Benign prostatic hyperplasia
|Benign prostatic hyperplasia|
Diagram illustrating normal prostate (left) and benign prostatic hyperplasia (right).
|Classification and external resources|
|Patient UK||Benign prostatic hyperplasia|
Benign prostatic hyperplasia (BPH), also called benign enlargement of the prostate (BEP or BPE), adenofibromyomatous hyperplasia and benign prostatic hypertrophy (technically incorrect usage), is a benign (noncancerous) increase in size of the prostate. BPH involves hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the transition zone of the prostate. When sufficiently large, the nodules impinge on the urethra and increase resistance to flow of urine from the bladder. This is commonly referred to as "obstruction," although the urethral lumen is no less patent, only compressed. Resistance to urine flow requires the bladder to work harder during voiding, possibly leading to progressive hypertrophy, instability, or weakness (atony) of the bladder muscle. BPH involves hyperplasia (an increase in the number of cells) rather than hypertrophy (a growth in the size of individual cells), but the two terms are often used interchangeably, even among urologists. Although prostate specific antigen levels may be elevated in these patients because of increased organ volume and inflammation due to urinary tract infections, BPH does not lead to cancer or increase the risk of cancer.
Adenomatous prostatic growth is believed to begin at approximately age 30. An estimated 50% of men have histologic evidence of BPH by age 50 and 75% by age 80; in 40–50% of these men, BPH becomes clinically significant. BPH was one of the ten most prominent and costly diseases in men older than 50 years of age in a study in the United States.
Signs and symptoms
BPH is the most common cause of lower urinary tract symptoms (LUTS), which are divided into storage, voiding, and symptoms which occur after urination. Storage symptoms include the need to urinate frequently, waking at night to urinate, urgency (compelling need to void that cannot be deferred), involuntary urination, including involuntary urination at night, or urge incontinence (urine leak following a strong sudden need to urinate). Voiding symptoms include urinary hesitancy (a delay between trying to urinate and the flow actually beginning), intermittency (not continuous), involuntary interruption of voiding, weak urinary stream, straining to void, a sensation of incomplete emptying, and terminal dribbling (uncontrollable leaking after the end of urination, also called post-micturition dribbling). These symptoms may be accompanied by bladder pain or pain while urinating, called dysuria.
Bladder outlet obstruction (BOO) can be caused by BPH. Symptoms are abdominal pain, a continuous feeling of a full bladder, frequent urination, acute urinary retention (inability to urinate), pain during urination (dysuria), problems starting urination (urinary hesitancy), slow urine flow, starting and stopping (urinary intermittence), and nocturia.
BPH can be a progressive disease, especially if left untreated. Incomplete voiding results in residual urine or urinary stasis, which can lead to an increased risk of urinary tract infection.
Symptoms can vary throughout the day with mild symptoms after standing or walking and more pronounced symptoms after lying down.
Most experts consider androgens (testosterone and related hormones) to play a permissive role in the development of BPH. This means that androgens have to be present for BPH to occur, but do not necessarily directly cause the condition. This is supported by evidence suggesting that castrated boys do not develop BPH when they age. In an unusual study of 26 eunuchs from the palace of the Qing dynasty still living in Beijing in 1960, the prostate was impalpable (could not be felt) in 81%. The average time since castration was 54 years (range, 41–65 years). On the other hand, some studies suggest that administering exogenous testosterone is not associated with a significant increase in the risk of BPH symptoms, so the role of testosterone in prostate cancer and BPH is still unclear. Further randomized controlled trials with more participants are needed to quantify any risk of giving exogenous testosterone. Dihydrotestosterone (DHT), a metabolite of testosterone, is a critical mediator of prostatic growth. DHT is synthesized in the prostate from circulating testosterone by the action of the enzyme 5α-reductase, type 2. This enzyme is localized principally in the stromal cells; hence, those cells are the main site for the synthesis of DHT.
DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. DHT is ten times more potent than testosterone because it dissociates from the androgen receptor more slowly. The importance of DHT in causing nodular hyperplasia is supported by clinical observations in which an inhibitor of 5α-reductase such as finasteride is given to men with this condition. Therapy with a 5α-reductase inhibitor markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and BPH symptoms.
Testosterone promotes prostate cell proliferation, but relatively low levels of serum testosterone are found in patients with BPH. One small study has shown that medical castration lowers the serum and prostate hormone levels unevenly, having less effect on testosterone and dihydrotestosterone levels in the prostate.
While there is some evidence that estrogen may play a role in the etiology of BPH, this effect appears to be mediated mainly through local conversion of androgens to estrogen in the prostate tissue rather than a direct effect of estrogen itself. In canine in vivo studies castration, which significantly reduced androgen levels but left estrogen levels unchanged, caused significant atrophy of the prostate. Studies looking for a correlation between prostatic hyperplasia and serum estrogen levels in humans have generally shown none.
In 2008, Gat et al. published evidence that BPH is caused by failure in the spermatic venous drainage system resulting in increased hydrostatic pressure and local testosterone levels elevated more than 100 fold above serum levels. If confirmed, this mechanism explains why serum androgen levels do not seem to correlate with BPH and why giving exogenous testosterone would not make much difference. This also has implications for treatment (see Minimally invasive therapies below).
Studies indicate that dietary patterns may affect development of BPH, but further research is needed to clarify any important relationship. Studies from China suggest that greater protein intake may be a factor in development of BPH. Men older than 60 in rural areas had very low rates of clinical BPH, while men living in cities and consuming more animal protein had a higher incidence. On the other hand, a study in Japanese-American men found a strong association with alcohol intake, but a weak association with beef intake. In a large prospective cohort study in the US (the Health Professionals Follow-up Study), investigators reported modest associations between BPH (men with strong symptoms of BPH or surgically confirmed BPH) and total energy and protein, but not fat intake. There is also epidemiological evidence linking BPH with metabolic syndrome (concurrent obesity, impaired glucose metabolism and diabetes, hypertriglyceridemia, low-density cholesterol and hypertension).
Benign prostatic hyperplasia is an age-related disease. Misrepair-accumulation aging theory suggests that development of benign prostatic hyperplasia is a consequence of fibrosis and weakening of the muscular tissue in the prostate. The muscular tissue is important in the functionality of the prostate, and provides the force for excreting the fluid produced by prostatic glands. However, repeated contractions and dilations of myofibers will unavoidably cause injuries and broken myofibers. Myofibers have low potential of regeneration; therefore collagen fibers need to be used to replace the broken myofibers. Such misrepairs make the muscular tissue weak in functioning, and the fluid secreted in glands cannot be excreted completely. Then, the accumulation of fluid in glands increases the resistance of muscular tissue during the movements of contractions and dilations, and more and more myofibers will be broken and replaced by collagen fibers. Progressive fibrosis of muscular tissue and accumulation of fluid are important causes for the expanding of the prostate in benign prostatic hyperplasia.
Both the glandular epithelial cells and the stromal cells (including muscular fibers) undergo hyperplasia in BPH.:694 Most sources agree that of the two tissues, stromal hyperplasia predominates, but the exact ratio of the two is unclear.:694
Anatomically the median lobe is usually enlarged in BPH. The anterior lobe has little in the way of glandular tissue and is seldom enlarged. (Carcinoma of the prostate typically occurs in the posterior lobe – hence the ability to discern an irregular outline per rectal examination). The earliest microscopic signs of BPH usually begin between the age of 30 and 50 years old in the PUG, which are posterior to the proximal urethra.:694 In BPH, the majority of growth occurs in the TZ.:694 In addition to these two classic areas, the peripheral zone (PZ) of the prostate is also involved to a lesser extent.:695 Prostatic cancer typically occurs in the PZ. However, BPH nodules, usually from the TZ are often biopsied anyway to rule out cancer in the TZ.:695 However, cancers of the prostate most frequently occur in the PZ rather than the TZ, thus, chippings taken from the PZ are of limited use.
BPH is diagnosed using the American Urological Association Symptom Index (AUA-SI), the internationally validated counterpart, the International Prostate Symptom Score (I-PSS), and more recently the UWIN score (urgency, weak stream, incomplete emptying, and nocturia). An IPSS score <7 is "mildly symptomatic" and does not usually require pharmacotherapy. Screening and diagnostic procedures for BPH are similar to those used for prostate cancer. The clinical diagnosis is based on a history of LUTS, a digital rectal exam, and exculsion of other causes. The degree of LUTS does not necessarily correspond to the size of the prostate. The differential diagnosis includes other diseases of the bladder, urethra, and prostate such as bladder cancer, urinary tract infection, urethral stricture, urethral calculi (stones), chronic prostatitis and prostate cancer.
Rectal examination (palpation of the prostate through the rectum) may reveal a markedly enlarged prostate, usually affecting the middle lobe. Blood tests are often performed to rule out prostatic malignancy. Elevated prostate specific antigen (PSA) levels need further evaluation, such as reinterpretation of PSA results, in terms of PSA density and PSA free percentage, rectal examination and transrectal ultrasonography. These combined measures can provide early detection. Ultrasound examination of the testicles, prostate, and kidneys is often performed, again to rule out malignancy and hydronephrosis.
Lifestyle alterations to address the symptoms of BPH include decreasing fluid intake before bedtime, moderating the consumption of alcohol and caffeine-containing products, and following a timed voiding schedule. Patients can also attempt to avoid products and medications that may exacerbate symptoms of BPH, including antihistamines, diuretics, decongestants, opiates, and tricyclic antidepressants; however, changes in medications should be done with input from a medical professional.
Voiding position when urinating may influence urodynamic parameters (urinary flow rate, voiding time, and post-void residual volume). A meta-analysis found no differences between the standing and sitting positions for healthy males, but that, for elderly males with lower urinary tract symptoms (LUTS), voiding in the sitting position:
- the post void residual volume was significantly decreased
- the maximum urinary flow was increased, comparable with pharmacological intervention
- the voiding time was decreased
The two main medications for management of BPH are alpha blockers and 5α-reductase inhibitors. Alpha blockers are the most common choice for initial therapy. They include doxazosin, terazosin, alfuzosin, tamsulosin, and silodosin. They have a small to moderate benefit. All five are equally effective but have slightly different side effect profiles. The older drugs phenoxybenzamine and prazosin are not recommended. Alpha blockers relax smooth muscle in the prostate and the bladder neck, thus decreasing the blockage of urine flow. Common side effects of alpha blockers include orthostatic hypotension, (a head rush or dizzy spell when standing up or stretching), ejaculation changes, headaches, nasal congestion, and weakness. Non-selective alpha blockers such as terazosin and doxazosin may also require titration (gradually adjusting the dose of a medication) as they can cause syncope (fainting) if the dose is too high. Side effects can also include erectile dysfunction.
The 5-alpha-reductase inhibitor finasteride and dutasteride are another treatment option. These medications inhibit 5a-reductase, which in turn inhibits production of DHT, a hormone responsible for enlarging the prostate. Effects may take longer to appear than alpha blockers, but they persist for many years. When used together with alpha blockers, no benefit was reported in short-term trials, but in a longer term study (3–4 years) there was a greater reduction in BPH progression to acute urinary retention and surgery than with either agent alone, especially in patients were more severe symptoms and larger prostates. Other trials have confirmed reductions in symptoms, within 6 months in one trial, an effect that was maintained after withdrawal of the alpha-blocker. Side effects include decreased libido and ejaculatory or erectile dysfunction. The 5-alpha-reductase inhibitors are contraindicated in pregnant women because of the interference with testosterone metabolism, and as a precaution, pregnant women should not handle crushed or broken tablets.
Antimuscarinics such as tolterodine may also be used, especially in combination with alpha blockers. They act by decreasing acetylcholine effects on the smooth muscle of the bladder, thus helping control symptoms of an overactive bladder.
Sildenafil citrate shows some symptomatic relief, suggesting a possible common cause with erectile dysfunction. Tadalafil was considered then rejected by NICE in the UK for the treatment of symptoms associated with BPH. In 2011, the U.S. Food and Drug Administration approved tadalafil to treat the signs and symptoms of benign prostatic hyperplasia, and for the treatment of BPH and erectile dysfunction (ED), when the conditions occur simultaneously.
Intermittent urinary catheterization is used to relieve the bladder in people with urinary retention. Self-catheterization is an option in BPH when the bladder is difficult or impossible to completely empty. Urinary tract infection is the most common complication of intermittent catheterization. Several techniques and types of catheter are available, including sterile (single-use) and clean (multiple use) catheters, but none is superior to others in reducing the incidence of urinary tract infection based on current information.
Minimally invasive therapies
Although medication is often prescribed as the first treatment option, many patients do not achieve success with pharmacotherapy. They may not achieve sustained improvement in symptoms or may stop taking the medication because of side-effects. There are options for treatment in a urologist's office before proceeding to surgery. The two most common types of office-based therapies are transurethral microwave thermotherapy (TUMT) and transurethral needle ablation (TUNA). Both of these procedures rely on delivering enough energy to create sufficient heat to cause cell death (necrosis) in the prostate. The goal is to cause enough necrosis so that, when the dead tissue is reabsorbed by the body, the prostate shrinks, relieving the obstruction of the urethra. These procedures are typically performed with local anesthesia, and the patient returns home the same day. Some urologists have studied and published long-term data on the outcomes of these procedures, with data out to five years. The most recent American Urological Association (AUA) Guidelines for the Treatment of BPH in 2003 lists minimally invasive therapies including TUMT and TUNA as acceptable alternatives for certain patients with BPH. However, European guidelines do not recommend the use of TUMT or TUNA over surgery.
Transurethral microwave therapy (TUMT) was originally approved by the United States Food and Drug Administration (FDA) in 1996, with the first generation system by EDAP Technomed. Since 1996, other companies have received FDA approval for TUMT devices, including Urologix, Dornier, Thermatrix, Celsion, and Prostalund. Multiple clinical studies have been published on TUMT. The general principle underlying all the devices is that a microwave antenna that resides in a urethral catheter is placed in the intraprostatic area of the urethra. The catheter is connected to a control box outside of the patient's body and is energized to emit microwave radiation into the prostate to heat the tissue and cause necrosis. It is a one-time treatment that takes approximately 30 minutes to 1 hour, depending on the system used. It takes approximately 4 to 6 weeks for the damaged tissue to be reabsorbed into the patient's body. Some of the devices incorporate circulating coolant through the treatment area with the intent of preserving the urethra while the microwave energy heats the prostatic tissue surrounding the urethra.
Transurethral needle ablation (TUNA) operates with a different type of energy, radio frequency (RF) energy, but is designed along the same premise as TUMT devices, that the heat the device generates will cause necrosis of the prostatic tissue and shrink the prostate. The TUNA device is inserted into the urethra using a rigid scope much like a cystoscope. The energy is delivered into the prostate using two needles that emerge from the sides of the device, through the urethral wall and into the prostate. The needle-based ablation devices are very effective at heating a localized area to a high enough temperature to cause necrosis. The treatment is typically performed in one session, but may require multiple sticks of the needles depending on the size of the prostate.
If medical treatment fails, and the patient elects not to try office-based therapies or the physician determines the patient is a better candidate for transurethral resection of prostate (TURP), surgery may need to be performed. In general, TURP is still considered the gold standard of prostate interventions for patients who require a procedure. This involves removing (part of) the prostate through the urethra. However, after this endoscopic surgery the ejaculations are dry and the person becomes sterile. For a man who wishes to father a child this is not the procedure of choice. Over the past couple of decades efforts to find newer surgical methods have resulted in newer approaches and different types of energies being used to treat the enlarged gland. However some of the newer methods for reducing the size of an enlarged prostate, have not been around long enough to fully establish their safety or side-effects. These include various methods to destroy or remove part of the excess tissue while trying to avoid damaging what remains. Transurethral electrovaporization of the prostate (TVP), laser TURP, visual laser ablation (VLAP), ethanol injection, and others are studied as alternatives.
Newer techniques involving lasers in urology have emerged in the last 5–10 years, starting with the VLAP technique involving the Nd:YAG laser with contact on the prostatic tissue. A similar technology called photoselective vaporization of the prostate (PVP) with the GreenLight (KTP or LBO crystal) laser have emerged very recently. This procedure involves a high-power 180-watt 532 nm wavelength laser with a 650-micrometre laser fiber inserted into the prostate. This fiber has an internal reflection with a 70-degree deflecting angle. It is used to vaporize the tissue to the prostatic capsule. GreenLight 532 nm lasers target haemoglobin as the chromophore and typically have a penetration depth of 0.8 mm (twice as deep as holmium). The procedure termed Holmium Laser Ablation of the Prostate (HoLAP) has been gaining acceptance around the world. Like KTP, the delivery device for HoLAP procedures is a 550 um disposable side-firing fiber that directs the beam from a high-power 100-watt laser at a 70-degree angle from the fiber axis. The holmium wavelength is 2,140 nm, which falls within the infrared portion of the spectrum and is invisible to the naked eye. Whereas GreenLight relies on haemoglobin as a chromophore, water within the target tissue is the chromophore for Holmium lasers. The penetration depth of Holmium lasers is <0.4 mm, avoiding complications associated with tissue necrosis often found with the deeper penetration and lower peak powers of Nd:YAG lasers used in the 1990s.
HoLEP, Holmium Laser Enucleation of the Prostate, is another Holmium laser procedure reported to carry fewer risks compared with either TURP or open prostatectomy. HoLEP is largely similar to the HoLAP procedure; the main difference is that this procedure is typically performed on larger prostates. Instead of ablating the tissue, the laser cuts a portion of the prostate, which is then cut into smaller pieces and flushed with irrigation fluid. As with the HoLAP procedure, there is little bleeding during or after the procedure. A recent review concludes that HoLEP is superior to TURP and should become the new gold standard.
Both wavelengths, GreenLight and Holmium, ablate approximately one to two grams of tissue per minute.
In summary, the surgical techniques used are:
- Open prostatectomy: not usually performed nowadays, even if results are very good.
- Trans-urethral resection of the prostate (TURP): the gold standard.
- Transurethral incision of the prostate (TUIP): rarely performed; the technique is similar to TURP but less definitive.
- Laser vaporization of the prostate: common treatment.
- Transurethral microwave therapy (TUMT): similar to laser ablation, but less effective and much less used.
- Transurethral needle ablation (TUNA): not very effective.
- Holmium laser enucleation of the prostate (HoLEP): more and more used, it will probably replace TURP in the future.
Herbal remedies are commonly used, and several are approved in European countries and available in the USA. Saw palmetto extract from Serenoa repens is one of the most commonly used and studied, having shown some promise in early studies. Later trials of higher methodological quality have shown it to be no better than placebo in both symptom relief and decreasing prostate size. Other herbal medicines include beta-sitosterol from Hypoxis rooperi (African star grass) and pygeum (extracted from the bark of Prunus africana), while there is less substantial support for the efficacy of pumpkin seed (Cucurbita pepo) and stinging nettle (Urtica dioica) root. A systematic review of Chinese herbal medicines found that the quality of studies was insufficient to indicate any superiority over Western medicines.
Globally, benign prostatic hyperplasia affects about 210 million males as of 2010 (6% of the population). The prostate gets larger in most men as they get older. For a symptom-free man of 46 years, the risk of developing BPH over the next 30 years is 45%. Incidence rates increase from 3 cases per 1000 man-years at age 45–49 years, to 38 cases per 1000 man-years by the age of 75–79 years. While the prevalence rate is 2.7% for men aged 45–49, it increases to 24% by the age of 80 years.
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