A scoping review of the role of heritability and environmental exposures in the development and severity of benign prostatic hyperplasia

Abstract

Background

Benign prostatic hyperplasia (BPH) is a common condition among aging men, significantly affecting quality of life and contributing to a substantial healthcare burden. The pathogenesis of BPH is strongly influenced by genetic factors, with heritability estimates showing a wide range from 20% to 83%. Emerging evidence also highlights the critical role of environmental exposures, including endocrine-disrupting chemicals (EDCs), in BPH risk, progression, and therapeutic response. This review synthesizes current knowledge on genetic and environmental determinants of BPH pathogenesis, severity, and management.

Methods

A scoping review of the literature was conducted using the databases PubMed, Scopus, and Web of Science. Relevant studies on genetic predisposition, environmental exposures, and their contributions to BPH were analyzed. Data from epidemiological studies, genome-wide association studies (GWAS), familial aggregation analyses, and research on environmental exposures were integrated to provide an understanding of these factors and BPH pathogenesis.

Results

Familial clustering indicates a significantly elevated risk, particularly among first-degree male relatives. Key genetic determinants include androgen receptor (AR) gene CAG repeat polymorphisms, where shorter repeats are linked to increased AR activity and prostate enlargement. Estrogen pathway genes, such as ESR1 and CYP19A1, and variants in dihydrotestosterone (DHT) synthesis genes, notably SRD5A2, influence disease progression and risk. GWAS have identified additional loci, such as MSMB and TERT, associated with prostate volume and aggressive BPH phenotypes. Polygenic risk scores offer promising applications in identifying individuals at high risk for severe BPH. Environmental exposures, particularly to EDCs such as bisphenol A (BPA), bisphenol S (BPS), and bisphenol AF (BPAF), were found to disrupt hormonal regulation, contributing to prostatic hyperplasia. Air pollution, primarily particulate matter, exacerbates prostate inflammation and hyperplasia, with regional differences in BPH symptom severity correlating with air quality. Lifestyle factors, including high-fat diets and sedentary behaviors, further modulate disease severity.

Conclusions

The development and progression of BPH are shaped by a complex interplay of genetic and environmental factors. EDCs contribute significantly to prostatic hyperplasia, while heritable factors influence disease onset, severity, and response to treatment. Integrating genetic risk profiling and environmental exposure assessments into clinical practice holds the potential to enhance BPH management and personalized therapeutic strategies.

Highlight box.

Key findings

• This review reveals that benign prostatic hyperplasia (BPH) development and progression are significantly influenced by a complex interplay of heritable genetic factors and environmental exposures. Key genetic determinants include polymorphisms in androgen and estrogen pathways, while environmental factors such as endocrine-disrupting chemicals (EDCs) (e.g., bisphenols, phthalates) and air pollution (e.g., particulate matter, nitrogen/sulfur oxides) contribute substantially to prostatic hyperplasia by disrupting hormonal balance and exacerbating inflammation.

What is known and what is new?

• It is known that BPH is a common urological condition in aging men, with aging and overall health being established contributors.

• This scoping review adds a synthesized understanding of how a wide array of genetic variants {including those in AR, SRD5A2, ESR1, CYP19A1, MSMB, TERT genes and findings from genome-wide association studies alongside specific EDCs [like bisphenol A, bisphenol S, bisphenol AF, and di-(2-ethylhexyl) phthalate]} influence BPH pathogenesis, severity, and potentially therapeutic responses.

What is the implication, and what should change now?

• The findings underscore the need to consider both genetic predispositions and environmental exposure histories in the clinical assessment and management of BPH. Future research should focus on the detailed interplay between these factors. Clinically, integrating genetic risk profiling and environmental exposure assessments could lead to earlier detection, targeted prevention strategies, and more personalized therapeutic interventions for BPH.

Introduction

Benign prostatic hyperplasia (BPH) is the most common urological disorder affecting males (1). Histologically, BPH refers to the nonmalignant proliferation of stromal and epithelial cells within the prostate’s transition zone, primarily driven by androgens, particularly dihydrotestosterone (DHT) (2,3). Progressive prostate enlargement is a major contributor to lower urinary tract symptoms (LUTS), with larger prostates being strongly associated with a higher risk of acute urinary retention, an increased likelihood of requiring pharmacotherapy [alpha-adrenergic blockers, 5-alpha reductase inhibitors (5ARI), phosphodiesterase-5 inhibitors], minimally invasive treatments, and surgical interventions (4,5).

The risk of BPH significantly increases with age, typically manifesting around 40 years old and becoming progressively more common (6). Previous investigations suggest that prostate size increases in older males by 2–2.5% each year, leading to drastic increases in the prevalence of BPH signs with increasing age (7). Recent findings indicate that the prevalence of clinical BPH begins to rise after age 40, ranging from 8% to 60% by the age of 90 (8).

Rising BPH prevalence is a global as well as a national issue. The reported prevalence of BPH in the USA has increased significantly between 1998 and 2007, with the number of cases nearly doubling during this period (9). Worldwide, the number of BPH cases has increased from 51.1 million in 2000 to 94.0 million in 2019 based on data from 204 countries and territories (10). As the global population ages, the proportion of individuals over 65 is projected to rise from 9.06% (680 million) in 2018 to 17% (1.6 billion) over the next 30 years (10,11).

Analyzing BPH-specific medical costs based on 2006–2012 Medicare claims data revealed that 61.1% of men over 65 used alpha-blocking medication. When multiplied by the global population of 303,788,086 men over 65 years, this equates to 185,614,521 men on this common medical therapy for BPH/LUTS, resulting in fee-for-service costs of $73.8 billion per year (12).

Despite its prevalence and costs, the exact mechanisms underlying BPH remain unclear, and current medical treatments are not always effective. BPH is a multifactorial and complex disease with genetic inheritance, environmental exposures and lifestyle choices all contributing to disease development and progression and potential need for treatment (13-16). The development of BPH can be described by a “two-hit hypothesis”, which provides a compelling framework for understanding its multifactorial nature. In this model, an individual’s genetic predisposition acts as the “first hit”, creating a susceptibility to the disease. Environmental exposures and lifestyle choices, encountered throughout life, then serve as the “second hit”, triggering or accelerating the prostatic cell proliferation that leads to symptomatic BPH (1,13-16).

This scoping review aims to investigate recent literature on the heritability and genetic patterns of BPH, as well as the impact of environmental exposures on its development, severity, and prognosis. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-342/rc).

Methods

A comprehensive literature search was performed using the PubMed, Scopus, and Web of Science databases. The search was limited to peer-reviewed articles and did not extend to grey literature (e.g., conference proceedings, dissertations) or preprints. The search was restricted to English-language articles, a decision made due to resource limitations for translation, with a publication date from 1970 to January 01, 2025. This broad date range was chosen to capture foundational literature, such as early familial aggregation studies. We included original research on human or animal models that examined the association between genetic or specific environmental factors [endocrine-disrupting chemicals (EDCs), air pollution] and BPH. We excluded editorials, commentaries, studies focused solely on prostate cancer without relevance to BPH, and articles where the specified BPH link was not a primary or secondary outcome. No direct contact with authors to identify additional sources was made for this initial scoping review.

The search strategy combined Medical Subject Headings (MeSH) terms and keywords related to BPH, genetic variants, and environmental disruptors. An example of the full electronic search strategy for PubMed for the “Endocrine-disrupting chemicals” subsection is as follows: ((“chemicals”[MeSH Terms] OR “endocrine disrupting”[MeSH Terms]) OR “endocrine disrupting chemicals”[All Fields] OR “EDCs”[All Fields]) AND ((“benign prostatic hyperplasia”[MeSH Terms] OR “benign prostatic hyperplasia”[All Fields] OR “BPH”[All Fields]) OR (“lower urinary tract symptoms”[MeSH Terms] OR “lower urinary tract symptoms”[All Fields] OR “LUTS”[All Fields])) AND (“1970”[Date-Publication]: “2025”[Date-Publication]).

Similar structured searches were adapted and executed across Scopus and Web of Science. Titles and abstracts of studies retrieved from the database searches were screened for relevance by 2 independent reviewers. Discrepancies were resolved through discussion or by a third reviewer. Full-text articles of potentially relevant studies were then retrieved and assessed for eligibility based on the predefined inclusion and exclusion criteria.

Results

Heritability of BPH and key genetic variants linked to BPH

Previous studies have underscored the significant role of genetic factors in clinical BPH severity and development. Family members of men with severe BPH who underwent prostatectomy before the age of 65 years showed a fourfold increased risk of prostatectomy for BPH, with the risk being six times higher in the brothers of these patients (17). These investigators further revealed that over half of severe BPH resulted in early prostatectomy and had a heritable form of the disease, which is classified as familial BPH, defined as having 3 or more family members with a diagnosis of BPH. In a follow-up study, they revealed that familial BPH was linked to larger prostate volumes and an earlier age of onset compared to sporadic cases (14). Single-nucleotide polymorphism (SNP)-based heritability estimates suggest that approximately 60% of the phenotypic variation in BPH is accounted for by genetic factors (18).

Twin studies also suggest a significant genetic influence on BPH and related conditions, estimating that genetics may account for 20–40% of the variation in LUTS (19), with some estimates reaching as high as 72% (20). However, heritability estimates vary across different LUTS. For instance, straining exhibits the strongest genetic effect with a heritability of 40%, while nocturia has the lowest heritability at 21% (19). This variability suggests that while LUTS are interconnected, they may have distinct etiologies influenced by both genetic and environmental factors.

The wide range in these heritability estimates can be attributed to key methodological differences, including the diversity of the study populations, the statistical models used, and the specific diagnostic criteria for BPH or LUTS being investigated. For example, heritability for a clear clinical outcome like requiring a prostatectomy may differ significantly from subjective and self-reported symptoms.

Genetic variations in steroid hormone pathways

The study of genetic factors related to BPH began by examining individual candidate genes and known gene pathways to identify meaningful changes associated with the incidence and severity of the condition. Among these genes, the androgen receptor (AR) gene has been the most extensively studied due to its critical role in androgen-dependent prostate development and growth. Multiple studies over the past few decades have identified distinct variations in the AR gene across ethnically diverse populations and have attempted to develop a meaningful algorithm to understand the impact of these variations on BPH risk, progression, and response to therapy (21,22).

Polymorphisms in exon 1 of the AR gene, including variations in CAG, CGG, and GGN repeat lengths, have been extensively studied for their potential role in BPH (23). In particular, the (CAG)_n microsatellite has been extensively examined. In vitro and in vivo studies have shown enhanced AR transactivation activity with shorter CAG repeat lengths, leading to increased AR activity in the prostate (24-26). This increased activity has been linked to greater prostate volume, as individuals with a CAG repeat length of fewer than 21 exhibit a higher likelihood of prostate enlargement (27,28). Several human studies have also reported significant associations between shorter CAG repeats and higher risk for and severity of BPH, including a greater likelihood of surgical intervention (29). However, recent studies with larger cohorts have reported inconsistent and controversial findings, highlighting the complexity of BPH as a disease process that is unlikely to have monogenic underpinnings (30,31). These discrepancies may be attributed to several factors, including differences in study design, insufficient statistical power in some earlier studies, and the ethnic diversity of the cohorts examined. Different populations exhibit distinct distributions of CAG repeat lengths and may possess other modifying genetic or environmental factors that influence the clinical effect of AR activity. Furthermore, inconsistent definitions of BPH across studies (e.g., clinical diagnosis vs. prostate volume) likely contribute to the conflicting results, underscoring the complexity of this genetic association.

Five-alpha reductase, encoded by the SRD5A gene, plays a critical role in the metabolism of testosterone into DHT. DHT is a potent androgen essential for prostate growth and development (32). Variations in the genes responsible for these enzymes, particularly SRD5A1, SRD5A2, and SRD5A3, have been studied for their potential links to BPH (33,34).

Previous studies demonstrated that almost one-third of healthy adult prostatic samples do not express SRD5A2. In addition, polymorphisms in SRD5A2, including V89L and A49T variants, have been associated with altered enzyme activity, leading to reduced DHT production, which may lower the risk or slow the progression of BPH (33,34).

However, the studies on the association between SRD5A variants and BPH across different countries remain controversial. A comprehensive meta-analysis, incorporating studies from PubMed, Embase, Wanfang, and the Chinese National Knowledge Infrastructure databases, examined the association between SRD5A2 V89L and A49T polymorphisms and BPH risk. The analysis revealed that the A49T polymorphism is significantly associated with an increased risk of BPH, particularly among Caucasians. In contrast, the V89L polymorphism exhibited ethnic-specific effects, with a potentially protective role in Caucasians but an increased risk in other populations (35). A study of Korean males reported that a shorter AC tandem repeat (<21 copies) in the SRD5A3 gene, combined with a shorter CAG repeat length (<23 copies) in the AR gene, was associated with an increased risk of BPH (36). However, studies conducted in Caucasian and other non-Asian populations have reported no significant association between these polymorphisms and BPH risk, highlighting ethnic and population-specific variations in genetic susceptibility (35,37-39).

Polymorphisms in estrogen receptor (ESR) genes, particularly ESR1 and ESR2, have also been investigated for their potential role in the pathogenesis of BPH (40). These genetic variations may influence the activity of ESRs, thereby modulating prostate tissue growth and development. Certain ESR1 polymorphisms, such as PvuII and XbaI, have been associated with an increased risk of BPH in some studies, though findings remain inconsistent across different populations (41). PvuII and XbaI polymorphisms occur in intron 1 of the ESR1 gene, a region containing regulatory elements such as promoters and enhancers. PvuII polymorphism involves a change in the T allele, which increases the transcriptional activity of ESR1, potentially affecting prostate tissue growth. The impact of XbaI on ESR1 activity remains unclear, though its proximity to PvuII suggests a possible interaction or regulatory effect on gene expression (41). Similarly, polymorphisms in ESR2, which encodes ESR beta, a receptor thought to have a protective role in the prostate, have yielded mixed results regarding their association with BPH (42).

CYP17 and CYP19 are key genes involved in steroidogenesis, influencing androgen and estrogen biosynthesis. Given that hormonal regulation plays a significant role in prostate growth, these genes have garnered attention for their potential involvement in the development of BPH and other prostate diseases (43). The CYP17A1 gene encodes 17α-hydroxylase/17,20-lyase, which is crucial in both the androgen and estrogen synthesis pathways (44). Polymorphisms in the CYP17A1 gene, particularly the GG genotype of the rs743572 SNP, have been linked to an increased risk of BPH, metabolic syndrome, and metabolic syndrome-associated BPH (45). Polymorphisms in CYP19, such as variations in the length of (TTTA) repeats in intron 4, have been reported in several investigations (46-50). A recent study by Yang et al. on prostate tissue from men with BPH revealed that men with accelerated progressive BPH exhibited higher expression of CYP19 and G protein-coupled estrogen receptor (GPER), leading to increased estrogen biosynthesis (51).

Hydroxysteroid dehydrogenase (HSD) enzymes, such as HSD17B2, play a critical role in regulating steroid hormone activity by primarily converting potent hormones like estradiol (E2) into less active forms, thereby modulating local estrogenic effects. Studies have also highlighted associations between the ESR1, ESR2, and HSD17B2 genes with BPH, along with CYP19A1, further suggesting that alterations in estrogen signaling and steroid biotransformation, driven by cytochrome P450 (CYP) and HSD enzymes, can be key factors in the development and progression of BPH (52).

Inflammation, extracellular matrix (ECM), and cellular remodeling

Inflammation contributes to the hyperplastic changes in the prostate by stimulating the proliferation of stromal and epithelial cells. The interaction between inflammatory cells and prostate cells creates a microenvironment that supports continued growth and abnormal tissue remodeling (53). Moreover, inflammation can lead to oxidative stress, further exacerbating cellular injury and contributing to the pathogenesis of BPH (54). Inflammation also plays a negative role in BPH outcomes. A study by Cakir et al. on clinical outcomes in patients undergoing transurethral resection of the prostate (TURP) for BPH revealed that patients with prostate inflammation at the time of surgery had worse preoperative symptoms and urinary flow rates and experienced less improvement after surgery compared to those without inflammation (55).

Histopathological studies have identified significant fibrosis and increased ECM production as key factors contributing to symptom persistence and impaired urinary function in men with LUTS (56). The MSMB gene encodes a microseminoprotein-beta protein primarily expressed in the prostate, believed to regulate prostate growth and function. Polymorphisms in MSMB have been linked to conditions like BPH and prostate cancer. A study analyzing promoter region SNPs in MSMB found that the rs12770171 (−184C/T) polymorphism was significantly more prevalent in patients with clinical BPH compared to unaffected controls (57).

Fan et al. investigated the association between specific SNPs of the telomerase gene (TERT) and the risk of clinical BPH in a Chinese Han population. The study found no direct correlation between the studied SNPs and overall BPH risk. However, four haplotypes (TCTGGT, TCTGTC, TGCCTC, and TGTGTC) were identified as risk factors for BPH development. Additionally, the SNP rs2853669 was highlighted as an independent risk factor for smooth muscle hyperplasia in the prostate. Furthermore, rs2736100, rs10078761, and rs10069690 were found to be associated with the severity of BPH symptoms (58).

Inflammatory cytokines, such as transforming growth factor-beta 1 (TGF-β1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), play pivotal roles in promoting the activation of fibroblasts and the deposition of ECM components. Several signaling pathways are involved in the fibrotic response in BPH. TGF-β1 signaling is particularly important, as it stimulates fibroblast proliferation and differentiation into myofibroblasts, leading to increased collagen synthesis. Afdal et al. investigated the expression of IL-6 and TGF-β1 in prostate hyperplasia and prostate cancer tissues. The outcomes showed that TGF-β1 expression was significantly higher in the stromal component of tissues from men with prostate hyperplasia than men those with prostate cancer (59). Variations in the TGF-β1 gene can influence its expression and activity within prostate tissue. The codon 10 polymorphism in the TGF-β1 gene, specifically the C/T polymorphism at nucleotide position 10 (rs1800470), is of particular interest in the context of BPH (60,61).

Kim et al. investigated the relationship between clinical features of BPH and genetic polymorphisms in epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) genes (62). Significant associations between specific SNPs in the EGF gene (rs11568943, rs11569017) and prostate volume, as well as between SNPs in both EGF and EGFR genes with prostate-specific antigen (PSA) levels, were observed (62).

Furthermore, Pang et al. investigated the association between three polymorphisms in chemokine genes—CCL2, CCR2, and CCL5—and the risk of BPH in patients and controls (13). Chemokines and their receptors are crucial mediators of inflammation and immune responses, processes that contribute to BPH pathogenesis. The study found that the CCL5 rs2107538 polymorphism was associated with a significantly lower risk of developing BPH, but it was also linked to larger prostate volumes, suggesting that CCL5 may influence prostate enlargement and tissue remodeling. In contrast, the CCR2 rs1799864 polymorphism was associated with lower International Prostate Symptom Scores (IPSS) and higher urinary flow rates (Q_max), indicating that CCR2 may help alleviate symptoms and improve urinary function in BPH patients. No significant association was observed between the CCL2 rs1024611 polymorphism and BPH (13).

Vitamin D receptor (VDR) gene

There are several lines of evidence suggesting a potential role of vitamin D in the development of BPH. Vitamin D is essential for numerous physiological processes, and its bioactivity is influenced by genetic variations within the VDR gene and related metabolic pathways (63,64). Several key polymorphisms have been identified in the VDR gene that can affect individual responses to vitamin D and may have implications for various health conditions, including BPH.

Notable polymorphisms include Fok-1 (rs2228570), a C>T substitution thought to alter transcriptional activity. The T allele has been linked conceptually to a reduced vitamin D response, potentially impacting inflammatory processes relevant to prostate health (50,65). However, evidence linking Fok-I directly to BPH risk is inconsistent; a meta-analysis encompassing 10 studies (1,539 BPH cases, 1,915 controls) reported significant heterogeneity across studies for this polymorphism (66). In contrast, the same meta-analysis found that the TaqI polymorphism (rs731236, T/C) was significantly associated with an increased risk of BPH across multiple genetic models. Furthermore, an association between the Bsm-I polymorphism and BPH risk was identified specifically within Caucasian and Asian populations (66). A case-control study involving 174 Iraqi men with BPH and 171 healthy controls found that those with BPH had significantly lower serum vitamin D levels compared to the control group (mean 7.67 vs. 34.97 ng/mL). Analysis of four VDR gene polymorphisms within this cohort revealed that specific SNPs in non-coding regions (rs3782905 C/G, rs1544410 G/A, rs7975232 A/C) were significantly associated with these decreased vitamin D levels. In contrast, the coding region SNP rs731236 (TaqI, T/C) showed no significant association in this analysis (67).

In summary, VDR gene variants are implicated in BPH susceptibility. Some polymorphisms appear directly associated with disease risk, while others may exert influence indirectly by affecting vitamin D levels. However, specific findings often vary depending on the SNP and population studied (Table 1).

Table 1. Genetic polymorphisms associated with BPH risk and severity: summary of candidate gene studies investigating polymorphisms in androgen/estrogen pathway genes and their associations with BPH development, progression, and treatment outcomes.

Author, year	Study type	Population/ethnicity	Evaluated genes	Summary of findings
Giovannucci et al., 1999 (29)	Human trial	USA	AR	Shorter CAG repeats linked to higher BPH severity and increased likelihood of surgical intervention
Zhang et al., 2017 (50)	Human epidemiological study	Northern Chinese	VDR	T allele of Fok-1 (rs2228570) associated with reduced vitamin D response, influencing prostate health and inflammatory processes
Roberts et al., 2004 (27)	Human prospective study	USA (Minnesota)	AR	Shorter CAG repeats lengths enhance AR activity, leading to increased prostate volume
Soni et al., 2012 (28)	Human epidemiological study	North Indian	AR	AR polymorphisms associated with prostate cancer and BPH in North Indian populations
Ruan et al., 2015 (65)	Human epidemiological study	Chinese	VDR	Fok-1 polymorphism associated with clinical progression of BPH
Zeng et al., 2017 (35)	Human epidemiological study	Caucasian	SRD5A2	A49T polymorphism significantly increases BPH risk in Caucasians, while V89L has ethnic-specific effects
Lee et al., 2016 (36)	Human epidemiological study	Korean	SRD5A3, AR	Shorter AC tandem repeat in SRD5A3 and shorter CAG repeat in AR associated with increased BPH risk in Korean males
Han et al., 2017 (41)	Human epidemiological study	Chinese	ESR1	PvuII and XbaI polymorphisms in ESR1 associated with increased BPH risk; PvuII linked to enhanced ESR1 transcription
Kim et al., 2015 (42)	Human epidemiological study	Korean	ESR2	Mixed results regarding the role of ESR2 polymorphisms in BPH risk
Chen et al., 2024 (45)	Human epidemiological study	Chinese	CYP17A1	GG genotype of rs743572 SNP linked to increased BPH risk, metabolic syndrome, and altered testosterone-to-estradiol ratio
Chen et al., 2018 (43)	Human epidemiological study	Chinese	CYP19	The TT genotype of rs700518 is a risk factor for BPH combined with metabolic syndrome, and the CYP19A1 gene regulation of estrogen leads to MetS-BPH
Yang et al., 2022 (51)	Human epidemiological study	Chinese	CYP19, GPER	Higher CYP19 and GPER expression in prostate tissue associated with progressive BPH
Na et al., 2017 (68)	Human epidemiological study	Finnish	GATA3	Variants associated with inherited BPH/LUTS risk
Surmeli et al., 2024 (64)	Human epidemiological study	Turkish	VDR	Vitamin D levels and sarcopenia impact BPH severity in older males
Ruan et al., 2024 (66)	Human epidemiological study	Caucasian and Asian	VDR	Meta-analysis of 10 studies: Taq1 associated with increased BPH risk; Bsm-1 associated with BPH in Caucasian and Asian populations; Fok-1 and Apa-1 showed inconsistent results
AlChalabi et al., 2020 (67)	Human epidemiological study	Iraqi	VDR	SNPs (rs3782905, rs1544410, rs7975232) in non-coding region of VDR gene linked to lower vitamin D levels and higher BPH risk, while rs731236 in coding region showed no effect
Chamberlain et al., 1994 (24)	In vivo/in vitro study	–	AR	Increased AR transactivation activity with shorter CAG repeats, contributing to greater prostate volume
Choong et al., 1996 (25)	In vivo/in vitro study	–	AR	CAG repeat expansion reduces AR gene expression
Ding et al., 2004 (26)	In vivo/in vitro study	–	AR	Short CAG repeats alter human AR function
Ghayee et al., 2008 (32)	In vivo/in vitro study	–	SRD5A	SRD5A gene variants influence testosterone metabolism and DHT levels
Cornu et al., 2017 (52)	In vivo/in vitro study	–	ESR1, ESR2, HSD17B2, CYP19A1	Altered estrogen signaling and steroid metabolism contribute to BPH development

AR, androgen receptor; BPH, benign prostatic hyperplasia; DHT, dihydrotestosterone; GPER, G protein-coupled estrogen receptor; LUTS, lower urinary tract symptoms; MetS, metabolic syndrome; SNP, single nucleotide polymorphism; VDR, vitamin D receptor.

Chromosomal loci and genome-wide association studies (GWAS)

GWAS and large biobank datasets have significantly advanced our understanding of the genetic underpinnings of BPH. These studies have identified numerous genetic variants on multiple chromosomes linked to the development and prognosis of BPH (69). Gudmundsson et al. identified 23 variants across 14 loci significantly associated with PSA levels and BPH development, including variants on chromosomes 11, 15, and 22 (69). Hellwege et al. assessed SNP-based heritability in BPH and conducted a GWAS with 2,656 BPH cases and 7,763 controls. While no genome-wide significant variants were identified, suggestive signals near several genes, including SYN3 on chromosome 22 and ETV4 on chromosome 17, highlighting the need for further research (18).

Polygenic risk scores (PRS) are a method used to estimate an individual’s genetic predisposition to a particular trait or disease based on the cumulative effect of multiple genetic variants, typically SNPs. Hung et al. investigated PRS effectiveness for BPH incidence and prognosis in a Han Chinese cohort (n=12,474) using the PGS001865 score, which incorporated 1,692 SNPs in their analysis (70). The PRS included SNP rs5754397, located within the SYN3 gene on chromosome 22, a region Hellwege et al. previously highlighted for its suggestive BPH association (18). Furthermore, the PRS contained variants at the TERT/CLPTM1L locus on chromosome 5, linking the polygenic risk to the telomerase gene pathway, also discussed earlier in relation to BPH symptoms (58). The study revealed that individuals in the highest PRS quartile exhibited a significantly greater BPH risk [odds ratio (OR) =1.51 vs. lowest quartile, P<0.001], larger prostate volumes, poorer response to 5ARI treatment, and a higher likelihood of requiring TURP; this highest quartile was also identified as an independent risk factor for the procedure (HR =1.45 vs. Q1, P=0.01) (70).

Judge et al. investigated the impact of monogenic variants on the development of BPH in a large cohort of 83,631 men from the UK Biobank, identifying nineteen candidate genes associated with the condition. While these genes showed a higher carrier rate in patients undergoing TURP, none of the associations reached significance after correcting for multiple testing, highlighting the need for further validation in independent populations (71).

A recent GWAS by Antoine et al. evaluated genetic variants associated with the need for BPH surgery. Analyzing data from 33,864 samples, they identified 131 significant SNPs associated with BPH surgery risk, located at or near 25 distinct gene loci. Implicated genes included DOCK4, MRAP, and NCOA3. These findings suggest a heritable component contributing to severe LUTS requiring surgical intervention for BPH and highlight potential targets for future research and therapeutic strategies (72). Na et al. reported that variants of GATA3 may contribute to the inherited susceptibility and etiology of BPH/LUTS, warranting further research in this area (68).

Although no single gene or SNP has been established as the sole driver of BPH, the collective evidence from genetic research, particularly through GWAS and the application of PRS, clearly demonstrates a significant heritable component influencing BPH development and severity. These investigations have successfully identified numerous genetic loci across various chromosomes (including 5, 11, 15, 17, and 22) associated not only with overall BPH risk but also with crucial clinical parameters such as PSA levels, prostate volume, and the eventual need for surgical intervention like TURP. This body of evidence strongly supports the view of BPH as a complex, polygenic trait, where individual susceptibility results from the cumulative impact of multiple genetic variants (Table 2).

Table 2. Genome-wide and PRS studies in BPH.

Author, year	Study type	Key findings
Gudmundsson et al., 2018 (69)	GWAS	Identified 23 variants across 14 loci linked to BPH/PSA
Hellwege et al., 2019 (18)	GWAS	Suggestive signals near SYN3/ETV4 (2,656 cases)
Antoine et al., 2021 (72)	GWAS	131 SNPs near DOCK4/MRAP/NCOA3 linked to BPH surgery risk (33,864 samples)
Hung et al., 2024 (70)	PRS analysis	High PRS predicts BPH severity/poor treatment response (6,237 cases)
Judge et al., 2023 (71)	Cohort study	Screened 19 genes in UK Biobank (n=83,631)

BPH, benign prostatic hyperplasia; GWAS, genome-wide association studies; PRS, Polygenic Risk Score; PSA, prostate-specific antigen; SNP, single nucleotide polymorphism.

Environmental disruptors and lifestyle factors

While the pathophysiology of BPH is multifactorial, growing evidence suggests that environmental exposures, including EDCs, may play a significant role in disease development and progression. EDCs are exogenous compounds or mixtures that interfere with hormone action and are commonly found in everyday products such as cosmetics, packaged and canned foods, cleaning supplies, herbicides, and pharmaceuticals (73).

EDCs can interfere with hormonal function and are associated with various adverse health outcomes, including metabolic disorders such as type II diabetes and cardiovascular disease, autoimmune disorders, reproductive toxicity, and associations with hormone-related malignancies such as testicular cancer (73-75). EDCs, such as bisphenol A (BPA), phthalates, and polychlorinated biphenyls (PCBs), have been implicated in various hormonally regulated conditions, including BPH. These compounds disrupt normal hormone signaling, either by prolonging receptor exposure to stimuli or by interfering with cellular hormone pathways in target cells (76). However, the current body of evidence is constrained by a significant knowledge gap. The vast majority of studies investigating the link between specific EDCs, such as BPA, and BPH have been conducted in animal models, particularly rodents. While these studies provide valuable mechanistic insights, their direct applicability to human disease faces considerable translational limitations, and there remains a notable scarcity of large-scale epidemiological studies in human populations.

Bisphenols

BPA is a widely recognized environmental endocrine disruptor that has been found to play a significant role in inducing prostatic hyperplasia by stimulating cell proliferation within the prostate (77). Recent findings revealed that BPA exposure, even in microdoses, can promote prostatic cell hyperplasia (78).

In an investigation by Liao et al., the authors evaluated the association between chronic BPA exposure and BPH risk (79). Men who frequently consumed food or beverages from plastic containers showed a higher likelihood of developing BPH, and this risk was even greater among alcohol drinkers, suggesting a potential synergistic interaction between BPA and alcohol. The authors proposed that alcohol may enhance BPA absorption from the gastrointestinal tract, thereby increasing the risk of BPH, as ethanol, a lipophilic solvent, facilitates BPA’s transfer into the bloodstream (79).

Studies in animal models have also shown adverse associations between exposure to BPA and BPH. In a study by Wu et al., low-dose BPA was found to worsen BPH in male rats. Exposed animals exhibited increased prostate weight and volume, reduced testosterone levels, and increased PSA levels (80). In a study by Wang et al. on adult beagle dogs exposed to low doses of BPA, significant prostatic changes were observed, including increased organ size, thickened epithelium, and abnormal hyperplasia. Additionally, hormone levels revealed elevated ratios of E2 to testosterone and prolactin to testosterone (81). Exposure to BPA could also induce prostatic fibrosis, a potential contributor to BPH progression, through stromal-epithelial interactions (82). In both mouse models and human prostate cells, BPA exposure increased collagen deposition and hydroxyproline levels, key indicators of fibrosis (82).

An experimental study by Castro et al. investigated the effects of adult BPA exposure on key enzymes involved in prostate hormone regulation using a rat model. Their findings revealed that BPA exposure decreased 5α-reductase (types 1 and 2) while increasing 5α-reductase type 3 and aromatase, both linked to prostate diseases. BPA-treated rats also exhibited a higher E2/testosterone ratio (83). The study by Wu et al. suggested additional mechanisms for BPA’s impact on BPH, highlighting the upregulation of COX-2, NF-κB, and L-PGDS (84). Their findings demonstrated that low-dose BPA exposure in a rat model increased prostate cell proliferation and altered hormone receptor expression, with COX-2 and L-PGDS playing key roles in mediating this effect through pathways involving cell proliferation and apoptosis (84).

The in vitro experimental study by Huang et al. demonstrated that environmental BPA exposure directly promotes prostate cell proliferation in a rat model. Their findings revealed that BPA increased ESR expression, reduced androgen receptor expression, and decreased apoptosis-induced cell death, contributing to prostate cell growth (85).

Some BPA analogs could have a stronger effect on hormone regulation than BPA, raising concerns about their health impact (86). Bisphenol AF (BPAF) is an estrogenic compound with a stronger binding affinity to ESRs compared to BPA (87). Huang et al. showed that BPAF promotes dorsal prostatic hyperplasia in rats, likely through interference with the NF-κB signaling pathway (87). An in vivo study with male rats demonstrated that low doses of BPA and BPAF, both alone and together, induced ventral prostatic hyperplasia (8). Other BPA analogs, such as bisphenol-F (BPF) and bisphenol-S (BPS), also exhibit estrogenic effects that may contribute to lower urinary tract dysfunction and BPH (88,89). Exposure to BPA, BPF, or BPS in adult male mice was associated with increased bladder and prostate mass, as well as structural changes in the prostatic urethra and cytometric abnormalities, indicating lower urinary tract dysfunction (88). Moreover, Wang et al. demonstrated that bisphenol H exposure in male rats can result in a dose-dependent decrease in testicular testosterone levels and altered expression of genes involved in steroidogenesis and cholesterol metabolism (90).

A recent study explored the molecular mechanisms of prostate injury induced by BPS exposure (91). Prostate injury in this context was characterized by inflammation, hyperplasia, and cancer by influencing cell apoptosis, proliferation, and inflammatory pathways. By analyzing multiple databases, 208 potential targets related to BPS and prostate injury were identified, with 21 core targets, including AKT1, EGFR, and MAPK3 (91).

Phthalates

Di-(2-ethylhexyl) phthalate (DEHP) exposure has been suggested as a potential contributor to BPH, with evidence indicating that DEHP may stimulate cell proliferation by modulating androgen and ESR expression (92). Yang et al. investigated the potential association between DEHP exposure and BPH using data from the 2001–2008 National Health and Nutrition Examination Survey. Urinary DEHP concentrations were measured in 280 men, with 208 having BPH and 72 without. A biphasic effect, a non-linear dose-response where the effect of the chemical changes direction with increasing concentration, was observed between DEHP and BPH: moderate DEHP exposure (second quartile of urinary concentrations: 6.07–6.57 ng/mg crt) increased the odds of BPH, while higher DEHP concentrations (third quartile: 6.58–7.17 ng/mg crt, and fourth quartile: >7.17 ng/mg crt) were associated with a decreased risk (92).

A study of 207 elderly men with BPH in southern Taiwan found that urinary levels of DEHP were positively associated with increased androgen, estrogen, hormone ratios, oxidative stress markers, PSA, and prostate volume. DEHP exposure was linked to the progression of BPH through multiple mechanisms: it elevated DHT and E2 levels, increased the activity of aromatase and 5α-reductase and promoted oxidative stress, as indicated by higher levels of inducible nitric oxide synthase (iNOS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). These factors contributed to an increase in prostate volume and PSA, reinforcing the role of sex hormones and oxidative stress in BPH development following phthalate exposure (93). Compared to the Yang et al. study, which identified a biphasic effect, moderate DEHP exposure increasing BPH risk while higher exposure showed a protective trend (92), the Taiwanese study reported a continuous positive correlation between DEHP metabolites and BPH-related markers (93). Differences in metabolite measurement, population characteristics, and exposure assessment may explain these variations.

While much of the research on phthalates and prostate health has focused on DEHP, other phthalates, such as di-n-butyl phthalate (DBP), have also been implicated in prostate pathology. de Jesus et al. investigated the combined effects of a high-fat diet and exposure to low doses of DBP on prostate health in adult gerbils (94). Both factors individually promoted dyslipidemia and increased the incidence of premalignant prostate lesions, with the high-fat diet also triggering inflammation and prostate hypertrophy. However, when combined, less severe effects were observed, with no significant inflammatory response or changes in serum lipids, suggesting that the interaction between these risk factors may mitigate some prostate-related outcomes (94).

Estrogenic compounds

EDCs with estrogenic activity can significantly alter prostate morphology and function. Neonatal exposure to ethinylestradiol (EE) in male offspring significantly increased prostate weight, doubling the prostatic complex weight by adulthood compared to controls (95). This increase was accompanied by enlarged epithelial and stromal compartments with heightened secretory activity, as observed at 120 days postnatal age. Postnatal EE exposure also led to stromal remodeling, epithelial hyperplasia, and inflammation in adult prostatic tissue, indicating that early-life endocrine disruption predisposes individuals to long-term prostatic alterations (95).

Moreover, investigations on a prostate-specific MT1-expressing mouse model (12.1ΔMT1) revealed an unexpected link between chronic treatment with testosterone (T) plus 17β-E2 and severe bladder outlet obstruction (BOO). E2-treated 12.1ΔMT1 mice showed a higher incidence of BOO compared to wild-type mice. This model offers valuable insight into the mechanisms underlying estrogen-induced BOO, including detrusor wall thinning, narrowing of the bladder neck and urethral lumen, and basal cell hyperplasia in the bladder and urethra (96). Taylor et al. explored the interaction between developmental and adult estrogen exposure in the development of obstructive voiding disorder and prostate diseases (97). Male mice were perinatally exposed to BPA, diethylstilbestrol (DES), and in adulthood, treated with testosterone and E2 for 4 months. Results showed that mice exposed to BPA or DES during early development had an increased likelihood of bladder and kidney issues, enlarged prostates, and dorsal prostate hyperplasia when subjected to elevated estrogen levels in adulthood. Based on these findings, the authors proposed a version of the “two-hit hypothesis” for prostate disease. Their model suggests an early-life developmental exposure (the “first hit”) sensitizes the prostate to damage from a subsequent hormonal trigger in adulthood (the “second hit”) (97). This provides strong experimental support for the broader concept of multi-step pathogenesis, demonstrating how an initial insult can create susceptibility to a later-life challenge.

Air pollution

The relationship between air pollution and BPH remains poorly understood, with limited studies exploring environmental contributors to BPH risk. Recent research, including a study conducted in South Korea from 2010 to 2013 involving 1,734 men, highlights a potential link between chronic exposure to air pollution and BPH (98). This study found that higher levels of air pollutants, particularly nitrogen oxides and sulfur oxides, were associated with an increased risk of BPH. Specifically, the risk of BPH rose in a dose-dependent manner as air pollution levels increased, with odds ratios of 1.73 for nitrogen oxides and 2.02 for sulfur oxides, indicating a statistically significant correlation between environmental pollutants and the risk of BPH (95% confidence intervals: 1.25–2.39 for nitrogen oxides, 1.42–2.88 for sulfur oxides) (98). While the exact pathways are still being elucidated, the mechanisms underlying this association are thought to be driven by systemic inflammation, oxidative stress, and increasing circulating pro-inflammatory cytokines that can promote proliferative changes in the prostate.

Further supporting this link, a large, nationally representative study from China involving over 8,800 men demonstrated that long-term exposure to particulate matter was also significantly associated with BPH (99). The authors reported that each 10 µg/m³ rise in fine particulate matter (PM_2.5) and coarse particulate matter (PM_2.5–10) corresponded to a 4% (OR 1.04) and 6% (OR 1.06) increased risk of prevalent BPH, respectively. Notably, this study also found that the association was more pronounced in participants who were overweight or obese, suggesting a potential synergistic effect between metabolic health and environmental exposures (99) (Table 3).

Table 3. Environmental and lifestyle factors in BPH pathogenesis.

Category/exposure	Author, year	Study design	Population/model	Key findings	Proposed mechanisms
Bisphenols
BPA	Liao et al., 2021 (79)	Case-control	412 Hong Kong men	BPA + alcohol synergism OR =2.1, 95% CI: 1.3–3.4	Enhanced GI absorption
Low dose BPA (10 µg/kg/day)	Wu et al., 2011 (80)	Animal	Male rats	↑ Prostate weight (42%), ↓ testosterone	COX-2/L-PGDS pathway
BPA (2, 6, 18 μg/kg/day)	Wang et al., 2022 (81)	Animal	Beagle dogs	↑ Prostate size (2.1×), ↑ E2/T ratio (4×)	KRAS/miR-204 axis
BPAF (10, 90 μg/kg/day)	Huang et al., 2023 (87)	Animal	SD rats	Dorsal lobe hyperplasia (P<0.001)	NF-κB activation
BPS/BPF (25,000 μg)	Nguyen et al., 2022 (88)	Animal	C57BL/6 mice	↑ Bladder mass (25%), urethral stricture	Estrogen receptor agonism
Phthalates
DEHP	Yang et al., 2021 (92)	Cross-sectional	NHANES (n=280)	Biphasic effect: Q2, OR =1.8 vs. Q4, OR =0.6	Non-monotonic dose response
DEHP	Chang et al., 2019 (93)	Cohort	Taiwanese men (n=207)	↑ PSA (β=0.34), prostate volume (β=0.28)	Oxidative stress (8-OHdG ↑)
DBP (5,000 μg/kg/day)	de Jesus et al., 2015 (94)	Animal	Mongolian gerbils	Premalignant lesions (67% incidence)	Lipid metabolism disruption
Estrogenic compounds
Ethinylestradiol (10 μg/kg/day, postnatal days 1–10)	Falleiros-Júnior et al., 2016 (95)	Animal	Gerbils (neonatal)	↑ Prostate weight (2×), stromal hyperplasia	Developmental reprogramming
BPA (20 µg/kg/day) or DES (0.2 µg/kg/day)	Taylor et al., 2020 (97)	Animal	CD-1 mice	82% obstruction rate	Two-hit hypothesis
Air pollution
NOx/SOx	Shim et al., 2016 (98)	Ecological	Korean men (n=1,734)	NOx, OR =1.73; SOx, OR =2.02	Chronic inflammation

CD-1 mice refers to inbred mouse strains that possess one or two functional CD1 genes. ↑, represents an increase; ↓, represents a decrease; β, beta coefficient, BPA, bisphenol A; BPF, bisphenol-F; BPS, bisphenol S; BPAF, bisphenol AF; CI, confidence interval; DBP, di-n-butyl phthalate; DEHP, di-(2-ethylhexyl) phthalate; DES, diethylstilbestrol; E2, estradiol; GI, gastrointestinal; NHANES, National Health and Nutrition Examination Survey; NOx, nitrogen oxides; OR, odds ratio; PSA, prostate-specific antigen; SD, Sprague-Dawley; SOx, sulfur oxides; T, testosterone.

Discussion

This review has several limitations that should be considered. First, our search was restricted to English-language publications, which introduces a potential language bias and may have led to the exclusion of relevant studies from non-English-speaking regions. Second, the primary literature itself presents challenges. Within the genetic studies, there was often a lack of specific reporting on the ethnic diversity of cohorts, which is a critical factor for interpreting the generalizability of genetic association findings.

Similarly, the environmental literature is marked by significant methodological heterogeneity. For instance, exposure assessment methods for factors like EDCs varied widely, from indirect self-report questionnaires to direct biomonitoring of metabolites. This diversity in methodology, each with different levels of precision and susceptibility to recall bias, makes direct comparison of outcomes between studies challenging.

A limitation of this review stems from the heterogeneity and frequent lack of specificity in the reporting of exposure metrics within the primary literature on environmental factors. This inconsistency prevents a direct quantitative comparison of effect sizes across different studies and complicates the establishment of clear dose-response relationships or potential safety thresholds. Consequently, future research in this field would benefit significantly from standardized reporting of exposure data to enable more robust meta-analyses and public health risk assessments.

A critical next step is the implementation of large-scale, prospective longitudinal studies. Such studies are uniquely capable of elucidating the temporal relationship between exposures and disease onset, which is essential for inferring causality. By collecting genetic data at baseline and repeatedly assessing environmental exposures (e.g., through biomonitoring) and clinical BPH outcomes over many years, researchers can effectively investigate gene-environment interactions. This approach will be vital for identifying specific genetic variants that confer susceptibility to environmental risk factors and for understanding how this interplay influences the progression of the disease.

Future research should focus on designing clinical trials that test targeted interventions in genetically stratified populations. For example, trials could assess whether individuals with genotypes linked to aggressive disease progression benefit from earlier pharmacological intervention (e.g., 5ARIs) or whether those with genetic susceptibility to environmental insults respond to targeted lifestyle modifications aimed at reducing specific exposures or mitigating their effects.

Conclusions

BPH is driven by a complex interplay of genetic and environmental factors. Genetic polymorphisms, particularly in androgen and estrogen pathways, and key risk loci significantly influence the risk of BPH. While aging and genetics have long been recognized as key drivers, emerging evidence underscores the substantial contributions of environmental exposures, particularly EDCs and air pollution, to the disease’s pathogenesis and progression. These factors not only disrupt hormonal homeostasis but also exacerbate inflammation and tissue remodeling, influencing BPH severity and symptom burden.

The integration of environmental and genetic factors into a unified framework is essential for advancing BPH research and clinical management. This review highlights the need for further investigation into the interplay of genetic and environmental determinants, with the ultimate goal of translating these findings into actionable strategies to mitigate disease risk and enhance patient care. As our understanding of these complex interactions grows, so too does the potential to improve outcomes and reduce the global burden of BPH.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.