The Prostate Gland and BPH
Progression of BPH (BPH a progressive disease)
A number of factors can characterise the progression of BPH, including an increase in prostate volume, deterioration in Qmax, worsening of LUTS, episodes of AUR and the need for BPH-related surgery.
Incidence of AUR increases with age
Substantial evidence on the progressive nature of BPH comes from the American Olmsted County epidemiological study, a prospective, cohort study involving 2,115 randomly selected men, aged 40-79 years, who were monitored for several years. Five- and 7-year data demonstrated a cumulative increase in prostate growth, LUTS severity and incidence of AUR, as well as a decrease in urinary flow rate.13-15
There was a large variation among patients in these clinical outcome parameters - particularly LUTS frequency and severity - indicating that the rate of BPH progression varies between individuals.
Another important finding in this study was that the percent growth of the prostate yearly depends on baseline volume, in that the larger the prostate at baseline, the greater the percent of growth every year thereafter. Similar findings were also reported in men participating in the Baltimore Longitudinal Study of Aging.7,8 Thus, while prostate volume correlates poorly with symptoms and urinary flow at any given time point, the larger the prostate, the greater the likelihood of future clinical deterioration.
Further support for the progressive nature of BPH is provided by the Medical Therapy of Prostatic Symptoms (MTOPS) study, in which clinical progression was defined as any of the following events: AUR, renal insufficiency due to BPH (³50% rise in baseline serum creatinine and ³1.5mg/dl), recurrent urinary tract infection or urosepsis, urinary incontinence, or a ³4-point rise in baseline AUA-SI confirmed within 2-4 weeks. In men receiving placebo, 17.4% experienced progression of their disease over the 4-year duration of the study; 13.6% exhibited deterioration in symptoms and 2.1% experienced an episode of AUR.16 Using a similar definition of BPH progression, data from the placebo arm of the 7-year Prostate Cancer Prevention Trial (PCPT) showed an incidence of 15.6%, 6.3%, 1.9% and 1.3% for worsening symptoms, AUR, BPH-related surgery and urinary tract infection, respectively.17
The identification of predictors of progression is useful to assess future prostate growth and BPH-related outcomes, such as the risk of AUR and BPH-related surgery. The two most extensively investigated and routinely assessable risk factors for BPH progression are prostate volume and serum PSA.18,24 Serum PSA levels can be used to estimate prostate volume with a high degree of confidence (about 70%) in men with BPH.19,25 Clinicians may therefore obtain an improved knowledge of the risk of the patient developing adverse outcomes, and consequently this may be a guide in the choice of therapy for BPH.26 The therapies available for the treatment of BPH are discussed further in Mangement of BPH.
Prostate volume
A number of large-scale studies have found a significant correlation between prostate volume and the risk of BPH progression, and although the relationship between prostate size and the magnitude of symptoms is not linear,14,21,27 the larger the prostate the greater the likelihood of future clinical deterioration. Men with a prostate volume ³30cc are more likely to have moderate-to-severe symptoms (3.5 times), decreased urinary flow rates (2.5 times), and AUR (3-4 times), compared with men with prostate volumes <30cc.27 The population of men with a prostate volume >30cc has been found to be 36.1%, 63.9%, 78.2%, and 83.0% in the 40-49, 50-59, 60-69, and 70-79 year-old age ranges, respectively.25 An enlarged prostate can be predictive of the need for BPH-related surgery.6,18,28
Prostate-specific antigen levels
A number of analyses conducted by the Proscar Long-term Efficacy and Safety Study (PLESS) group, involving 3,040 men with BPH, have established that serum PSA levels are a powerful predictor of progressive BPH.18,20
When assessed against the other predictors of progression - age and baseline prostate volume - serum PSA levels were the strongest predictor of prostate growth.29 The changes in prostate volume after 4 years were stratified by baseline PSA level and age in the PLESS study.
The mean change in prostate volume from baseline when assessed by age ranged from 12.0% for men aged 50-59 years to 16.6% for men aged 70-79 years. When assessed by PSA tertiles the mean change in prostate volume was 7.4% for the lowest PSA tertile (0-1.3ng/ml) and 22.0% for the highest PSA tertile (3.3-12.0ng/ml). The mean prostate growth at 4 years varied little among age groups compared with differences in growth rates among patients stratified by serum PSA levels.18 Patients with a serum PSA level of 1.4ng/ml and above are thus considered to be at increased risk for severe symptoms, prostate enlargement, AUR and BPH-related surgery.
Baseline PSA levels are predictive of prostate growth18
PSA as a predictor of prostate volume
Both PSA and total prostate volume increase with advancing age. Indeed, PSA and total prostate volume have an age-dependent relationship.30
The relationship between age, PSA and prostate volume
The relationship between PSA and prostate volume was demonstrated by the Olmsted study.20,31 A subgroup of patients underwent transrectal ultrasonography to establish an accurate prostate volume (n=471) and serum PSA values were measured. Over the entire range of prostate sizes, the serum PSA concentration correlated directly with prostate volume (p<0.0001).
A review of trials, by Roehrborn et al, enrolling men with PSA values of <10 ng/mL, in whom prostate cancer had been ruled out, investigated the relationship between PSA values and prostate volume. A linear relationship between the logarithms of prostate volume and serum PSA values, that was dependent on age, was demonstrated.19
Estimation of an exact prostate volume using serum PSA is not possible due to variability. However, analysis of the PLESS data showed that the PSA thresholds for detecting men with a prostate volume of >30mL were > 1.3ng/mL, >1.5ng/mL and >1.7ng/mL in men with BPH aged 50-59, 60-69 and 70-79 years respectively.19
This relationship has also been shown in a retrospective database analysis of 1859 Dutch patients which showed that for a PSA of at least 1.5ng/mL 89% have a prostate volume > 30mL.25
Risk factors for acute urinary retention
The greatest risk factor for progression of BPH and development of AUR is age, owing to a predisposition for prostatic growth with ageing. Other risk factors include symptom severity, urinary flow rate and prostate volume. Although prostate volume is not directly correlated with symptom severity - which varies on an individual basis - it is important for overall long-term disease control. With the combination of risk factors, an average 60-year-old man has a 23% risk of developing AUR if he lives to 80 years.6 The risk factors for AUR are summarised in table below.
| Risk factor | Relative risk of AUR |
| Age | 8 x risk, 70-79 years vs 40-49 years |
| Symptoms | 4 x risk, IPSS >7 |
| Peak urine flow (Qmax) | 3 x risk, Qmax <12ml/s |
| Prostate volume | 3 x risk, prostate volume >30cc (PSA level can be used as a proxy for prostate volume) |
| The average 60-year-old man has a 23% risk of developing AUR if he lives to 80 years7 | |
The role of androgens in BPH progression
DHT is the primary prostatic androgen responsible for cell growth and proliferation, and for facilitation of cell atrophy and apoptosis. The enzyme 5a-reductase, which exists in two distinct isoforms - type 1 and type 2, converts testosterone into DHT.
The type 2 isoenzyme is located primarily in stromal tissue of the prostate, and is critical for the normal development of the prostate; it is also involved in the development of BPH. The type 1 isoenzyme converts testosterone into DHT in peripheral tissues such as the skin and liver, but is also present in the prostate, in lower concentrations than the type 2 isoenzyme.
There is evidence to indicate that DHT is a causative factor in the development of BPH. Most importantly, BPH does not develop in men castrated before puberty, and prostate growth is significantly impaired in patients with a variety of genetic diseases that inhibit androgen-androgen production or androgen action (e.g. a type 2, 5Α-reductase deficiency).5 Furthermore, levels of intraprostatic DHT are not elevated in men with BPH, and remain normal despite the fact that circulating testosterone levels decline with ageing. Additionally, the androgen receptors are down-regulated in many androgen responsive organs after puberty, but this down-regulation does not occur in the ageing prostate. Thus, DHT-dependent growth can continue, despite the age-related declines in plasma testosterone.