Testicular disorders, including male infertility and hypogonadism, are increasingly prevalent and current diagnostic tools have important limitations. The testicular microcirculation underpins testicular function. Ultrasound localisation microscopy (ULM) enables super-resolution mapping of microvascular structure and flow at clinically relevant organ depth.
Prospective case-control study of ULM-assessed testicular activity in men and rodents using clinical and research ultrasound systems. Study 1 compared healthy men (n = 10) with hypogonadotrophic hypogonadism (HH) (n = 9). Study 2 included men with HH receiving testosterone (n = 11), gonadotrophins (n = 9), or no treatment (n = 12). Study 3 assessed 12-month fertility treatment response in HH (n = 7). A rodent pubertal-blockade model was also studied (n = 5).
ULM markers discriminated HH from controls (vessel density p < 0.01; diameter p = 0.01; tortuosity p < 0.01) and correlated with testosterone (r = 0.53-0.67, p < 0.05) and inhibin B (r = -0.61, p < 0.01). Vessel density, diameter, area and flow-related index were reduced in azoospermia (p < 0.01). ULM distinguished HH treatment groups (vessel density p < 0.001; diameter p < 0.05), with density and diameter correlating with testosterone (r = 0.69, 0.62; p < 0.001) and inhibin B (r = 0.64, 0.65; p < 0.001). Vessel density (p < 0.001) and diameter (p < 0.01) were reduced in azoospermia irrespective of treatment. During fertility therapy, ULM parameters increased (p < 0.05) and detected testicular activation earlier than volume or inhibin B. In rodents, pubertal development showed dynamic microvascular remodelling driven by testis growth.
ULM provides a treatment-responsive, biologically grounded biomarker of testicular function enabling patient stratification, early detection of therapeutic response, and potential for both refinement of clinical decision-making in HH, and application within other testicular disorders.
MRC, NIHR Biomedical Research Centre Funding Scheme and the NIHR/Imperial Clinical Research Facility, Diabetes UK, BBSRC, MRC, Imperial Private Healthcare Clinical Research Fellowship Scheme, NWLP Research Grant.
EBioMedicine. 2026 Jun 18 [Epub ahead of print]
Nikoleta Papanikolaou, Jipeng Yan, Biao Huang, Rhianna Davies, Cecilia Dunsterville, Nipun Laksitha De Silva, Cara Go, Pasha Grachev, Rong Luo, Jacob Broughton-Venner, Suks Minhas, Gavin Bewick, Waljit Dhillo, Kevin Murphy, Adrian Lim, Meng-Xing Tang, Channa N Jayasena
Division of Diabetes, Endocrinology and Metabolism, Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK., Department of Bioengineering, Imperial College London, London, UK; State Key Laboratory of Robotics and System, Harbin Institute of Technology, Harbin, China., Department of Bioengineering, Imperial College London, London, UK., Division of Diabetes, Endocrinology and Metabolism, Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK; Department of Clinical Sciences, Faculty of Medicine, General Sir John Kotelawala Defence University, Ratmalana, Sri Lanka., Department of Urology, Charing Cross Hospital, London, UK., Department of Diabetes and Obesity, King's College London, London, UK., Department of Imaging, Imperial College London and Healthcare NHS Trust, Charing Cross Hospital Campus, London, UK., Department of Bioengineering, Imperial College London, London, UK. Electronic address: ., Division of Diabetes, Endocrinology and Metabolism, Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK. Electronic address: .