovascular risk and bone protection; and appropriate hormonal and non-hormonal therapeutic strategies should be implemented where indicated.
Sperm DNA fragmentation is a recognized factor in male infertility with direct implications for embryo development, implantation and pregnancy outcomes. Historically, standard semen analysis has not included assessments...Sperm DNA fragmentation is a recognized factor in male infertility with direct implications for embryo development, implantation and pregnancy outcomes. Historically, standard semen analysis has not included assessments of DNA integrity, creating a clear need for advanced diagnostic tools. DNA damage can arise through pathways such as apoptosis, oxidative stress and exposure to environmental toxins, all of which compromise reproductive potential. Several methodologies exist for measuring sperm DNA fragmentation, including the sperm chromatin structure assay, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), the Comet assay and sperm chromatin dispersion, each of which has unique advantages and limitations. Novel automated imaging platforms incorporating machine learning algorithms have emerged, enabling high-throughput, single-sperm assessment and reducing subjectivity associated with manual scoring. Species differences further complicate the understanding of DNA stability and sperm quality, especially in livestock and models of artificial insemination; nonetheless, physiological similarities between humans and species close to humans provide useful translational insights. Emerging sperm selection technologies, including microfluidics, hyaluronic acid affinity systems and magnetic-activated cell sorting, show promise in reducing DNA fragmentation, improving reproductive outcomes and decreasing pregnancy loss. As the field progresses toward increasingly personalized fertility treatments, measures of DNA integrity will remain central to optimizing assisted reproduction success rates across species.
Wilms tumour is the most common kidney tumour in children. Owing to global collaboration and advances in clinical care, 90% of affected children, including those with metastatic disease, can now be cured. Further improve...Wilms tumour is the most common kidney tumour in children. Owing to global collaboration and advances in clinical care, 90% of affected children, including those with metastatic disease, can now be cured. Further improvements in this outstanding outcome will depend on implementing strategies to prevent treatment-related mortality and gaining insights into the molecular and clinical drivers of Wilms tumour to introduce tailored therapies. The main treatments for Wilms tumour are nephrectomy and chemotherapy, with radiotherapy used selectively. Wilms tumour therapies can lead to long-term chronic health conditions, such as chronic kidney disease, infertility, second primary neoplasms and cardiovascular disease, despite the use of risk-adapted protocols to optimize the therapeutic index. Research into therapy de-escalation has been enhanced by survivor cohort studies investigating the chronic health conditions associated with specific Wilms tumour therapies. Understanding these relationships and which patients are most susceptible to specific toxic effects is crucial for counselling Wilms tumour survivors and their health-care providers on survivorship care planning. A classification framework could stratify survivors by their risk of treatment-related long-term morbidity, to tailor long-term follow-up monitoring and care.
Prostate cancer is characterized by multifocality, inter- and intra-patient tumour heterogeneity, and differences in risk of progression to metastatic disease, castration resistance and lethality, which can make prognosi...Prostate cancer is characterized by multifocality, inter- and intra-patient tumour heterogeneity, and differences in risk of progression to metastatic disease, castration resistance and lethality, which can make prognosis challenging. Consequently, sampling methods that provide accurate insight into disease phenotype to facilitate risk-stratification of patients are crucial. The variable biology of prostate cancer seems to be recapitulated in the phenotypic heterogeneity of circulating tumour cells (CTCs). CTC sampling offers a liquid biopsy method to achieve minimally invasive longitudinal sampling for disease monitoring. CTC analysis has also offered a crucial insight into aggressive phenotypes, disease metastasis and treatment response, particularly in clinical trials. The clinical use of CTC count for prognosis in advanced prostate cancer has been approved by the FDA, but is not routinely used clinically, as these cells are technically challenging to isolate and analyse. However, methodological advances continue to improve CTC enrichment and profiling. Understanding the clinical utility of CTCs and future innovations is crucial to incorporating CTCs into the clinical management of prostate cancer.
Bladder cancer remains a major global health challenge, characterized by diagnostic uncertainty, substantial treatment costs and high recurrence rates. Current diagnostic and treatment modalities, including cystoscopy, t...Bladder cancer remains a major global health challenge, characterized by diagnostic uncertainty, substantial treatment costs and high recurrence rates. Current diagnostic and treatment modalities, including cystoscopy, transurethral resection of bladder tumour and standard histopathology, have limitations, including the inability to detect flat lesions, frequent understaging and interobserver variability, highlighting a crucial need for improved approaches. Advances in artificial intelligence (AI), blue-light cystoscopy, narrow-band imaging, cytology and urinary markers show promise in enhancing early detection and diagnosis. Developments in multiparametric MRI, radiomics, genomics and AI-driven algorithms for histopathological analyses have demonstrated considerable improvements in staging and risk stratification of bladder tumours, enabling personalized therapy selection and prognostication. Despite these promising developments, challenges remain regarding standardization, external validation, cost-effectiveness and ethical considerations in clinical implementation. Future research should prioritize addressing these barriers through collaborative, multi-institutional studies and robust validation frameworks. Ultimately, adopting a comprehensive multimodal strategy, such as proposed, novel, multimodal decision-making frameworks in which these advances and technologies are integrated, promises to considerably advance precision oncology in bladder cancer, improving patient outcomes and reducing health care burdens.
Benign prostatic hyperplasia (BPH) is one of the most prevalent urological disorders in ageing men. Medical therapies are widely used to treat BPH, but truly effective long-term treatments remain limited. Among the most...Benign prostatic hyperplasia (BPH) is one of the most prevalent urological disorders in ageing men. Medical therapies are widely used to treat BPH, but truly effective long-term treatments remain limited. Among the most commonly prescribed drugs are 5α-reductase inhibitors (5ARIs), which alleviate symptoms and slow disease progression by inhibiting steroid 5α-reductase (SRD5A) enzymes, particularly the SRD5A1 and SRD5A2 isoforms. SRD5A2, the dominant isoform in the prostate, has a pivotal role in androgen metabolism by converting testosterone into dihydrotestosterone, a potent driver of prostate growth. Proper regulation of SRD5A2 is essential to maintain the balance between androgenic and oestrogenic signalling, thereby supporting healthy prostate physiology. Emerging evidence links SRD5A2 alterations, such as genetic polymorphisms, epigenetic silencing and inflammation-induced changes to disease risk and progression, positioning these factors as promising biomarkers for personalized therapy. Beyond BPH, SRD5A2 has also been implicated as a potential therapeutic target in prostate cancer and androgenic alopecia. Thus, SRD5A2 has clinical relevance in BPH, prostate cancer and other androgen-mediated conditions. However, limitations of SRD5A2-targeted therapies need to be overcome for future strategies to enhance the efficacy of 5ARI-based treatments.
The quest for therapeutics to manage erectile dysfunction has evolved in the past few decades, with attention now directed towards interventions that facilitate and retain natural erectile ability. Electrical neurostimul...The quest for therapeutics to manage erectile dysfunction has evolved in the past few decades, with attention now directed towards interventions that facilitate and retain natural erectile ability. Electrical neurostimulation of the penis is a technique that could meet this objective. Although only in the early stages of development, this intervention could act as an authentic restorative therapy, targeting the penile-nerve supply that is impaired by disease states, injury or ageing. The concept is in accordance with well-substantiated neuromodulatory management approaches to erectile dysfunction, aimed at promoting neuronal integrity and function of the nerves, which are essential for regulating penile erections. The use of this technique is supported by intensive research over the past 150 years, from early experimental observations of erection responses following electrical stimulation of pelvic nerves to contemporary clinical investigations showing recovery of erection after implantation of pelvic neurostimulators in men with spinal-cord injury or undergoing radical prostatectomy. Thus, this therapy could be considered an emerging subspecialty, spanning the establishment of the neuroregulatory basis of penile erection and the invention of technologies that capitalize on the science of pelvic neurophysiology. The clinical use of penile neurostimulation could, therefore, offer a revolutionary new therapeutic approach in the field of sexual medicine.
Sexual pleasure is a fundamental aspect of human sexuality and well-being, but it has often been overshadowed by the clinical focus on dysfunction and reproduction in sexual medicine, particularly in urology. The histori...Sexual pleasure is a fundamental aspect of human sexuality and well-being, but it has often been overshadowed by the clinical focus on dysfunction and reproduction in sexual medicine, particularly in urology. The historical neglect of sexual pleasure, particularly in female and queer people, has been perpetuated by sociocultural and gender biases. However, advances in understanding and identification of research gaps help to illustrate the potential of multidisciplinary approaches that address the diverse experiences and needs of individuals across their lifespan. Integrating pleasure into research, clinical practice, sexuality education and public health initiatives has transformative potential to enhance individual well-being, intimate relationships and overall quality of life. A biopsychosocial view of the subject offers actionable strategies for redefining sexual medicine to embrace the complexity and universality of pleasure as a driver of sexual health and equity, demonstrating that it is time for a paradigm shift, positioning sexual pleasure as a vital component of sexual health.
Ortiz MV, Wens FSPL, Hong AL
… +16 more, Quarello P, Verschuur AC, Tracy ET, Daw NC, Dome JS, Walz AL, Sprokkerieft J, Tytgat GAM, Kentsis A, Libes-Bander J, Schoettler PJ, Perotti D, Drost J, Venkatramani R, Geller JI, van den Heuvel-Eibrink MM
Paediatric kidney tumours are generally associated with a favourable survival rate. Most children are diagnosed with Wilms tumour, which has a 90% long-term survival rate with conventional front-line and salvage therapie...Paediatric kidney tumours are generally associated with a favourable survival rate. Most children are diagnosed with Wilms tumour, which has a 90% long-term survival rate with conventional front-line and salvage therapies. However, treatments and outcomes of children with relapsed non-Wilms tumours, such as malignant rhabdoid tumour of the kidney, renal-cell carcinoma (including renal medullary carcinoma), clear-cell sarcoma of the kidney, anaplastic sarcoma of the kidney and congenital mesoblastic nephroma are not well defined. Several of these non-Wilms tumours include unfavourable prognostic subtypes. Currently available data on non-Wilms tumours support advancing studies that pivot from conventional strategies towards disease-specific, biologically driven novel treatments to improve outcomes for each of these rare childhood kidney tumours.