Ultrasound localisation microscopy tracks testicular microvascular adaptations to endocrine function in male infertility.
ULM shows promise as a biomarker for testicular function, distinguishing HH from controls and tracking treatment response, but further research is needed to confirm its clinical utility.
Where it sits
this study against the rest of the degarelix corpusSummary and findings
The study evaluated testicular microvascular adaptations using ultrasound localisation microscopy (ULM) in men with hypogonadotrophic hypogonadism (HH) and a rodent model. ULM markers distinguished HH from controls and correlated with hormone levels. Treatment response was tracked over 12 months in humans and during pubertal development in rodents.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Findings</h4>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.<h4>Interpretation</h4>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.<h4>Funding</h4>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.
Background
The study addresses the need for improved diagnostic tools for testicular disorders, such as male infertility and hypogonadism. Current methods have limitations in assessing testicular microcirculation, which is crucial for testicular function. Ultrasound localisation microscopy (ULM) offers a novel approach to map microvascular structures and flow at clinically relevant depths, potentially enhancing diagnostic accuracy and treatment monitoring.
Methods
This was a prospective case-control study involving both human and rodent subjects. In humans, the study included healthy men and those with hypogonadotrophic hypogonadism (HH), with subgroups receiving testosterone, gonadotrophins, or no treatment. The sample sizes were small, with n ranging from 7 to 12 in different groups. A rodent model was also used to study pubertal blockade. ULM was employed to assess testicular microvascular parameters, with primary outcomes including vessel density, diameter, and flow-related indices.
Results
ULM markers effectively distinguished between HH and controls, with significant differences in vessel density (p < 0.01), diameter (p = 0.01), and tortuosity (p < 0.01). These markers correlated with testosterone (r = 0.53-0.67, p < 0.05) and inhibin B (r = -0.61, p < 0.01). In treatment groups, ULM parameters such as vessel density and diameter correlated strongly with hormone levels, showing significant treatment effects (p < 0.001). In azoospermia, vessel density and diameter were reduced regardless of treatment. ULM detected testicular activation earlier than traditional markers during fertility therapy.
Interpretation
The study suggests that ULM could serve as a valuable biomarker for assessing testicular function and monitoring treatment response in HH. The correlations with hormone levels indicate that ULM markers are biologically relevant. However, the clinical significance of these findings is limited by the small sample sizes and the use of surrogate endpoints. The study provides a basis for further research but does not establish ULM as a definitive clinical tool.
Key findings
- Vessel density p < 0.01; diameter p = 0.01; tortuosity p < 0.01 in HH vs controls.
- Correlation with testosterone r = 0.53-0.67, p < 0.05 and inhibin B r = -0.61, p < 0.01.
- Vessel density and diameter correlate with testosterone r = 0.69, 0.62; p < 0.001.
- ULM parameters increased during fertility therapy p < 0.05.
- Rodent model showed dynamic microvascular remodelling.
Limitations
- Small sample sizes in human cohorts.
- Mixed human and rodent data.
- Surrogate endpoints may not translate to clinical outcomes.
- Short follow-up duration in some groups.
- Potential variability in ULM measurements.