Introduction

Benign prostatic hyperplasia (BPH) stands as one of the most prevalent urological conditions in aging men, affecting nearly half of individuals over the age of 50 and up to 90% by age 80. Although benign by definition, its clinical manifestations—lower urinary tract symptoms (LUTS), nocturia, increased post-void residual volume, and reduced urinary flow—substantially impair quality of life. Traditionally, the therapeutic arsenal against BPH has centered on α-blockers and 5-α-reductase inhibitors, each improving symptoms through distinct mechanisms involving smooth muscle relaxation and hormonal modulation, respectively.
But as the understanding of prostatic biology evolves, so does recognition that BPH is not merely a disease of androgens and prostate volume. Inflammation, oxidative stress, pelvic ischemia, and cyclic nucleotide signaling increasingly appear to shape its pathology.

The study under review presents a compelling and somewhat unconventional inquiry: can sildenafil citrate, a phosphodiesterase-5 (PDE5) inhibitor best known for its vascular effects in erectile dysfunction, mitigate the structural and biochemical alterations in a testosterone-induced rat model of BPH?

This question stems from emerging evidence that PDE5 is expressed in prostatic smooth muscle and may influence stromal proliferation, intracellular calcium dynamics, oxidative stress responses, and stromal–epithelial crosstalk. Functional PDE5 inhibition therefore has the potential to extend beyond penile hemodynamics into the domain of prostatic pathophysiology.

Here we analyze the scientific rationale, methodological integrity, biochemical findings, histological evidence, and broader implications of the study. The result is a comprehensive exploration of how sildenafil may influence prostate biology in a context of androgen-induced hyperplasia.

Testosterone-Induced BPH: Understanding the Experimental Model

To interpret the findings meaningfully, one must examine the biological model used in this study. The authors induced BPH in adult male rats using exogenous testosterone, a well-established method for experimentally reproducing prostatic hyperplasia. According to the PDF (pages 2–3), daily subcutaneous injections of testosterone effectively increased prostate weight, glandular proliferation, and histological markers of hyperplasia.

This model mirrors several key features of human BPH:

enhanced androgenic signaling
stromal and epithelial proliferation
increased oxidative stress
elevated inflammatory mediators

Table 1 (page 4) shows that testosterone treatment led to a significant increase in prostate weight and prostate weight index, validating successful induction of hyperplasia.

Although rat prostate anatomy differs from that of humans—being lobulated and distinctly more sensitive to hormonal perturbation—the model remains widely accepted for preclinical evaluation of anti-BPH agents.

Why Sildenafil? The Rationale Beyond Erectile Physiology

The choice of sildenafil is grounded in well-documented physiological principles. PDE5 is expressed not only in penile smooth muscle but also in the:

bladder
prostate
lower urinary tract vasculature
pelvic floor musculature

In the prostate specifically, PDE5 influences smooth muscle contractility and intracellular cyclic guanosine monophosphate (cGMP) levels. Since prostatic obstruction in BPH arises partially from dynamic smooth muscle tone, PDE5 inhibition has the theoretical potential to reduce resistance at the bladder outlet.

But the authors investigate a deeper dimension: whether sildenafil can attenuate the structural progression of BPH itself. This idea is supported by research showing that cyclic nucleotide signaling modulates proliferation, apoptosis, vascular perfusion, and nitric oxide bioavailability—all processes dysregulated in hyperplastic prostates.

Thus, the study’s hypothesis is neither accidental nor speculative—it is grounded in molecular reasoning that PDE5 inhibition may influence BPH pathology at multiple levels.

Study Design and Methodology: A Solid Experimental Foundation

According to the methodology section (pages 2–3):

Rats were divided into three groups: control, testosterone-induced BPH, and testosterone + sildenafil.
Testosterone induced hyperplasia over four weeks.
Sildenafil was administered orally at a therapeutic dose relevant to rodent physiology.
Biochemical assays included measurements of oxidative stress markers: malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH).
Histological evaluation employed H&E staining to assess architecture, glandular proliferation, and stromal hypertrophy.

This combination of morphologic and molecular endpoints provides a robust evaluation of sildenafil’s impact beyond simple prostate weight reduction.

Effects on Prostate Weight and Gross Morphology

Sildenafil administration significantly reduced prostate weight compared to the testosterone-only group. The PDF’s Table 1 (page 4) shows:

The testosterone group had markedly increased prostate weight.
The sildenafil-treated group exhibited a noticeable reduction in both absolute and relative prostate weight index.

The magnitude of reduction is biologically meaningful: sildenafil reversed roughly one-third of the testosterone-induced weight gain. While not restoring prostate size to control levels, the attenuation signifies a genuine anti-hyperplastic effect.

Gross examination of excised prostates (page 5 images) supports these quantitative findings. Testosterone-treated glands appear enlarged, congested, and more lobulated compared to the smoother, less engorged organs of sildenafil-treated rats.

Oxidative Stress and Antioxidant Capacity: A Biochemical Turning Point

BPH pathology is tightly linked to chronic oxidative stress. Elevated reactive oxygen species (ROS) promote proliferation, decrease apoptosis, activate inflammatory cascades, and impair nitric oxide bioactivity.

The study’s biochemical assays (Table 2, page 6) reveal a striking pattern:

MDA, a marker of lipid peroxidation, was significantly elevated in the testosterone-treated group—confirming oxidative damage.
SOD and CAT activity were significantly reduced in testosterone-treated rats, demonstrating compromised enzymatic antioxidant defense.
GSH, a non-enzymatic antioxidant vital for redox homeostasis, was depleted.

Sildenafil administration reversed all these abnormalities:

MDA levels decreased markedly.
SOD and CAT activities rebounded toward control levels.
GSH content increased significantly.

These results are biologically meaningful, suggesting sildenafil exerts antioxidant effects in prostatic tissue.

Possible mechanisms include:

enhanced nitric oxide signaling → reduced ROS accumulation
increased cGMP → modulation of protein kinase G → reduced NADPH oxidase activity
improved pelvic blood flow → decreased ischemia-induced oxidative stress

The oxidative stress data provide strong mechanistic support for sildenafil’s protective effects on prostate tissue.

Histological Findings: Sildenafil Normalizes Prostatic Architecture

The histopathological analysis (pages 7–8) provides some of the most visually compelling evidence of sildenafil’s impact.

Testosterone-Only Group

Microscopic examination shows:

hypertrophied epithelial cells
papillary infoldings protruding into the lumen
crowded glands with reduced luminal space
increased stromal cellularity

These features confirm active hyperplasia.

Sildenafil-Treated Group

Sildenafil treatment markedly improved architecture:

epithelial heights appeared closer to normal
glandular arrangement was more regular
stromal overgrowth was significantly reduced
luminal spaces appeared wider and more uniform

The authors’ photomicrographs visually demonstrate this normalization, with sildenafil-treated tissues exhibiting far fewer proliferative distortions.

Notably, sildenafil did not produce atrophy or apoptotic collapse of prostate tissue; rather, it countered pathological proliferation without damaging normal glandular integrity.

Mechanistic Insights: Why Sildenafil Modulates BPH Progression

Based on the study’s findings and broader literature in urological and endocrine physiology, several mechanistic explanations emerge.

1. Reduction of Oxidative Stress

By restoring antioxidant enzyme activity and lowering lipid peroxidation, sildenafil disrupts the ROS–proliferation cycle that fuels hyperplastic growth.

2. Improved Prostatic Perfusion

PDE5 inhibition enhances blood flow not only in penile tissue but also in the prostate. Better perfusion reduces tissue hypoxia—a known stimulus for stromal expansion in BPH.

3. Modulation of Intracellular Signaling

Enhanced cGMP levels may:

inhibit smooth muscle proliferation
reduce intracellular calcium
modulate growth factor expression
regulate stromal–epithelial communication

These pathways are central to BPH pathogenesis.

4. Anti-inflammatory Effects

Although inflammation markers were not directly measured in the study, sildenafil’s known microvascular effects likely reduce inflammatory infiltration.

Collectively, these mechanisms align with the structural and biochemical improvements observed in the study.

Comparisons With Standard BPH Therapies

While this study does not directly compare sildenafil with α-blockers or 5-α-reductase inhibitors, it is possible to contextualize the results.

α-blockers primarily reduce smooth muscle tension; they do not shrink the prostate or reduce oxidative stress.
5-α-reductase inhibitors shrink prostate volume but require months to work and often cause sexual side effects.
Sildenafil appears to offer a hybrid benefit—functional improvement via smooth muscle relaxation plus structural improvement via anti-oxidative and microvascular effects.

Although sildenafil may never replace standard BPH therapies, it may complement them, especially in patients with concomitant erectile dysfunction.

Strengths and Limitations of the Study

Strengths

Clear induction of BPH via testosterone.
Comprehensive biochemical assays.
High-quality histopathological evaluation.
Mechanistically coherent findings.

Limitations

Animal results may not directly translate to humans.
Sildenafil dosing does not reflect chronic human use.
Molecular markers of proliferation (Ki-67, PCNA) were not measured.
No functional urinary parameters (flow rate, voiding patterns) were assessed.

Nonetheless, the study provides a compelling foundation for further research.

Implications for Future Research

This work opens several important avenues:

Clinical trials combining PDE5 inhibitors with standard BPH therapies.
Investigation of sildenafil’s anti-inflammatory and anti-fibrotic effects in prostate tissue.
Exploration of cGMP signaling as a broader therapeutic target in BPH.
Long-term studies on LUTS outcomes in human populations using PDE5 inhibitors chronically.

The translational potential is real: PDE5 inhibitors are already widely used, safe, and well-tolerated—making them strong candidates for repurposing.

Conclusion

The study “Effect of sildenafil citrate in testosterone induced benign prostate hyperplasia rat model” provides robust evidence that sildenafil exerts significant protective and modulatory effects in androgen-induced BPH. Through a combination of oxidative stress reduction, improved tissue perfusion, normalization of histoarchitecture, and attenuation of prostate enlargement, sildenafil demonstrates potential beyond its established role in erectile physiology.

While caution is necessary when extrapolating animal findings to human pathology, the mechanistic plausibility and therapeutic accessibility of sildenafil make it an exciting candidate for further exploration in BPH management. As our understanding of prostate biology evolves, so too must our willingness to reconsider drugs whose mechanisms extend well beyond their original clinical indication.

FAQ

1. Does sildenafil actually shrink the prostate in BPH?

In this rat model, sildenafil significantly reduced prostate weight and counteracted testosterone-induced hyperplasia. It may not “shrink” the prostate in the same way as finasteride, but it meaningfully attenuates pathological enlargement.

2. How does sildenafil help the prostate?

It reduces oxidative stress, improves microvascular perfusion, and modulates intracellular signaling that influences proliferation and stromal hypertrophy.

3. Could sildenafil be used clinically to treat BPH?

Not as a monotherapy—not yet. But evidence suggests it may complement standard therapies, especially in men with both BPH and erectile dysfunction, and may one day serve as part of a multi-targeted therapeutic strategy.