Letter to the Editor on “Effects of Surgical and Medical Androgen Deprivation on Bladder Remodeling and Steroid Receptor Expression: An Experimental Rat Study”

Dear Editor,

We read with great interest the study by Yenmez et al. demonstrating that surgical and medical androgen deprivation induce bladder remodeling, including urothelial alterations, detrusor smooth‐muscle atrophy, a reduced smooth muscle‐to‐collagen ratio, steroid receptor imbalance, and increased apoptosis [1]. These findings are important because androgen deprivation therapy (ADT)‐related urinary effects are often interpreted mainly through prostate downsizing and relief of bladder outlet obstruction (BOO). We suggest that ADT should instead be viewed as a lower urinary tract remodeling intervention with potentially divergent effects on voiding and storage symptoms.

Clinically, this distinction may explain why improvement in voiding lower urinary tract symptoms (LUTS) does not always parallel improvement in storage LUTS. A recent narrative review frames testosterone deficiency as a systemic contributor to LUTS through inflammatory, vascular, metabolic, bladder, prostate, and pelvic‐support pathways [2]. In patients with prostate cancer undergoing ADT, Bang et al. showed that total and voiding IPSS generally improve, but storage symptoms may remain unchanged or worsen, especially in men with small prostates and greater testosterone reduction [3]. Li et al. likewise reported an increased risk of overactive bladder (OAB) after ADT, with a treatment‐duration‐dependent pattern and a marked increase after 5 years [4]. These observations suggest that prostate shrinkage and storage symptom biology can diverge.

Yenmez et al. now provide a plausible bladder‐side mechanism for this divergence [1]. Their findings fit modern OAB concepts: urgency is not always a direct manifestation of detrusor overactivity, and OAB may arise from myogenic, urothelial/suburothelial, afferent, central, metabolic, or urethrogenic pathways [5]. Thus, ADT‐related urgency may reflect altered bladder and afferent biology rather than persistent obstruction alone.

A second pathway may occur at the outlet. Testosterone ablation in rats attenuates prostatic smooth‐muscle contractility and PDE5 signaling [6]. Koraitim described the lissosphincter as the smooth‐muscle component primarily responsible for continence at rest [7]. We therefore propose that ADT may weaken a gasket‐like passive urethral seal: prostate shrinkage may relieve BOO, while loss of androgen‐dependent smooth‐muscle tone or organization in the prostatic urethra/lissosphincter may reduce resting coaptation. Such outlet‐side dysfunction could facilitate proximal urethral afferent activation and urgency, consistent with the urethrogenic OAB hypothesis [5]. This remains a testable hypothesis, since direct human evidence of ADT‐induced lissosphincter thinning is lacking.

A third, longer‐term pathway is fibrotic remodeling. Rodriguez‐Nieves and Macoska noted ADT‐associated histological changes in prostate tissue architecture, including inflammation and fibrosis, and raised the possibility that myofibroblast phenoconversion and fibrosis in nonmalignant prostate tissue could contribute to BPH/LUTS progression in some men [8]. If periurethral fibrotic remodeling develops during prolonged androgen deprivation, it could increase tissue stiffness or irritative signaling despite glandular involution.

This duality is clinically important. Treatments providing greater urodynamic de‐obstruction generally provide greater symptom benefit [9], while BOO itself induces progressive remodeling of human bladder tissue involving the urothelium, suburothelium, detrusor smooth muscle, extracellular matrix, and nerves [10]. ADT may therefore subtract one LUTS driver, obstruction, while adding others: endocrine bladder remodeling, outlet passive‐seal dysfunction, and possible periurethral fibrosis.

Future ADT studies should separate voiding and storage endpoints, document prostate volume, testosterone nadir and magnitude of reduction, ADT duration, OAB medication use, urodynamic parameters, and imaging or biomarker evidence of bladder and periurethral remodeling. Rather than asking whether ADT improves LUTS, the more precise question is which LUTS phenotype improves, which worsens, and through which tissue compartment. Yenmez et al. have opened the door to this more nuanced model of ADT as a lower urinary tract remodeling intervention, not simply a prostate shrinker.

Author Contributions

Kuo‐Jen Lin: conceptualization, investigation, writing – original draft. Po‐Ting Lin: conceptualization, Investigation, writing – review and editing. Yu‐Hsiang Lin: conceptualization, investigation, writing – original draft, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Declaration of Generative AI and AI‐Assisted Technologies in the Writing Process

During the preparation of this work, the author(s) used ChatGPT in order to refine the manuscript and enhance the fluency of the English language. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.