Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(3):14142 1 ORIGINAL PAPER Telmisartan, an angiotensin II receptor blocker with partial PPAR-γ agonist activity, has been shown to enhance testicu- lar health and mitigate testicular damage in diabetic rat models (4). Furthermore, moderate-intensity aerobic exercise (MIAE) for ten weeks has been reported to improve Johnsen score and increase seminiferous tubule diameter by reduc- ing reactive oxygen species (ROS) in diabetic rats (5, 6). We selected moderate-intensity aerobic exercise over high-intensity protocols because the latter is widely rec- ognized as a physiological stressor that may negatively impact overall health. High-intensity exercise has been linked to increased oxidative stress, which can detrimen- tally affect the male reproductive system (7). Additionally, excessive training may induce overtraining syndrome, characterized by hormonal imbalances that disrupt spermatogenesis. Prior evidence indicates that high-intensity exercise impairs germ cell development and compromises the viability of germinal lineages and Sertoli cells within the seminiferous tubules (8, 9). Therefore, based on previous studies, moderate-intensity aerobic exercise for ten weeks is considered the optimal regimen for supporting reproductive health while mini- mizing potential adverse effects (5, 6). Telmisartan (6 mg/kg body weight) has been shown to prevent diabetes- induced testicular damage when administered for a min- imum of four weeks (4). However, to our knowledge, no prior study has directly investigated the combined effects of these two interventions. This study examined the synergistic effects of telmisartan and moderate-intensity aerobic exercise on testicular his- toarchitecture in STZ-induced diabetic rats. MATERIALS AND METHODS Study Design This study used a true experimental, post-test-only con- trol group design to evaluate the effects of telmisartan and MIAE on testicular histopathology in diabetic rats. Thirty-nine healthy male Wistar rats (12 weeks old, 140- 180 grams) were randomly assigned to five groups: • K0: Healthy control • K1: Diabetic control Background: Diabetes mellitus (DM) is associated with testicular damage, leading to male infertility. This study investigates the effects of telmisartan, moderate-intensity aerobic exercise, and their combination on testicular histopathology in a streptozotocin-induced diabetic rat model. Methods: Male Wistar rats were divided into five groups: healthy control (K0), diabetic control (K1), telmisartan monotherapy (K2), aerobic exercise monotherapy (K3), and combination therapy (K4). Diabetes was induced using strepto- zotocin (STZ), and treatments were administered for 10 weeks. Testicular histopathology was assessed by evaluating Johnsen score, Sertoli cell count, Leydig cell count, and seminiferous tubule diameter. Results: Diabetic rats (K1) showed significant declines in Johnsen score, Sertoli and Leydig cell counts, and seminiferous tubule diameter (p < 0.05). Telmisartan (K2) and combination therapy (K4) significantly improved all parameters, with values approaching those of healthy controls (K0). Aerobic exercise (K3) improved seminiferous tubule diameter but had limited effects on Johnsen score, Sertoli, and Leydig cells. Kruskal- Wallis, Mann-Whitney U, ANOVA, Games-Howell, and LSD tests confirmed these findings. Conclusions: Telmisartan, either as monotherapy or in combina- tion with moderate-intensity aerobic exercise, effectively amelio- rates testicular damage in diabetic rats. Aerobic exercise alone has a partial protective effect. These findings suggest potential therapeutic strategies for preventing diabetes-induced male infertility. KEY WORDS: Diabetes mellitus; Telmisartan; Aerobic exercise; Testicular histopathology; Male infertility. Submitted 14 July 2025; Accepted 28 July 2025 INTRODUCTION Diabetes mellitus (DM) is known to impair male repro- ductive health, often leading to infertility (1). In diabetic conditions, testicular function is compromised, with sig- nificant reductions in testosterone levels, as well as impaired spermatogenesis and sperm motility (2). The prevalence of infertility among men with DM is reported to range from 35% to 51% (3). Guarding masculinity: Telmisartan and aerobic exercise preserve testicular histomorphometry in diabetic rats Ali Akbar Firasi 1, 2, Mohammad Ayodhia Soebadi 1, 2, Soetojo Wirjopranoto 1, 2, Ghazian Adli 1, 2, Anny Setijo Rahaju 3, 4 1 Department of Urology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; 2 Department of Urology, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia; 3 Department of Anatomical Pathology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; 4 Department of Anatomical Pathology, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia. DOI: 10.4081/aiua.2025.14142 Summary Archivio Italiano di Urologia e Andrologia 2025; 97(3):14142 A. Akbar Firasi, M. Ayodhia Soebadi, S. Wirjopranoto, et al. 2 • K2: Diabetic + telmisartan • K3: Diabetic + MIAE • K4: Diabetic + telmisartan + MIAE After 10 weeks of intervention, all rats were euthanized via intraperitoneal injection of ketamine (300 mg/kg) and xylazine (30 mg/kg), followed by cervical dislocation and decapitation to ensure humane and complete sacrifice. Induction of Diabetes Mellitus Diabetes was induced by a single STZ injection (35 mg/kg, i.p.). Rats with fasting glucose > 150 mg/dL after 7 days were classified as diabetic. Treatment protocols • Telmisartan: 6 mg/kg/day orally via gavage for 10 weeks. • Moderate intensity aerobic exercise: Rats in the K3 and K4 groups performed swimming exercises in a cylindri- cal tank (diameter 45 cm, water depth 55 cm) for 60 minutes/day, 5 days/week (Monday-Friday) for 10 weeks. Swimming was supervised, and sessions were terminated if rats could not keep their heads above water for more than 3 seconds without effort. Non-com- pliance in three consecutive sessions led to exclusion. Sample collection and histological preparation At week 10, after euthanasia testes were collected from rats, fixed, and embedded in paraffin. Sections (5 µm) were stained with H&E for analysis of: • Johnsen score • Sertoli cell count • Leydig cell count • Seminiferous tubule diameter A single anatomical pathology specialist evaluated five non-overlapping fields per rat using a Leica Flexacam i5 microscope and Enersight software. Tubule diameter was assessed at 100×; Johnsen score, Sertoli, and Leydig cells at 400×. Johnsen score The Johnsen scoring system rates spermatogenesis from 1 to 10, with higher scores reflecting greater germ cell maturity and better testicular function (Table 1) (1). Statistical analysis Data were analyzed using SPSS. Normality was tested with Shapiro-Wilk; homogeneity with Levene’s test. One- way ANOVA with Tukey’s post hoc was applied for nor- mal data, and Kruskal-Wallis with Mann-Whitney U for non-normal data. Significance was set at p < 0.05. Ethical considerations This study received ethical approval for animal experi- mentation from the institutional ethics committee 88/EC/KEPK/FKUA/2025. RESULTS Diabetic rat model Thirty-nine healthy male Wistar rats (12 weeks old) were randomly assigned to five groups. Diabetes was induced in all except the healthy control group (K0) using a single STZ injection (35 mg/kg, intraperitoneal). Rats with fast- ing glucose > 150 mg/dL after 7 days were classified as diabetic. The groups were: • K0: Healthy control • K1: Diabetic control • K2: Diabetic + telmisartan (6 mg/kg/day, oral) for 10 weeks • K3: Diabetic + exercise (60 min/day, 5 days/week) for 10 weeks • K4: Diabetic + telmisartan + exercise All interventions were administered for a duration of 10 weeks. Final fasting glucose was measured before euthanasia, and testicular tissues were collected for analy- sis (Figures 1, 2). Histological evaluation of testicular parameters The histological evaluation focused on four key testicular parameters: Johnsen score, Sertoli cell count, Leydig cell count, and seminiferous tubule diameter. Blood glucose levels All STZ-induced groups (K1-K4) maintained fasting glu- cose levels > 150 mg/dL, confirming sustained hyper- glycemia. No significant differences were found among diabetic groups (p > 0.05), indicating that treatments did not affect blood glucose levels (Table 2). Johnsen score analysis Shapiro-Wilk and homogeneity tests indicated a non- parametric distribution for Johnsen scores (p < 0.05). Table 1. Johnsen score criteria for histological evaluation of testicular damage. Score Histological criteria 10 Normal tubular epithelium, complete spermatogenesis, open lumen, ≥ 10 spermatozoa 9 Damaged tubular epithelium, closed lumen, ≥ 10 spermatozoa 8 Fewer than 10 spermatozoa 7 No spermatozoa, ≥ 10 spermatids 6 No spermatozoa, < 10 spermatids 5 No spermatozoa or spermatids, ≥ 5 spermatocytes 4 No spermatozoa or spermatids, < 5 spermatocytes 3 Only spermatogonia present 2 Only Sertoli cells present 1 No cells present in the tubule Table 2. Blood glucose level. Group Blood Sugar Blood Sugar 7 days After STZ Injection Before Termination K0 108.29 ± 9.84 K1 456.14 ± 137.001 490.43 ± 107.35 K2 349.13 ± 137.001 339.13 ± 156.76 K3 382.57 ± 136.15 381.42 ± 138.12 K4 344.71 ± 135.624 320.71 ± 131.35 Archivio Italiano di Urologia e Andrologia 2025; 97(3):14142 3 Telmisartan and aerobic exercise in diabetic rats Figure 1. Representative hematoxylin and eosin (H&E)-stained sections of seminiferous tubules at 400× magnification. (a) Spermatozoa; (b) Spermatids; (c) Spermatocytes; (d) Sertoli cells; (e) Leydig cells. K0: Healthy control with normal tubular architecture and spermatogenesis (Johnsen Score 10). K1: Diabetic control showing degeneration of seminiferous epithelium (Johnsen Score 5). K2: Telmisartan-treated group showing near- complete restoration (Johnsen Score 10). K3: Exercise-treated group with partial recovery (Johnsen Score 9). K4: Combination therapy group showing near- complete restoration (Johnsen Score 10). Figure 2. Representative hematoxylin and eosin (H&E)-stained sections of seminiferous tubules at 100× magnification. The K1 group (diabetic control) exhibited the smallest average seminiferous tubule diameter (0.17 mm), which was significantly lower than that of all other groups. This reduction is visually apparent through the collapsed and irregular architecture of the seminiferous tubules, in stark contrast to the preserved tubular structure and normal diameter observed in groups K0, K2, K3, and K4. Archivio Italiano di Urologia e Andrologia 2025; 97(3):14142 A. Akbar Firasi, M. Ayodhia Soebadi, S. Wirjopranoto, et al. 4 The Kruskal-Wallis test showed significant differences among groups (p < 0.001) (Table 4). Diabetic controls (K1) had the lowest mean Johnsen score (4.53 ± 0.73), indicating severe testicular degeneration, while healthy controls (K0) showed normal sper- matogenesis (9.50 ± 0.70). All treatment groups improved significant- ly: K2 (9.43 ± 0.37), K3 (8.44 ± 1.14), and K4 (9.69 ± 0.32), with K4 achieving the highest score. Post hoc Mann-Whitney U tests showed significant differences between K1 and all treatment groups (p < 0.001). Johnsen scores in K2 and K4 were compa- rable to K0, indicating effective preserva- tion of testicular histology (Figure 3). Sertoli cell count Shapiro-Wilk and homogeneity tests indi- cated non-parametric distribution for Sertoli cell counts (p < 0.05). Kruskal-Wallis analysis revealed significant Table 3. Mean values of Johnsen score, Sertoli cell count, Leydig cell count, and seminiferous tubule diameter. Group Johnsen Score Sertoli Cell Leydig Cell Seminiferous Tubule Diameter (mm) K0 9.50 ± 0.70 4,40 ± 2.41 6.48 ± 1.97 0.33 ± 0.05 K1 4.53 ± 0.73 1.60 ± 1.15 1.70 ± 0.89 0.17 ± 0.04 K2 9.43 ± 0.37 5.11 ± 1.36 4.69 ± 0.63 0.28 ± 0.06 K3 8.44 ± 1.14 3.58 ± 1.07 3.18 ± 0.95 0.30 ± 0.05 K4 9.69 ± 0.32 6.00 ± 1.45 4.97 ± 1.02 0.32 ± 0.05 Table 4. Mean, median, normality test, and Kruskal-Wallis test for Johnsen score. Group Mean ± SD Median Normality Kruskal-Wallis (Min-Max) (p-value) (p-value) K0 9.50 ± 0.70 9.80 (8.00 – 10.00) 0.013 < 0.001* K1 4.53 ± 0.73 4.60 (3.20 – 5.60) 0.498 K2 9.43 ± 0.37 9.60 (8.80 – 9.80) 0.271 K3 8.44 ± 1.14 8.80 (5.80 – 9.60) 0.052 K4 9.69 ± 0.32 9.80 (9.00 – 10.00) 0.011 Figure 3. Graphical presentation of the Mann- Whitney U test for Johnsen score. Significant differences are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001. Archivio Italiano di Urologia e Andrologia 2025; 97(3):14142 5 Telmisartan and aerobic exercise in diabetic rats (1.60 ± 1.15), indicating marked cellular impairment, while healthy controls (K0) showed significantly higher counts (4.40 ± 2.41). All treatments increased Sertoli cell numbers: K2 (5.11 ± 1.36), K3 (3.58 ± 1.07), and K4 (6.00 ± 1.45). Post hoc Mann- Whitney U tests confirmed significant differ- ences between K1 and all treatment groups (p < 0.05). Counts in K2 and K4 were com- parable to K0, suggesting effective preserva- tion of Sertoli cells (Figure 4). Leydig cell count Shapiro-Wilk and homogeneity tests con- firmed normal distribution of Leydig cell counts (p > 0.05), permitting parametric analysis. One-way ANOVA showed signifi- cant group differences (p < 0.001). Diabetic controls (K1) had the lowest count (1.70 ± 0.89), indicating severe depletion, while healthy controls (K0) had substantial- ly higher counts (6.48 ± 1.97) (Table 6). All treatment groups showed significant increases in Leydig cell count: K2 (4.69 ± 0.63), K3 (3.18 ± 0.95), and K4 (4.97 ± 1.02). Post hoc Games-Howell tests confirmed significant differences between K1 and all treatment Table 5. Mean, median, normality test, and Kruskal-Wallis test of Sertoli cell count. Group Mean ± SD Median Normality Mann-Whitney (Min-Max) (p-value) (p-value) K0 4.40 ± 2.41 4.70 (1.00 – 7.80) 0.241* < 0.001* K1 1.60 ± 1.15 1.50 (0.20 – 3.60) 0.665* K2 5.11 ± 1.36 5.40 (3.80 – 7.00) 0.116* K3 3.58 ± 1.07 4.00 (1.00 – 4.40) 0.002 K4 6.00 ± 1.45 5.40 (4.00 – 8.60) 0.565* Table 6. Mean, median, normality test, and Kruskal-Wallis test of Sertoli cell count. Group Mean ± SD Median Normality ANOVA (Min-Max) (p-value) (p-value) K0 6.48 ± 1.97 6.80 (3.20 – 8.80) 0.666* < 0.001* K1 1.70 ± 0.89 2.10 (0.20 – 2.80) 0.227* K2 4.69 ± 0.63 4.60 (4.00 – 6.00) 0.058* K3 3.18 ± 0.95 3.20 (1.00 – 4.40) 0.078* K4 4.97 ± 1.02 5.00 (3.00 – 6.20) 0.377* Figure 4. Graphical presentation of the Mann-Whitney U test for Sertoli cell count. Significant differences are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001. group differences (p < 0.001) (Table 5). The diabetic control group (K1) had the lowest mean Sertoli cell count Archivio Italiano di Urologia e Andrologia 2025; 97(3):14142 A. Akbar Firasi, M. Ayodhia Soebadi, S. Wirjopranoto, et al. 6 groups (p < 0.001). Leydig cell counts in K2 and K4 were comparable to K0, indicating effective mitigation of diabetes-induced Leydig cell depletion (Figure 5). Seminiferous tubules diameter Shapiro-Wilk and homogeneity tests confirmed normal distribution of seminiferous tubule diameter data (p > 0.05), permitting parametric analysis. One-way ANOVA revealed significant differences among groups (p < 0.001) (Table 7). The diabetic control group (K1) had the smallest seminif- erous tubule diameter (0.17 ± 0.04 mm), while the healthy control (K0) had the largest (0.33 ± 0.05 mm). Treatment groups showed significant improvements: K2 (0.28 ± 0.06 mm), K3 (0.30 ± 0.05 mm), and K4 (0.32 ± 0.05 mm). Post hoc LSD analysis confirmed sig- nificant differences between K1 and all treatment groups (p < 0.05). Telmisartan (K2), aerobic exercise (K3), and combination therapy (K4) all restored seminiferous tubule diameters to levels comparable with healthy controls (K0), indicating reversal of diabetes-induced tubular atrophy (Figure 6). Figure 5. Graphical presentation of the Post Hoc Games- Howell test for Leydig cell count. Significant differences are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001. Figure 6. Graphical representation of the Post Hoc LSD test for seminiferous tubule diameter. Significant differences are indicated as follows: P < 0.05, P < 0.01, *P < 0.001. Table 7. Mean, median, normality test, and One-Way ANOVA analysis of seminiferous tubule diameter. Group Mean ± SD Median Normality ANOVA (Min-Max) (p-value) (p-value) K0 0.33 ± 0.05 0.32 (0.26 – 0.42) 0.284* < 0.001* K1 0.17 ± 0.04 0.17 (0,12 – 0.22) 0.561* K2 0.28 ± 0.06 0.26 (0,22 – 0.40) 0.185* K3 0.30 ± 0.05 0.28 (0,24 – 0.38) 0.193* K4 0.32 ± 0.05 0.32 (0.24 – 0.38) 0.568* Archivio Italiano di Urologia e Andrologia 2025; 97(3):14142 7 Telmisartan and aerobic exercise in diabetic rats DISCUSSION This study evaluated the protective effects of telmisartan, moderate-intensity aerobic exercise, and their combina- tion in STZ-induced diabetic rats. All interventions sig- nificantly improved Johnsen score, Sertoli and Leydig cell counts, and seminiferous tubule diameter compared to untreated diabetic controls. In diabetic controls, histopathology showed marked tes- ticular damage, with reduced Johnsen score (4.53 ± 0.73), Sertoli cells (1.60 ± 1.15), Leydig cells (1.70 ± 0.89), and seminiferous tubule diameter (0.17 ± 0.04 mm), indicating impaired spermatogenesis. These find- ings support prior evidence linking diabetes to oxidative stress, inflammation, and hormonal imbalance that dis- rupt testicular structure and function (1). Rats with STZ-induced diabetes maintained blood glu- cose levels above 150 mg/dL. Compared to healthy con- trols, they showed significant reductions in Johnsen score (4.53 ± 0.73), Sertoli cell count (1.60 ± 1.15), Leydig cell count (1.70 ± 0.89), and seminiferous tubule diameter (0.17 ± 0.04 mm), indicating testicular dysfunction. These findings align with evidence that chronic hyper- glycemia increases ROS, damages Sertoli cells, disrupts the blood-testis barrier, and downregulates FSH receptor expression, ultimately impairing spermatogenesis (1). Testicular tissue is highly vulnerable to oxidative stress, which can trigger germ and Leydig cell apoptosis, impair function, and reduce sperm count and motility, as previ- ously reported (12). Chronic oxidative stress induces morphological changes in the seminiferous tubules, including degeneration of various germ cells, such as Sertoli cell, spermatogonia, and spermatocytes (5, 13). In this study, telmisartan (K2), aerobic exercise (K3), and combination therapy (K4) significantly improved all tes- ticular histological parameters compared to diabetic con- trols (K1). Telmisartan alone markedly increased the Johnsen score (9.43 ± 0.37), Sertoli cells (5.11 ± 1.36), Leydig cells (4.69 ± 0.63), and seminiferous tubule diam- eter (0.28 ± 0.06 mm). These effects are likely due to its anti-inflammatory and antioxidant actions, including TNF-α, NF-κB, and ROS suppression, PPAR-γ activation, enhanced insulin sensitivity, and stimulation of the hypo- thalamic-pituitary-gonadal axis (14-16). Moderate-intensity aerobic exercise (K3) significantly improved testicular histology, with increased Johnsen score (8.44 ± 1.14), Sertoli cells (3.58 ± 1.07), Leydig cells (3.18 ± 0.95), and seminiferous tubule diameter (0.30 ± 0.05 mm). These benefits are likely mediated by upregulation of Hsp70, Hsp90, GDNF, and enhanced GLUT-4-dependent glucose regulation (17-19). Combination therapy (K4) produced the most favorable outcomes, with Johnsen score (9.69 ± 0.32), Sertoli cells (6.00 ± 1.45), Leydig cells (4.97 ± 1.02), and seminifer- ous tubule diameter (0.32 ± 0.05 mm). However, differ- ences between K4 and telmisartan alone (K2) were not statistically significant, suggesting that telmisartan monotherapy may be sufficient to restore testicular his- tology in diabetic conditions. Compared to exercise alone (K3), telmisartan (K2) showed superior efficacy. Aerobic exercise has limited ability to suppress pro-inflammatory mediators like TNF-α, caspase- 3, COX-2, and iNOS, and does not significantly affect PPAR-γ or VEGF expression. As a result, exercise primarily enhances structural recovery, especially seminiferous tubule diameter, without fully restoring Johnsen score, Sertoli and Leydig cell count (14, 15, 20). Telmisartan monotherapy (K2) significantly improved all histomorphometric parameters to levels comparable with healthy controls (K0). Its protective effect is likely due to modulation of oxidative stress and inflammation, includ- ing reduced TNF-α, IL-6, and ROS, along with enhanced antioxidant enzyme activity. Telmisartan also activates PPAR-γ, a key regulator of spermatogenesis and testicular homeostasis (4). Moderate-intensity aerobic exercise (K3) offered partial protection, notably preserving seminiferous tubule diame- ter. While it modestly improved Johnsen score, Sertoli, and Leydig cell counts, the effects were less pronounced than with telmisartan or combination therapy. These findings suggest that exercise mainly supports structural integrity via improved blood flow and tissue remodeling but is insufficient for fully restoring spermatogenesis (5, 16, 21). Combination therapy (K4) yielded the greatest improve- ments across all histomorphometric parameters, surpass- ing either monotherapy. This synergistic effect likely stems from telmisartan’s anti-inflammatory and antioxi- dant actions coupled with exercise-induced enhance- ments in blood flow and tissue repair. Histological out- comes in K4 closely matched those of healthy controls, underscoring its potential as an effective strategy to pre- serve testicular function in diabetes (21). Both telmisartan monotherapy and combination therapy effectively preserved testicular histology in diabetic rats, with outcomes comparable to healthy controls. In con- trast, exercise alone primarily maintained seminiferous tubule diameter. These findings suggest that telmisartan’s broader protective mechanisms, anti-inflammatory, antioxidant, and hormonal are essential for preventing testicular damage and supporting spermatogenesis. Telmisartan provides broad and potent protection of tes- ticular histomorphometry in diabetic conditions through multiple molecular pathways. Its key mechanisms include: (1) reducing oxidative stress; (2) activating the hypothalamic-pituitary-gonadal (HPG) axis via PPAR-γ and improving insulin sensitivity; (3) suppressing inflam- matory mediators such as TNF-α, IL-6, NF-κB, caspase- 3, COX-2, iNOS, ROS, NO, 3-nitrotyrosine, and p- ERK1/2; and (4) enhancing VEGF expression to support testicular vascularization and function. In contrast, moderate-intensity aerobic exercise protects testicular tissue mainly through two mechanisms: (1) reducing oxidative stress and (2) enhancing insulin sensi- tivity via GLUT-4 activation, indirectly stimulating the HPG axis. While beneficial, its limited molecular targets likely account for its reduced efficacy in preserving Johnsen score, Sertoli and Leydig cell count compared to telmisartan. Moderate-intensity aerobic exercise primarily improves testicular structure particularly seminiferous tubule diameter by enhancing blood flow, oxygenation, and tis- sue remodeling. These changes promote rapid morpho- logical recovery even in diabetic conditions. However, full functional restoration reflected by Johnsen score and Sertoli and Leydig cell activity – depends on more com- plex endocrine and molecular adaptations, such as HPG Archivio Italiano di Urologia e Andrologia 2025; 97(3):14142 A. Akbar Firasi, M. Ayodhia Soebadi, S. Wirjopranoto, et al. 8 axis normalization, hormonal balance, and germinal epithelium regeneration, which are slower to respond to exercise alone (5, 16, 22). While exercise may lead to early improvements in semi- niferous tubule diameter, full restoration of Johnsen score as well as Sertoli and Leydig cell counts requires more tar- geted metabolic and hormonal modulation. In comparison to the untreated diabetic group, all three therapies tested – telmisartan monotherapy, moderate- intensity aerobic exercise monotherapy, and the com- bined therapy – demonstrated significant improvements in Johnsen score, Sertoli and Leydig cell counts, and sem- iniferous tubule diameter. When compared to the healthy control group, only telmisartan monotherapy (K2) and combination therapy (telmisartan + exercise, K4) restored Johnsen score, Sertoli and Leydig cell counts, and seminiferous tubule diameter to levels approaching those of healthy controls. Aerobic exercise (K3) improved seminiferous tubule diameter but had limited effects on other parameters. Telmisartan monotherapy was as effective as combination therapy in restoring Johnsen score, normalizing Sertoli and Leydig cell counts, seminiferous tubule diameters in diabetic rats, with both approaches achieving near-com- plete recovery compared to healthy controls. While this study provides valuable insights into the tes- ticular protective effects of telmisartan and aerobic exer- cise, several limitations must be acknowledged. First, the study used a rat model, and caution is required when extrapolating these findings to human clinical contexts. Additionally, fertility-related outcomes, such as sperm quality, fertilization rates, and pregnancy success, were not assessed and should be the focus of future studies. The telmisartan dosage of 6 mg/kg body weight per day, while effective in the rat model, may not be directly trans- latable to human equivalents, necessitating dose opti- mization studies to determine the most appropriate and safe human dosage. The use of Wistar rats, rather than human subjects, lim- its the broader applicability of these findings to clinical populations. Furthermore, the study did not evaluate direct fertility measures, such as sperm quality, sperm retrieval, or pregnancy rates. The relatively high dose of telmisartan administered in this study (6 mg/kg) may also present challenges for potential human application. CONCLUSIONS Both telmisartan and moderate-intensity aerobic exercise, whether individually or combined, offer protective effects against testicular damage in diabetic rats. 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J Peneliti Kesehatan Suara Forikes. 2020; 11:277-82. 22. Chigurupati S, Son TG, Hyun DH, et al. Lifelong running reduces oxidative stress and degenerative changes in the testes of mice. Journal of Endocrinology. 2008; 199:333-41. Correspondence Ali Akbar Firasi aliakbarfirasi@gmail.com Mohammad Ayodhia Soebadi (Corresponding Author) yodisoebadi@gmail.com Soetojo Wirjopranoto s.tojowirjopranoto@yahoo.com Ghazian Adli ghazianadli@gmail.com Department of Urology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia Anny Setijo Rahaju anny_sr@fk.unair.ac.id Department of Anatomical Pathology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia