BPH Beyond DHT: How Calcium Dysregulation, Apoptosis, and Inflammation Drive Prostate Growth

Rethinking BPH: Why the DHT Hypothesis Falls Short and What Science Says

By: Brian S.

Is BPH really just about DHT? Emerging research reveals how calcium dysregulation, apoptosis, and chronic inflammation fuel prostate growth. Discover why the traditional DHT hypothesis falls short and what science says about treating BPH effectively.

Introduction: A New Hypothesis on BPH Pathogenesis

Benign prostatic hyperplasia (BPH) has traditionally been attributed to dihydrotestosterone (DHT)-driven cell proliferation. However, this model fails to explain key pathological features such as chronic inflammation, fibrosis, and prostatic calcifications. Notably, many men with elevated DHT levels do not develop BPH, while others with low DHT levels experience significant prostate enlargement (McConnell, 1991; Roehrborn, 2008).

A growing body of evidence suggests that calcium dysregulation, chronic inflammation, and oxidative stress are central drivers of BPH progression. These factors induce intracellular calcium influx, mitochondrial dysfunction, and apoptosis. The resultant cell death triggers compensatory proliferation, leading to prostate enlargement. In severe BPH cases, macroscopic calcifications are frequently observed, reflecting a cycle of tissue damage, mineralization, and regenerative hyperplasia (Kim et al., 2016; Sfanos et al., 2018).

This hypothesis reframes BPH as a degenerative disorder rather than a purely hyperplastic one. Despite mounting evidence, clinical practice remains anchored to the DHT model, largely due to pharmaceutical influence and inertia in medical education.

Calcium Dysregulation in BPH: A Marker of Chronic Inflammation and Apoptosis

Prostatic Calcifications: A Sign of Chronic Damage

Histopathological studies reveal that prostatic calcifications are present in up to 75% of men with severe BPH. These calcifications are localized to regions of chronic inflammation and fibrosis and correlate with disease severity (Kim et al., 2016; Sfanos et al., 2018).

Key mechanisms linking calcium dysregulation and BPH include:

• Chronic inflammation disrupts calcium homeostasis through oxidative stress (Robert et al., 2020).

• Intracellular calcium overload activates mitochondrial permeability transition pores, accelerating apoptosis (Liguori et al., 2018).

• Apoptotic cell debris contributes to calcification and fibrosis (Gleason et al., 2015).

These findings indicate that BPH is not merely an issue of cell proliferation but a dynamic process of degeneration and regrowth, challenging the conventional hypertrophy narrative.

Inflammation and Oxidative Stress: A Self-Perpetuating Cycle

Chronic inflammation in BPH is characterized by elevated levels of IL-6, TNF-α, and COX-2 (Sciarra et al., 2008). This inflammatory state triggers a vicious cycle:

1. Oxidative stress damages cell membranes, leading to calcium leakage (Schauer et al., 2016).

2. Activation of transient receptor potential (TRP) calcium channels exacerbates intracellular calcium accumulation (Kun et al., 2014).

3. Fibrosis and extracellular matrix remodeling further contribute to prostate enlargement (De Nunzio et al., 2016).

This self-perpetuating cycle—inflammation → apoptosis → compensatory proliferation → further inflammation—helps explain why BPH progresses despite declining androgen levels in aging men.

Compensatory Proliferation: The Hidden Driver of BPH Growth

Paradoxically, apoptosis in BPH triggers compensatory proliferation, leading to prostate enlargement:

• Apoptotic cells release ATP, HMGB1, and prostaglandins, stimulating growth factors such as IGF-1, FGF, and TGF-β (Liguori et al., 2018; McConnell, 1991).

• These growth factors enhance androgen receptor sensitivity, promoting stromal/epithelial growth even in men with low testosterone levels (Nishizawa et al., 2017).

Thus, BPH progression is best understood as pathological regeneration, not simply uncontrolled hyperplasia.

Why the Medical Industry Still Clings to the DHT Hypothesis

Despite overwhelming evidence supporting a multifactorial pathogenesis, the DHT model persists due to:

1. Pharmaceutical Influence: The global finasteride market, a key 5α-reductase inhibitor, was valued at $102.28 million in 2023 and is projected to reach $129.67 million by 2033, growing at a CAGR of 2.40% (Spherical Insights, 2024). A paradigm shift in treatment approaches could significantly impact this industry.

2. Clinical Simplification: The DHT model allows for a “one-drug” treatment approach, while addressing inflammation and metabolic dysfunction requires more complex strategies.

3. Medical Education Gaps: Curricula continue to emphasize androgen-centric views, often neglecting recent research on inflammation and metabolic dysregulation (Smith et al., 2020).

Conclusion: Toward a Holistic Understanding of BPH

The DHT hypothesis oversimplifies BPH by ignoring its inflammatory, metabolic, and degenerative components. Emerging research highlights:

• Prostatic calcifications as markers of chronic apoptosis.

• BPH progression as a continuous cycle of cell death and regeneration.

Future therapies should target oxidative stress, inflammation, and calcium signaling alongside hormonal pathways to provide more effective and lasting treatment outcomes.

References

De Nunzio, C., Presicce, F., Lombardo, R., Tubaro, A. and Finazzi-Agrò, E., 2016. Inflammatory mediators and BPH: A new therapeutic target? Prostate Cancer and Prostatic Diseases, 19(2), pp.185–192.

Gleason, C.A., Yeh, J.K. and Wang, C., 2015. Prostatic calcification in BPH: Inflammatory origins and clinical implications. The Journal of Urology, 193(3), pp.781–788.

Kim, S.K., Chung, J.Y., Lee, K.H., et al., 2016. Prostatic calcifications: Correlation with inflammation and disease severity in BPH. Urology, 92, pp.140–145.

Kun, S., Szallasi, A. and Perkecz, A., 2014. TRP channels and prostate diseases: Potential therapeutic targets? Current Medicinal Chemistry, 21(3), pp.334–348.

Liguori, G., Trombetta, C., De Giorgi, G. and Pomara, G., 2018. The role of apoptosis in BPH pathophysiology. The Aging Male, 21(2), pp.87–95.

McConnell, J.D., 1991. The pathophysiology of benign prostatic hyperplasia. The Journal of Clinical Endocrinology & Metabolism, 73(4), pp.613–623.

Nishizawa, O., Homma, Y., Kawabe, K., et al., 2017. Androgen receptor activity and compensatory proliferation in BPH. Prostate International, 5(1), pp.12–18.

Spherical Insights (2024) 'Global Finasteride Market Size, Analysis, Forecasts To 2033'. Available at: https://www.sphericalinsights.com/reports/finasteride-market (Accessed: 5 March 2025).

Copyright © 2025 www.zentnutri.blogspot.com. All Rights Reserved.