A Study On The Medication Regularity Of TraditionalChinese Medicine in Treating Benign Prostatic Hyperplasiaand Its Network Pharmacology Ⅱ

2. Overview of Western Medicine Research on Benign Prostatic Hyperplasia (BPH)

2.1 Epidemiology of BPH

BPH is a common disease among middle-aged and elderly men. According to a meta-analysis based on domestic literature, the overall prevalence of BPH in men over 40 years old is 36.6%. The prevalence rates by age group are as follows:

Ages 40–49: 29.0%

Ages 50–59: 29.0%

Ages 60–69: 44.7%

Ages 70–79: 58.1%

Ages 80 and above: 69.2%

The prevalence in urban and rural areas differs, with 41.5% in urban areas and 38.6% in rural areas[^47]. Overall, BPH has a high prevalence in China, and the rate increases significantly with age. The prevalence is higher in urban than in rural areas.

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2.2 Pathogenesis of BPH

2.2.1 Androgens and Their Interaction with Receptors

Androgens are currently recognized as the most important regulators of prostatic growth. The two major androgens are testosterone (T) and dihydrotestosterone (DHT). Among them, DHT is a more potent active metabolite, converted from testosterone by 5α-reductase. In humans, there are two types of 5α-reductase:

Type I: Mainly found in the liver and skin

Type II: Mainly found in the prostate

Studies have shown that Type II 5α-reductase plays a critical role in the development of BPH[^48]. DHT levels in the prostate are significantly higher than in serum, especially in older men. DHT binds with high affinity to androgen receptors (AR) in prostate cells, promoting prostatic epithelial and stromal cell proliferation[^49][^50].

In the 1970s, JD Wilson and others demonstrated that DHT is a key factor in prostatic growth. However, not all elderly men with high DHT levels develop BPH, suggesting that other factors-such as receptor sensitivity and local microenvironment-are also involved[^51][^52]. Studies have found that AR expression does not significantly decline with age, but AR activity and downstream pathways may be altered, affecting the development and progression of BPH[^53].

Estrogens and Receptors

Estrogens also play a role in the pathogenesis of BPH. In aging males, estrogen levels remain relatively stable or even increase, while testosterone levels decline, disrupting the androgen–estrogen balance. Estrogen can act on estrogen receptors (ER) in prostatic tissue, including:

ERα: Promotes proliferation

ERβ: Inhibits growth and induces apoptosis

An imbalance between ERα and ERβ expression may promote BPH development[^54][^55]. Estrogen stimulation may also increase the expression of estrogen response elements (ERE) in prostate cells, activating genes associated with proliferation and inflammation[^56].

2.2.2 Growth Factors

Growth factors are another key group of regulators involved in cell growth, proliferation, differentiation, and migration. Several growth factors are associated with BPH, including:

Fibroblast Growth Factors (FGFs)

Insulin-like Growth Factor (IGF)

Transforming Growth Factor-β (TGF-β)

Epidermal Growth Factor (EGF)

In humans, the FGF family includes 23 subtypes, many of which have been found to stimulate epithelial and stromal cell proliferation in the prostate. Among them:

FGF-2 (basic fibroblast growth factor, bFGF) is highly expressed in the stromal component of BPH

Studies have shown that FGF-2 levels are 2–3 times higher in BPH tissue compared to normal prostate tissue[^65][^66]

Continued research by Roquier and others has further confirmed the role of growth factors in BPH pathogenesis.

2.2.2 Growth Factors (Continued)

FGF-7, also known as Keratinocyte Growth Factor (KGF), is highly expressed in BPH tissues[^67]. FGF-7 promotes the proliferation of epithelial cells derived from the urogenital sinus while having little effect on basal cells. Animal experiments have confirmed that FGF-7 significantly promotes the proliferation of BPH cells[^69]. Studies have also found that FGF-7 expression increases during the early stages of BPH, suggesting its possible role as a major initiating factor. FGF-6 and FGF-9 levels are also elevated in BPH tissues, with FGF-9 showing particularly high expression in stromal tissues, indicating a role in stromal cell proliferation[^70]. Comparatively, FGF-2 shows stronger activity in promoting epithelial cell proliferation[^71]. FGF-10, which is closely related to FGF-7, is also highly expressed in BPH and contributes to epithelial proliferation and prostate hyperplasia[^72].

Insulin-like Growth Factors (IGFs), including IGF-I and IGF-II, are multifunctional growth factors that promote cell proliferation and differentiation. IGF is widely distributed in the prostate and is regulated by androgens. Studies have shown that IGF-I is mainly produced in the prostate stroma, while IGF-II is expressed in both epithelium and stroma[^73]. In addition, IGF Binding Proteins (IGFBPs), especially IGFBP-3 and IGFBP-4, regulate IGF bioavailability and activity[^74]. Aberrations in the IGF/IGFBP axis may promote BPH progression by enhancing IGF signaling or reducing apoptosis.

Transforming Growth Factor-β (TGF-β) is a large family of cytokines involved in cell growth regulation. Among them, TGF-β1 inhibits epithelial proliferation and promotes stromal fibrosis[^78]. TGF-β1 also induces epithelial-to-mesenchymal transition (EMT), contributing to prostate tissue remodeling[^79]. In contrast, TGF-β2 is more associated with inflammatory responses and may further contribute to BPH progression[^84].

In summary, various growth factors and signaling pathways are deeply involved in the pathogenesis of BPH, although their exact regulatory mechanisms remain to be fully clarified.

2.2.3 Inflammatory Factors

BPH is closely associated with chronic inflammation. In a study of 167 BPH patients, 75–90% of prostate tissues showed signs of inflammation. Inflammatory cytokines promote glandular epithelial and stromal hyperplasia, including overexpression of FGF-2 and FGF-21, resulting in increased cellular proliferation and reduced apoptosis[^85][^86].

Studies have identified elevated levels of IL-2, IL-4, IL-7, and IFN-γ in BPH tissues[^88–90]. IL-2 and IL-7 promote epithelial proliferation, while IL-8 can induce basal cell proliferation. Macrophage Inhibitory Cytokine-1 (MIC-1) is also increased in BPH tissues and may promote inflammatory responses. Additionally, COX-2, a key enzyme in prostaglandin synthesis, is upregulated in BPH tissues[^91][^92]. However, the causal relationship between inflammation and BPH progression remains unclear.

2.3 Treatment of Benign Prostatic Hyperplasia

2.3.1 Watchful Waiting

Watchful waiting is a non-invasive management strategy mainly used for patients with mild lower urinary tract symptoms (LUTS), defined as IPSS ≤ 7, or for elderly patients with moderate to severe symptoms (IPSS > 8) who are not suitable for active intervention due to poor general health or personal preference[^93].

2.3.2 Pharmacological Treatment

Pharmacological therapy is the mainstay treatment for patients with moderate to severe LUTS. The goal is to improve symptoms, delay disease progression, and reduce the need for surgical intervention, while maintaining quality of life and minimizing adverse effects.

2.3.2.1 α1-Adrenergic Receptor Blockers

α1-blockers act by relaxing smooth muscle in the prostate and bladder neck, thereby relieving urinary obstruction. They help increase maximum urinary flow rate and reduce residual urine. Common drugs include Tamsulosin, Alfuzosin, Terazosin, Doxazosin, and Silodosin. These medications are the first-line treatment for BPH, especially for patients with dynamic obstruction[^94].

Adverse effects may include dizziness, hypotension, fatigue, or retrograde ejaculation. They are not recommended for patients with significant prostatic enlargement or those with hypotension.

2.3.2.2 5α-Reductase Inhibitors (5-ARIs)

5-ARIs inhibit the conversion of testosterone to DHT, leading to reduced prostate volume and epithelial cell apoptosis. There are two main types:

Finasteride (selectively inhibits Type II 5α-reductase)

Dutasteride (inhibits both Type I and II)

These drugs are particularly effective for patients with enlarged prostate volume (>30 mL) and high DHT levels. They help improve symptoms and reduce the risk of urinary retention and the need for surgery. However, symptom relief may take 3–6 months[^95]. Common side effects include reduced libido, erectile dysfunction, and gynecomastia.

2.3.2.3 M Receptor Antagonists

M receptor antagonists inhibit muscarinic receptors, primarily M2 and M3 subtypes, which help relieve detrusor overactivity and reduce bladder sensitivity, thus alleviating lower urinary tract symptoms (LUTS) in BPH patients. Currently, medications with selectivity for M2 and M3 receptors, such as oxybutynin and tolterodine, are commonly used. These drugs are mostly applied in BPH patients with storage symptoms like urinary urgency, nocturia, and frequent urination, especially when residual urine volume is less than 50 mL. However, they may cause side effects such as dry mouth, dizziness, constipation, blurred vision, and urinary retention. Therefore, M receptor antagonists are not recommended for patients with significant residual urine or urinary retention[^95].

2.3.2.4 PDE5 Inhibitors

Phosphodiesterase type 5 inhibitors (PDE5i) increase intracellular cGMP levels, leading to smooth muscle relaxation, which can reduce lower urinary tract resistance and improve urinary flow. Though originally used for treating erectile dysfunction, evidence from meta-analyses suggests that PDE5i can reduce IPSS and improve erectile function (IIEF) in BPH patients. However, their effect on maximum urinary flow (Qmax) is limited. PDE5i are generally well tolerated, with mild adverse effects such as nasal congestion and flushing[^96].

2.3.2.5 β3-Adrenergic Receptor Agonists

β3-adrenergic receptor agonists act on detrusor smooth muscle β3 receptors to promote relaxation and alleviate overactive bladder (OAB) symptoms. Although primarily used for OAB, they can also benefit BPH patients with irritative symptoms. Common side effects include hypertension, headache, and dry mouth. Caution is advised when used in hypertensive patients[^98].

2.3.2.6 Phytotherapy

Currently used plant-based therapies include Serenoa repens (saw palmetto), Pygeum africanum, Cucurbita pepo (pumpkin seed extract), and Tadenan (African plum extract). These herbal extracts may relieve LUTS, reduce prostate inflammation, and improve QOL to some extent[^99]. Due to their mild effects and low side effect profile, they are suitable for long-term use and for patients with mild symptoms. However, further clinical trials are needed to confirm their efficacy before widespread use in BPH treatment.

2.3.3 Surgical Treatment

Surgery remains the most effective treatment for moderate to severe BPH, especially in patients with complications such as bladder stones, recurrent urinary retention, or upper urinary tract damage. Surgical options include:

Transurethral Resection of the Prostate (TURP)

Transurethral Incision of the Prostate (TUIP)

Holmium Laser Enucleation of the Prostate (HoLEP)

TURP is considered the gold standard for BPH surgery. Minimally invasive techniques such as laser vaporization, microwave ablation, and needle ablation are increasingly used. For patients with prostate volume >80 mL, open or laparoscopic procedures may be applied.

3. Conclusion

Surgery has long been regarded as the most effective treatment for BPH, especially in moderate to severe cases. Although surgical outcomes are positive, risks such as bleeding, urinary retention, reduced sexual function, retrograde ejaculation, infection, and recurrence can occur. Patients with cardiovascular or pulmonary comorbidities may not tolerate surgery well.

Therefore, in mild to moderate cases, medication remains the first-line treatment. Current drugs such as α1-blockers, 5α-reductase inhibitors, and combination therapy have shown good efficacy in alleviating symptoms, delaying disease progression, and reducing the need for surgery. However, some drugs can cause adverse effects such as hypotension, reduced libido, and gynecomastia, which cannot be ignored.

Herbal medicines are widely used in China due to their mild effects and fewer side effects, but their efficacy remains controversial due to a lack of high-quality evidence. Traditional Chinese Medicine (TCM) is a valuable resource, and many TCM-based therapies are rooted in holistic and individualized treatment principles. However, clinical trials on TCM for BPH are limited, and mechanisms of action are still not well understood.

It is necessary to standardize and modernize TCM research, develop evidence-based treatment protocols, and integrate clinical pharmacology and network pharmacology to explore the pharmacodynamics of herbal compounds and active ingredients. This will promote the development of safe, effective, and affordable BPH treatments.