Epidemiology and pathophysiology of benign prostatic hyperplasia

INTRODUCTION/DEFINITION — 

Benign prostatic hyperplasia (BPH) is a common problem among older males that negatively impacts quality of life and results in considerable medical intervention and expense [1]. BPH is a histologic diagnosis defined as an increase in the total number of stromal and glandular epithelial cells within the transition zone of the prostate gland. This hyperplasia causes formation of large, discrete prostatic nodules.

The diagnosis and management of BPH are discussed separately. (See "Clinical manifestations and diagnostic evaluation of benign prostatic hyperplasia" and "Medical treatment of benign prostatic hyperplasia" and "Surgical treatment of benign prostatic hyperplasia (BPH)".)

In this topic, when discussing study results, we use the term "men" as it is used in the studies presented. We recognize that not all patients who identify as men have a prostate and that BPH is a condition that exclusively affects patients with male reproductive anatomy. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals as they relate to the information presented in this topic. This topic also uses racial and ethnic descriptors as they were used in the studies presented. We recognize the historical use of race and ethnicity in scientific studies that oversimplify the intragroup variation present within each construct. A detailed discussion of the use of race and ethnicity in medicine is presented separately. (See "Use of race and ethnicity in medicine".)

TERMINOLOGY — 

BPH is often confused with benign prostatic hypertrophy, which is an archaic term for BPH describing an increase in cell size rather than cell number. BPH results in benign prostatic enlargement (BPE) in some, but not all, patients. This enlargement can, in turn, lead to benign prostatic obstruction (BPO) and bladder outlet obstruction (BOO). While BPH alone does not require treatment, BPE and BPO are often associated with lower urinary tract symptoms (LUTS), which may require treatment.

LUTS is a clinical term describing symptoms related to the bladder and the urethra. It can be caused by a variety of conditions but is often attributed to BPH. LUTS can be subdivided into symptoms of urinary storage (eg, urgency, frequency, nocturia, etc), symptoms of urinary voiding (eg, straining to void, urinary intermittency, dysuria, hesitancy, etc) and post-voiding symptoms (eg, sensation of incomplete bladder emptying, post-void urinary dribbling, etc).

In the discussion below, LUTS/BPH will be used to indicate LUTS attributed to BPH, in accordance with the American Urological Association BPH clinical guidelines. LUTS is described in detail elsewhere. (See "Lower urinary tract symptoms in males".)

EPIDEMIOLOGY

Prevalence — The prevalence of BPH increases with age.

●Based on medical records, it has been estimated that nearly 70 percent of United States men between the ages of 60 and 69 years, and nearly 80 percent of men ≥70 years, have some degree of BPH [1].

●The prevalence of histologically diagnosed BPH increases from 8 percent in patients 31 to 40 years old, to 40 to 50 percent between the ages of 51 to 60, to over 80 percent in patients older than age 80 (figure 1) [2].

●Mirroring changes in BPH, the prevalence and severity of lower urinary tract symptoms (LUTS) appears to be age-related. (See "Lower urinary tract symptoms in males", section on 'Prevalence and risk factors'.)

Risk factors

Unmodifiable risk factors

●Race – Some studies have shown an association between race and BPH severity [3,4], though these associations may be confounded by socioeconomic factors such as income and insurance [5]. In one study, while the age-adjusted relative risk (RR) of BPH necessitating surgery was similar for Black and White patients, Black patients younger than 65 years old needed treatment more often compared with White patients [3]. In a community sample of 2480 men in the United States, moderate to severe LUTS was more common in Black men than White men (41 versus 34 percent) [4], and Black patients had greater total and transitional zone prostate volume [6,7].

In a study of 34,624 men, Asian patients had a lower risk of clinician-diagnosed BPH (RR 0.7, 95% CI 0.2-0.5) compared with Black and White patients with similar risk [8]. Additionally, in the American Male Health Professional Study, Asian American patients were less likely (RR 0.4, 95% CI 0.2-0.8) to undergo surgery for BPH compared with White patients [9].

●Genetic susceptibility – A role for genetic factors is suggested by studies of familial tendencies towards BPH. Familial BPH is characterized by larger prostate size and diagnosis at an earlier age than sporadic BPH [10]. Twin studies suggest that genetic factors are a more important determinant of LUTS than age, transition zone volume, or total prostate volume [11].

Various studies have shown familial tendencies. In one study, patients with three or more affected family members had large prostate glands, above-normal serum androgen concentrations, and a normal response to 5-alpha-reductase inhibition [10]. In a survey of patients in Olmsted County, Minnesota, 21 percent of 2119 participants between 40 and 70 years of age had a family history of an enlarged prostate [12]. The odds ratio (OR) of a male patient with a positive family history of BPH having moderate to severe LUTS was 1.3 (95% CI 1.1-1.7).

The possible role of genetic factors was evaluated in several studies. A genome-wide association study (GWAS) of men from three independent populations indicated that genetic variants of GATA3 may play a role in the inherited susceptibility and etiology of BPH/LUTS [13] A 2014 systematic review and meta-analysis of genes that may cause urinary symptoms in men only found a variant of the vitamin D receptor that was consistently protective across different populations [14]. In a case-control study of men under 64 years of age who had undergone prostatectomy for BPH and in whom more than 37 grams of tissue were resected, the first-degree relatives of these men had a fourfold increased risk of developing BPH that required surgical therapy as compared with the relatives of normal men [15]. Segregation analysis suggested an autosomal dominant mode of disease transmission (with an estimated penetrance of 0.89) and an allele frequency of 3.4 percent in the population.

●Hormone levels – Serum testosterone or dihydrotestosterone (DHT) concentrations do not appear to be higher in men who develop prostate hyperplasia; the Physicians' Health Study found similar serum testosterone concentrations at the initial examination in 320 patients who had BPH treated surgically up to nine years later and 320 patients who did not develop prostatic disease [16]. In fact, higher serum levels of testosterone and estradiol were associated with decreased risk of future development of symptomatic BPH in the Prostate Cancer Prevention Trial [17].

The role of estrogen is unclear. There is an increase in the ratio of estrogen-to-androgen in the serum in older males that suggests a possible role for estrogen in the maintenance, but not necessarily the causation, of BPH. The age-related increase in the serum estrogen-androgen ratio is associated with an increase in the estrogen-androgen ratio in prostatic tissue, especially in the stroma [18].

●Family history of cancer – The risk of BPH is increased in men with a family history of bladder cancer but not with a family history of prostate cancer [19].

Modifiable risk factors — Some modifiable factors may play a role in the development of LUTS/BPH [20-23].

●Metabolic factors: Obesity and metabolic syndrome – The development of LUTS/BPH appears to be related, in part, to increased autonomic tone and to the metabolic syndrome (obesity, glucose intolerance, dyslipidemia, and hypertension) [20-22,24]. This relationship may be due to increased aromatization of circulating testosterone in adipose tissue, which alters the testosterone-to-estrogen ratio, or to hyperinsulinemia [21]. Two meta-analyses found that patients with the metabolic syndrome had higher prostate growth rates and larger prostate volume than those without the metabolic syndrome [25,26].

●Beverage consumption – Greater coffee or total caffeine intake increases the odds of LUTS/BPH progression. Citrus juice intake was associated with 50 percent lower odds of LUTS/BPH progression [27].

●Physical activity – Lower levels of physical activity are associated with greater development of LUTS [28]. Frailty is also associated with a greater risk of BPH progression and serious adverse events requiring hospitalization [29].

●Alcohol consumption – Moderate alcohol consumption is not associated with LUTS/BPH [28]. However, excessive consumption (three or more drinks per day) may lower the risk of BPH due to depression of androgen levels [30].

●Dietary factors – LUTS/BPH may be related to micronutrients involved in the prevention of oxidative damage or cell growth and differentiation. Dietary lycopene, beta-carotene, total carotenoids, and vitamin A are inversely associated with LUTS, although high-dose supplemental and total vitamin C are positively associated with LUTS [31].

Conditions exacerbating LUTS/BPH — Many medical conditions can influence the severity of lower urinary tract symptoms (LUTS).

●Cardiovascular risk factors – Alpha-adrenergic fibers and receptors play important roles in both hypertension and symptomatic BPH. Autonomic hyperactivity is believed to be involved in the development of LUTS [32], and heart disease and hypertension are associated with greater LUTS severity [33]. In patients with heart failure, changes in cardiac ventricular pressure cause the release of B-type natriuretic peptide (BNP). This, in addition to peripheral edema, can increase urine production resulting in worsening of urinary symptoms, especially at night [34].

●Neurologic factors – Neurologic conditions that influence detrusor function and stability are important in patients with LUTS/BPH because they may add to the complexity of diagnosis and affect therapeutic decision-making. Patients with Parkinson disease frequently develop voiding dysfunction, most commonly detrusor overactivity with impaired detrusor contractility. Patients with multiple sclerosis (MS) will likely develop urinary symptoms at some point in the disease process. Cerebral vascular accidents may result in a transient spinal shock-like period of detrusor areflexia, placing the patient at risk for urinary retention, followed by most commonly neurogenic detrusor overactivity.

●Diabetes mellitus – Diabetes can worsen LUTS due to decreased bladder sensation, decreased detrusor contractility, and incomplete bladder emptying. Additionally, increased glucose filtration in the urine leads to osmotic diuresis and polyuria, thereby potentially worsening LUTS due to increased urine production.

PATHOPHYSIOLOGY — 

The pathophysiology of lower urinary tract symptoms (LUTS)/BPH is likely multifactorial, with the prostate playing a significant, but likely overemphasized, role in its etiology [35]. Nevertheless, the prostatic contribution to LUTS can be thought of as having a static component, referring to enlargement of the prostatic gland leading to benign prostatic obstruction (BPO), and a dynamic component consisting of increased smooth muscle tone and resistance. Benign prostatic enlargement (BPE) with BPO can have secondary effects on detrusor activity, leading to detrusor instability or overactive bladder (OAB). This effect, in combination with age-related changes to detrusor contraction and compliance, compounds BPH-associated LUTS.

Several processes are likely involved, including the following:

●Cell immortalization – Androgens play a key role in the proliferation of prostatic cells and inhibition of cell death [36]. While prostatic hyperplasia is not observed in prepubertal males, the incidence of prostatic hyperplasia rises during the postpubertal period as androgen levels increase. In addition, individuals who have had castration prior to puberty or who exhibit impairment in androgen production or androgen receptors do not develop BPH. Lastly, prostatic tissue undergoes involution in androgen withdrawal [37].

●Systemic and local inflammation – Systemic and localized inflammation are associated with LUTS/BPH [38-40]. Although causal factors are unknown, possible etiologies include obesity-related inflammation, autoimmune processes, and chronic infections.

Serum level C-reactive protein levels correlate with LUTS severity [41]. In addition, cytologic and immunohistochemical markers of inflammation are associated with higher International Prostate Symptom Scores (IPSS) and greater prostate volume [42]. This association may explain the association between obesity and LUTS/BPH, as obesity is associated with increased inflammatory cytokines. Dietary fats have been implicated, and lipopolysaccharides can induce prostatic inflammation in experimental animals. It has been hypothesized that macrophages secrete cytokines that stimulate stromal and epithelial hyperplasia. Investigators have found increased concentrations of hypoxia-inducible factor (HIF)-1 alpha, which can be secreted by epithelial cells and is known to be induced by proinflammatory cytokines and to be involved in testosterone-mediated hyperplasia [43].

If inflammation is a causal mechanism for LUTS/BPH, it also could provide an explanation for improvement with nonsteroidal anti-inflammatory drugs (NSAIDs) [44]. There is also some evidence that phosphodiesterase-5 inhibitors decrease fibroblast to myofibroblast transdifferentiation, which could be a mechanism by which they decrease symptoms [45].

Inflammation could be caused by an autoimmune process or in response to chronic infection. Investigators have failed to associate BPH with any of 17 single-nucleotide polymorphisms in genes involved in obesity [46]. The lymphotoxin-beta-receptor (LT-beta-R) gene has been reported to be involved in autoimmune disease and inflammatory disorders. Korean investigators found nucleotide polymorphisms located in the promoter and coding regions of LT-beta-R in BPH tissue, and an allele was significantly associated with BPH [47]. Heat shock protein (HSP) 27 is also known as a mediator in immune responses. Expression of HSP27 is reported to increase with increasing inflammation in BPH tissue [48].

Investigators have sought to identify chronic infections that might cause prostatitis. One possibility is Escherichia coli. It is postulated that phospholipase D, which is attached to the outer membrane of E. coli, stimulates the production of lysophosphatidic acid (LPA), and LPA stimulates other factors that cause inflammation [49]. Another approach to understanding inflammation in BPH tissue has been to measure heme oxygenase (HO). HO has been found to be inversely related to inflammation in the prostate [50].

●Prostatic fibrosis – Prostatic fibrosis is an emerging concept in the pathophysiology of symptomatic BPH [51]. Through paracrine secretion of chemokines, prostatic stromal cells and epithelial cells may influence fibroblast conversion to myofibroblasts, which in turn promote collagen deposition, fibrosis, and periurethral rigidity. The increased abundance of osteopontin, a profibrotic and proinflammatory molecule, in the transition zone of prostate samples from patients with symptomatic BPH supports the prostatic fibrosis theory [52]. Further, in the Medical Therapy of Prostatic Symptoms (MTOPS) study, the authors found that increased levels of prostate transition zone collagen identified on prostate biopsy carried a significantly increased risk of BPH progression in participants on doxazosin plus finasteride [53].

HISTOLOGY — 

BPH develops primarily in the periurethral or transitional zone of the prostate. The hyperplastic nodules are comprised primarily of stromal components and, to a lesser degree, epithelial cells. In one immunohistochemical study, stroma comprised 62 percent of the volume, epithelium 15 percent, and glandular lumens 23 percent; the stromal to epithelial ratio was 4.6 [54].

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Benign prostatic hyperplasia (enlarged prostate) (The Basics)")

●Beyond the Basics topic (see "Patient education: Benign prostatic hyperplasia (BPH) (Beyond the Basics)")

SUMMARY

●Epidemiology – The prevalence of histologically diagnosed benign prostatic hyperplasia (BPH) increases with age. (See 'Epidemiology' above.)

●Risk factors – The development of lower urinary tract symptoms (LUTS)/BPH appears to be related, in part, to metabolic factors, including obesity, glucose intolerance, dyslipidemia, hypertension, and physical activity. Comorbid conditions influencing autonomic tone, detrusor function, and bladder sensation also contribute to LUTS due to BPH. (See 'Modifiable risk factors' above.)

Although testosterone, dihydrotestosterone (DHT), and estrogen may be involved in the development of BPH, changes in these hormones alone are not sufficient to cause BPH. (See 'Unmodifiable risk factors' above.)

●Pathophysiology – The pathophysiology of BPH remains incompletely understood but is likely multifactorial. Increased risk of BPH may be related to inflammation and metabolic factors. (See 'Pathophysiology' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Glenn Cunningham, MD, and Dov Kadmon, MD, who contributed to an earlier version of this topic review.