ABSTRACT
Aims
This exploratory experimental study aimed to characterize bladder structural alterations and steroid receptor expression associated with different androgen deprivation strategies in a rat model.
Methods
Male rats were assigned to surgical castration, medical androgen deprivation with oral bicalutamide (25 mg/kg/day), leuprolide acetate (0.75 mg/kg subcutaneously on Days 1 and 14), combined androgen blockade, or control groups. Animals were evaluated after a 28‐day experimental period using histopathological, morphometric, and immunohistochemical analyses. Androgen receptor (AR), estrogen receptor beta (ERβ), and caspase‐3 expression were assessed to evaluate receptor‐level alterations and apoptotic activity.
Results
Androgen deprivation resulted in significant bladder remodeling characterized by urothelial alterations, smooth muscle atrophy, and a reduced smooth muscle‐to‐collagen ratio. These changes were most pronounced in the combined androgen blockade and surgical castration groups. AR immunoreactivity was markedly reduced in androgen‐deprived groups, whereas ERβ and caspase‐3 expression were significantly increased, indicating steroid receptor imbalance and enhanced apoptosis. Caspase‐3 expression demonstrated a graded increase across treatment groups, with the highest levels observed in the combined androgen blockade group. Bicalutamide treatment produced intermediate changes, while leuprolide acetate showed alterations comparable to surgical castration in most parameters.
Conclusion
Different androgen deprivation strategies induce distinct patterns of bladder remodeling through alterations in steroid receptor expression and apoptotic pathways. These findings identify the bladder as a direct target of androgen deprivation and demonstrate a graded, receptor‐mediated, and apoptosis‐associated remodeling process across different ADT modalities.
Keywords: androgen deprivation therapy, androgen receptor, bladder remodeling, caspase‐3, estrogen receptor beta, lower urinary tract symptoms
1. Introduction
Androgen deprivation therapy (ADT) represents a cornerstone in the management of advanced and metastatic prostate cancer and may be achieved through surgical castration, luteinizing hormone–releasing hormone (LHRH) analogues, antiandrogen therapy, or combined androgen blockade [1, 2]. Although these approaches effectively suppress androgen signaling, increasing evidence suggests that androgen deprivation may also induce structural and functional alterations in the lower urinary tract beyond its effects on the prostate [3, 4].
Lower urinary tract symptoms (LUTS) are common among aging men and substantially impair quality of life. While LUTS have traditionally been attributed to prostatic enlargement and outlet obstruction, bladder remodeling and detrusor dysfunction are increasingly recognized as important contributors to symptom development [5]. Experimental studies have demonstrated that androgen deprivation may promote detrusor muscle loss, collagen accumulation, altered smooth muscle/collagen balance, dysregulation of steroid hormone receptors, and increased apoptotic activity within the bladder wall [6, 7, 8]. Among estrogen receptor subtypes, estrogen receptor beta (ERβ) has been reported to be the predominant receptor expressed in lower urinary tract tissues and has been implicated in bladder remodeling and smooth muscle regulation [9].
However, the comparative effects of different androgen deprivation strategies on bladder histology and receptor‐level alterations remain insufficiently characterized. Therefore, this exploratory experimental study aimed to evaluate the impact of surgical and medical androgen deprivation on bladder structure, steroid receptor expression, and apoptosis‐related changes in a rat model, providing mechanistic insight into bladder remodeling associated with androgen suppression. An overview of the proposed mechanisms is provided in Figure 3.
Figure 3.
Conceptual relationship between androgen deprivation intensity and bladder remodeling. Increasing androgen deprivation was generally associated with reduced androgen signaling, decreased smooth muscle‐to‐collagen fibril (SM/CF) ratio and androgen receptor (AR) expression, together with increased ERβ expression and caspase‐3‐associated apoptotic activity. Figure 3 presents a conceptual overview of the overall relationship between androgen deprivation intensity and bladder remodeling patterns observed in the present study, rather than an exact quantitative ranking of individual experimental groups. AA, antiandrogen; CAB, combined androgen blockade; LHRH, luteinizing hormone–releasing hormone analogue; SC, surgical castration.
2. Materials and Methods
2.1. Study Design and Animals
This controlled experimental animal study was designed to evaluate the effects of different androgen deprivation strategies on bladder tissue morphology, serum hormone levels, and receptor expression. A total of 48 male Sprague–Dawley rats aged 12–16 weeks and weighing 250–300 g were included. The study protocol was approved by the institutional animal research ethics committee (Approval No: 2010/76). All animals were housed and cared for under the supervision of a veterinary surgeon at the an accredited experimental research facility.
2.2. Experimental Groups
Rats were randomly allocated into six groups (n = 8 per group):
Group 1: Control (no intervention),
Group 2: Sham (laparotomy without orchiectomy),
Group 3: Surgical castration (bilateral orchiectomy),
Group 4: Antiandrogen group (oral bicalutamide 25 mg/kg/day for 28 days),
Group 5: LHRH analogue group (leuprolide acetate 0.75 mg/kg subcutaneously on Days 1 and 14),
Group 6: Combined androgen blockade group (leuprolide acetate 0.75 mg/kg subcutaneously on Days 1 and 14 plus oral bicalutamide 9 mg/kg/day for 28 days).
The selected treatment doses and duration were based on previously established experimental androgen deprivation protocols designed to achieve sustained androgen suppression in rat models [10, 11, 12]. This design enabled comparison of surgical, pharmacological, and combined androgen deprivation strategies with respect to their effects on bladder tissue.
2.3. Surgical Castration (Orchiectomized Rat Model)
Rats in the surgical castration group were anesthetized with intraperitoneal ketamine (50–100 mg/kg) and received a single prophylactic dose of ciprofloxacin (20 mg/kg). Under sterile conditions, a midline abdominal incision was performed to access the lower abdominal cavity, and bilateral orchiectomy was carried out. Sham‐operated rats underwent identical surgical exposure without removal of the testes. The rectus fascia was closed using running 4‐0 absorbable catgut sutures, and the skin was closed with interrupted 3‐0 silk sutures.
2.4. Sample Collection and Hormonal Analysis
At the end of the 28‐day experimental period, all animals were sacrificed under general anesthesia. Blood samples were obtained via cardiac puncture and centrifuged at 3000 rpm for 10 min. Serum testosterone levels were measured using an enzymatic immunoassay method with a fully automated ELISA analyzer (TKA 313).
2.5. Histological and Morphometric Analysis
Bladder tissue specimens were fixed in 10% buffered neutral formaldehyde at +4°C for 24 h and embedded in paraffin. Sections of 4 μm thickness were stained with hematoxylin–eosin, Mallory's trichrome, and periodic acid–Schiff (PAS). Slides were examined using an Olympus CX‐31 light microscope and photographed with an Olympus LC20 photomicroscope. Histological and PAS staining findings were evaluated in all animals included in each experimental group, and the figures present representative images selected from the overall histological observations.
Quantitative morphometric analysis of smooth muscle and collagen fibrils was performed on Mallory's trichrome–stained sections using ImageJ software (National Institutes of Health, Bethesda, MD, USA). Digital images were obtained from randomly selected, non‐overlapping fields. Smooth muscle and collagen fibril areas were measured separately, and the smooth muscle‐to‐collagen fibril (SM/CF) ratio was calculated by dividing the smooth muscle area by the collagen fibril area. For morphometric and immunohistochemical analyses, tissue sections were coded prior to evaluation, and the investigator performing image selection and quantitative assessment was blinded to group allocation. High‐power fields were selected using a systematic random sampling approach by examining non‐overlapping areas from different regions of each section.
PAS staining was performed to evaluate glycoprotein content and basement membrane integrity within the urothelium.
2.6. Immunohistochemical Analysis
Immunohistochemical evaluation was performed to assess androgen receptor (AR), ERβ, and caspase‐3 expression in bladder tissue sections using the streptavidin–biotin–peroxidase method. Paraffin‐embedded sections (4 μm) were deparaffinized and rehydrated through graded alcohols. Antigen retrieval was performed using citrate buffer (pH 6.0) with microwave heating. Endogenous peroxidase activity was blocked with 3% hydrogen peroxide, followed by pepsin treatment.
Sections were incubated with primary antibodies against AR, ERβ, and caspase‐3 at manufacturer‐recommended dilutions and incubation times. Immunoreactivity was visualized using 3,3′‐diaminobenzidine (DAB) as the chromogen and counterstained with hematoxylin.
Immunoreactivity was evaluated semi‐quantitatively in both urothelial and smooth muscle compartments. For each specimen, at least five randomly selected, non‐overlapping high‐power fields were analyzed. The proportion of positively stained cells was scored as follows: 0 (none), 1 ( < 10%), 2 (10%–50%), 3 (51%–80%), and 4 ( > 80%). Staining intensity was graded as 0 (absent), 1 (weak), 2 (moderate), or 3 (strong), based on the predominant intensity observed within the evaluated field. An immunoreactivity score (IRS) was calculated by multiplying extent and intensity scores (range: 0–12). Urothelial and smooth muscle layers were evaluated separately using identical criteria. For comparative statistical analyses presented in Table 1, overall IRS were derived from the combined semiquantitative assessment of urothelial and smooth muscle staining patterns.
Table 1.
Comparative effects of surgical and medical androgen deprivation on serum testosterone levels, bladder smooth muscle/collagen ratio, and immunohistochemical parameters.
| Parameter | Control | Sham | Surgical castration | Antiandrogen | LHRH analogue | Combined androgen blockade | p value |
|---|---|---|---|---|---|---|---|
| Serum total testosterone (ng/mL) | 3.97 ± 0.99 | 3.89 ± 0.73 | 0.05 ± 0.02 | 2.89 ± 0.44 | 0.25 ± 0.13 | 0.22 ± 0.11 | < 0.001a |
| Smooth muscle/collagen ratio | 1.69 ± 0.29 | 1.79 ± 0.23 | 0.59 ± 0.16 | 0.99 ± 0.25 | 0.83 ± 0.23 | 0.79 ± 0.23 | < 0.001b |
| AR immunoreactivity score | 9.5 (6–12) | 9.5 (6–12) | 2 (0–4) | 3.5 (2–6) | 3 (2–6) | 3 (2–6) | < 0.001b |
| ERβ immunoreactivity score | 3 (2–4) | 3 (2–4) | 9 (8–10) | 6 (5–7) | 8 (7–9) | 10 (9–11) | < 0.001b |
| Caspase‐3 score | 1.5 (1–2) | 1.5 (1–2) | 9 (8–10) | 5 (4–6) | 7 (6–8) | 10 (9–11) | < 0.001b |
Note: Values are presented as mean ± SD or median (minimum–maximum), as appropriate.
• Post hoc analyses were performed to evaluate descriptive intergroup differences among androgen deprivation modalities.
• Immunoreactivity scores represent combined semiquantitative evaluation of urothelial and smooth muscle compartments.
Abbreviations: AR, androgen receptor; ERβ, estrogen receptor beta; IRS, immunoreactivity score; SM/CF, smooth muscle‐to‐collagen fibril ratio.
• aAnalysis of variance (ANOVA) was used for normally distributed variables.
• bKruskal–Wallis test followed by Dunn–Bonferroni post hoc correction was used for non‐normally distributed variables.
Primary antibodies used were anti‐AR, anti‐ERβ, and anti–caspase‐3 antibodies. All antibodies were applied according to the manufacturers' recommended protocols and had been previously validated for immunohistochemical application in rat tissue in experimental studies.
2.7. Statistical Analysis
Statistical analyses were conducted using SPSS software (version 22.0; IBM Corp., Armonk, NY, USA). Continuous variables are presented as mean ± standard deviation (SD) or median (minimum–maximum), as appropriate. Data normality was assessed using the Shapiro–Wilk test.
Serum total testosterone levels were compared among the six study groups using one‐way analysis of variance (ANOVA), followed by Tukey's honestly significant difference (HSD) test for post hoc comparisons. Histomorphometric parameters, including the smooth muscle‐to‐collagen fibril (SM/CF) ratio, as well as immunohistochemical scores for AR, ERβ, and caspase‐3, did not meet normality assumptions and were therefore analyzed using the Kruskal–Wallis test. When overall group differences were identified, post hoc comparisons were performed using Dunn's test with Bonferroni correction.
As this study was exploratory in nature and did not include a prespecified primary endpoint, statistical analyses were interpreted descriptively. Accordingly, p values were considered supportive measures and interpreted together with the magnitude and overall pattern of observed effects rather than as formal hypothesis‐testing outcomes.
3. Results
3.1. General Observations
All animals completed the 28‐day experimental period without mortality or major complications. No signs of systemic infection or postoperative morbidity were observed.
3.2. Serum Testosterone Levels
Serum testosterone levels were markedly reduced in the surgical castration, leuprolide acetate, and combined androgen deprivation groups relative to the control and sham groups. In contrast, bicalutamide treatment produced partial, but incomplete, androgen suppression (Table 1).
3.3. Histological Findings
Hematoxylin–eosin staining demonstrated generally preserved urothelial architecture across study groups, although mild urothelial thinning and irregularity were observed in some androgen‐deprived animals. Smooth muscle organization appeared relatively preserved in the control and leuprolide acetate groups, whereas focal irregularity and reduced smooth muscle density were observed in some androgen‐deprived groups (Figure 1A,B).
Figure 1.
Histological evaluation of rat bladder tissue following androgen deprivation. Representative hematoxylin–eosin (H&E) staining of the bladder urothelium (A1–A5) and detrusor muscle (B1–B5) in the control (A1, B1), surgical castration (A2, B2), bicalutamide (A3, B3), leuprolide acetate (A4, B4), and combined androgen blockade (A5, B5) groups. Periodic acid–Schiff (PAS) staining of the bladder urothelium (C1–C5) and detrusor muscle (D1–D5) in the control (C1, D1), surgical castration (C2, D2), bicalutamide (C3, D3), leuprolide acetate (C4, D4), and combined androgen blockade (C5, D5) groups. Mallory's trichrome staining of rat bladder tissue, demonstrating smooth muscle (red) and collagen deposition (blue), in the control (E1), surgical castration (E2), bicalutamide (E3), leuprolide acetate (E4), and combined androgen blockade (E5) groups. Images are representative of histological findings consistently observed across all animals within each experimental group. Reduced PAS reactivity, focal urothelial attenuation, and stromal irregularity were observed in androgen‐deprived groups. PAS, periodic acid–Schiff; SM/CF, smooth muscle‐to‐collagen fibril ratio.
“PAS staining showed intense urothelial positivity in the control and sham groups. Reduced PAS reactivity was observed in the surgical castration, bicalutamide, and combined androgen blockade groups, particularly within the urothelial and subepithelial stromal regions, suggesting altered glycoprotein content and impaired urothelial functional integrity. In contrast, leuprolide acetate‐treated rats demonstrated PAS staining patterns relatively comparable to controls (Figure 1C,D).”
3.4. Smooth Muscle‐to‐Collagen Fibril Ratio
The smooth muscle‐to‐collagen fibril ratio was highest in the control and sham groups and progressively lower across the androgen deprivation groups. Surgical castration, leuprolide acetate, and combined androgen deprivation demonstrated markedly reduced SM/CF ratios, whereas bicalutamide treatment showed intermediate values between the complete androgen deprivation and control groups (Figure 1E, Table 1).
3.5. Immunohistochemical Findings
Kruskal–Wallis analysis revealed significant differences in AR, ERβ, and caspase‐3 IRS among the study groups (all p < 0.001).
AR immunoreactivity was greatest in the control and sham groups and markedly reduced in the surgical castration, leuprolide acetate, and combined androgen blockade groups. Bicalutamide treatment demonstrated intermediate AR expression levels between the control/sham and complete androgen deprivation groups (Figure 2A,B, Table 1).
Figure 2.
Immunohistochemical staining of steroid receptors and apoptosis‐related markers in rat bladder tissue. Representative immunohistochemical staining for androgen receptor (AR) in the bladder urothelium (A1–A5) and detrusor muscle (B1–B5) of the control (A1, B1), surgical castration (A2, B2), bicalutamide (A3, B3), leuprolide acetate (A4, B4), and combined androgen blockade (A5, B5) groups. Immunohistochemical staining for estrogen receptor beta (ERβ) in the bladder urothelium (C1–C5) and detrusor muscle (D1–D5) of the control (C1, D1), surgical castration (C2, D2), bicalutamide (C3, D3), leuprolide acetate (C4, D4), and combined androgen blockade (C5, D5) groups. Immunohistochemical staining for caspase‐3 in rat bladder tissue, predominantly within the detrusor smooth muscle layer, in the control (E1), surgical castration (E2), bicalutamide (E3), leuprolide acetate (E4), and combined androgen blockade (E5) groups. Images are representative of immunohistochemical findings consistently observed across all animals within each experimental group. Scale bar = 50 µm. AR, androgen receptor; ERβ, estrogen receptor beta.
ERβ immunoreactivity demonstrated an overall increase following androgen deprivation, with the highest expression observed in the surgical castration and combined androgen blockade groups compared with the control and sham groups (Figure 2C,D, Table 1).
Caspase‐3 immunoreactivity within the bladder tissue, predominantly in the smooth muscle layer, showed a marked increase following androgen deprivation. The highest staining intensity was observed in the combined androgen blockade group, followed by the leuprolide acetate and surgical castration groups, indicating enhanced apoptotic activity. Bicalutamide treatment was associated with a moderate increase in caspase‐3 expression, whereas minimal immunoreactivity was detected in the control and sham groups (Figure 2E, Table 1).
IRS (range, 0–12) is presented as median (minimum–maximum) values. Intergroup comparisons were performed using the Kruskal–Wallis test followed by Dunn's post hoc test with Bonferroni correction.
3.6. Overall Interpretation
Taken together, these findings demonstrate a graded relationship between the intensity of androgen deprivation and bladder structural and molecular alterations (Figure 3).
4. Discussion
As an exploratory experimental study, the present findings provide descriptive evidence that both surgical and medical androgen deprivation are associated with structural and molecular alterations in bladder tissue. Across androgen‐deprived groups, varying degrees of androgen suppression were associated with a marked reduction in the smooth muscle‐to‐collagen ratio, indicating detrusor muscle loss and fibrotic remodeling of the bladder wall. These findings are consistent with previous experimental studies supporting the essential role of androgen signaling in maintaining bladder structure and detrusor integrity [13, 14].
From a functional perspective, reduced smooth muscle content and increased collagen deposition are well‐recognized contributors to impaired bladder compliance and contractility, which represent key pathophysiological mechanisms underlying storage and voiding LUTS [15, 16]. Accordingly, the histological alterations observed in this study provide a plausible structural basis for the urinary symptoms frequently reported in patients undergoing ADT [17, 18, 19].
At the receptor level, androgen deprivation resulted in a marked downregulation of AR immunoreactivity in both the urothelium and detrusor muscle. AR signaling plays a critical role in bladder development and smooth muscle maintenance, and its suppression may increase the susceptibility of bladder tissue to atrophy and functional impairment [20, 21]. In contrast, ERβ expression was significantly upregulated following androgen deprivation, particularly in the surgical castration and combined androgen blockade groups. This reciprocal alteration in steroid receptor expression suggests a shift in the hormonal microenvironment of the bladder, potentially promoting fibrotic remodeling and altered smooth muscle homeostasis [9, 22]. ERβ was specifically selected because previous experimental studies have suggested a more prominent role for this receptor subtype in lower urinary tract physiology and bladder tissue remodeling.
Caspase‐3 immunoreactivity, predominantly observed in the bladder smooth muscle layer, was increased in androgen‐deprived groups, indicating enhanced apoptotic activity. Apoptosis is a well‐recognized consequence of androgen withdrawal in urogenital tissues and likely contributes to the observed reduction in smooth muscle content [23, 24]. The highest caspase‐3 expression was observed in the combined androgen blockade group, followed by the leuprolide acetate and surgical castration groups, whereas bicalutamide treatment demonstrated a comparatively moderate increase. Minimal staining was observed in the control and sham groups. Taken together, these descriptive findings support an overall trend toward a graded relationship between the intensity of androgen suppression, receptor‐level alterations, apoptotic activity, and bladder structural remodeling, as summarized schematically in Figure 3.
A potential limitation of this study is the well‐known transient testosterone surge (“flare effect”) associated with LHRH analogue therapy. Although tissue analysis was performed at Day 28, reflecting a chronic androgen‐deprived state, early hormonal fluctuations may have influenced the remodeling process. In addition, immunohistochemical evaluation was semi‐quantitative and may be subject to observer variability. Furthermore, the exploratory design of the study and the absence of a prespecified primary endpoint should be considered when interpreting the statistical findings. However, consistent trends across multiple markers (AR, ERβ, and caspase‐3) support the overall robustness of the observed patterns. Longer‐duration experimental studies are warranted to further clarify the chronic effects of androgen deprivation on bladder remodeling and to better distinguish sustained tissue alterations from potential transient hormonal effects.
Although previous studies have reported bladder structural changes following androgen deprivation, most have evaluated individual treatment modalities in isolation. In contrast, the present study provides a direct comparative analysis of multiple androgen deprivation strategies within a unified experimental framework and demonstrates a graded relationship between the intensity of androgen suppression and bladder remodeling. The coordinated changes in AR, ERβ, and caspase‐3 expression suggest that bladder alterations are dynamically regulated by the degree of androgen signaling suppression rather than representing a binary phenomenon.
Unlike previous studies that evaluated single androgen deprivation modalities, the present study provides a direct comparative analysis of surgical, medical, and combined androgen deprivation strategies. Importantly, we demonstrate a graded, receptor‐mediated and apoptosis‐associated pattern of bladder remodeling, highlighting a dose–response relationship between androgen suppression and bladder structural and molecular alterations.
These findings have important clinical implications for the management of LUTS in patients undergoing ADT. The results suggest that LUTS in this population should not be attributed solely to prostatic factors or age‐related changes but may arise, at least in part, from direct bladder remodeling induced by androgen deprivation [4, 5, 6]. Recognition of the bladder as an active target of ADT‐related injury may help explain the high prevalence of storage symptoms, such as urgency, frequency, and nocturia, observed in prostate cancer patients receiving hormonal therapy [15, 25]. This bladder‐centered perspective supports early assessment of urinary symptoms and highlights the potential value of bladder‐directed or protective strategies in this patient group. Figure 3 provides a conceptual framework for these observations.
5. Conclusion
These findings indicate that androgen deprivation induces structural and molecular remodeling of the bladder through steroid receptor imbalance and apoptosis. This study provides integrated evidence of a graded, receptor‐mediated, and apoptosis‐associated remodeling process across different androgen deprivation strategies, offering a mechanistic basis for LUTS development in androgen‐deprived states.
Author Contributions
Yavuz Güler: conceptualization. Yavuz Güler and Mustafa Kemal Yenmez: methodology. Yavuz Güler and Cüneyt Sevinç: data collection. Yavuz Güler: analysis. Yavuz Güler: writing–original draft. Yavuz Güler, Mustafa Kemal Yenmez, and Cüneyt Sevinç: writing–review and editing.
Funding
The authors have nothing to report.
Ethics Statement
This study was approved by the institutional animal care and use committee (Approval No: 2010/76).
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.