Benign Prostatic Hyperplasia Nodular hyperplasia, still referred to by the term benign prostatic hyperplasia (BPH), is an extremely common

disorder in men over age 50. It is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of the prostate. When sufficiently large, the nodules compress and narrow the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra. Incidence Histologic evidence of nodular hyperplasia can be seen in approximately 20% of men 40 years of age, a figure that increases to 70% by age 60 and to 90% by age 70. There is no direct correlation, however, between histologic changes and clinical symptoms. Only 50% of those who have microscopic evidence of nodular hyperplasia have clinically detectable enlargement of the prostate, and of these individuals, only 50% develop clinical symptoms. Nodular hyperplasia of the prostate is a problem of enormous magnitude, approximately 30% of white American males over 50 years of age have moderate to severe symptoms. Etiology and Pathogenesis Much has been learned about the origins of prostatic hyperplasia. There is little doubt that this form of prostatic enlargement is related to the action of androgens. For example, prepubertal castration prevents the development of nodular hyperplasia. Dihydrotestosterone (DHT), a metabolite of testosterone, is the ultimate mediator of prostatic growth. It is synthesized in the prostate from circulating testosterone by the action of the enzyme 5-reductase, type 2. This enzyme is localized principally in the stromal cells; hence, these cells are the main site for the synthesis of DHT. Once synthesized, 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. Although testosterone can also bind to the androgen receptors and cause growth stimulation, DHT is 10 times more potent because it dissociates from the androgen receptor more slowly. While DHT appears to be the major trophic factor mediating prostatic hyperplasia, estrogens also appear to play a role, perhaps by rendering cells more susceptible to the action of DHT. Stromal-epithelial interactions mediated by peptide growth factors are also integral to the process. In addition to the mechanical effects of the enlarged prostate, clinical symptoms of lower urinary tract obstruction are also due to smooth muscle-mediated contraction of the prostate. The tension of prostate smooth muscle is mediated by the 1-adrenoreceptor localized to the prostatic stroma. This is the basis of the common use of -adrenergic receptor antagonists for the relief of urinary obstruction in patients with BPH. The importance of DHT in causing nodular hyperplasia is supported by clinical observations in which an inhibitor of 5-reductase is given to men with this condition. Therapy with 5-reductase inhibitor markedly reduces the DHT content of the prostate, and in a proportion of cases, there is a decrease in prostatic volume and urinary obstruction. The fact that not all patients benefit from androgendepriving therapy suggests that prostatic hyperplasia may be etiologically heterogeneous, and in some cases, factors other than androgens may be more important. Morphology In the usual case of prostatic enlargement, the prostate weighs between 60 and 100 gm. Careful studies have demonstrated that nodular hyperplasia of the prostate originates almost exclusively in the inner aspect of the prostate gland, in the transition zone. The first nodules are composed almost entirely of stromal cells; later, predominantly epithelial nodules arise. From their origin in this strategic location, the nodular enlargements may encroach on the lateral walls of the urethra to compress it to a slitlike orifice. In some cases, nodular enlargement may project up into the floor of the urethra as a hemispheric mass directly beneath the mucosa of the urethra, which is termed "median lobe hypertrophy" by clinicians. On cross-section of the affected prostate, the nodules usually are fairly readily identified. They vary in color and consistency. In nodules with primarily glandular proliferation, the tissue is yellow-pink with a soft consistency, and a milky white prostatic fluid oozes out of these areas. In those primarily due to fibromuscular involvement, each nodule is pale gray, tough, does not exude fluid, and is less clearly demarcated from the surrounding prostatic capsule. Although the nodules do not have true capsules, the compressed surrounding prostatic tissue creates a plane of cleavage about them, which the surgeon uses in the enucleation of prostatic masses as a treatment for very large growths of BPH. Microscopically, the hallmark of BPH is nodularity due to glandular proliferation or dilation and to fibrous or muscular proliferation of the stroma. The proportion of these elements varies from nodule to nodule, ranging from purely stromal fibromuscular nodules to fibroepithelial nodules with a glandular predominance. Glandular proliferation takes the form of aggregations of small to large to cystically dilated glands, lined by two layers, an inner columnar and an outer cuboidal or flattened epithelium, based on an intact basement membrane. Although the epithelium is characteristically thrown up into numerous papillary buds and infoldings, this finding is not specific for BPH. The diagnosis of BPH cannot usually be made on needle biopsy, as the histology of glandular or mixed glandular-stromal nodules of BPH cannot be appreciated on this limited sampling. Also, needle biopsies do not typically sample the transition zone where BPH occurs, and with the exception of stromal nodules, the histology of the prostate glands on needle biopsy does not correlate with gland size or lower urinary tract obstructive symptoms. Two other histologic changes associated with BPH are (1) foci of squamous metaplasia and (2) small areas of infarction. The former tend to occur in the margins of the foci of infarction as nests of metaplastic reactive squamous cells that can be confused with adenocarcinoma of the prostate or urothelial carcinoma involving the prostate.

Clinical Course Symptoms of nodular hyperplasia, when present, relate to two secondary effects: (1) compression of the urethra with difficulty in urination and (2) retention of urine in the bladder with subsequent distention and hypertrophy of the bladder, infection of the urine, and development of cystitis and renal infections. Patients experience frequency, nocturia, and difficulty in starting and stopping the stream of urine, overflow dribbling, and dysuria (painful micturition). In many cases, sudden, acute urinary retention appears for unknown reasons and persists until the patient receives emergency catheterization. In addition to these difficulties in urination, prostatic enlargement results in the inability to empty the bladder completely. Presumably, this inability is due to the raised level of the urethral floor so that, at the conclusion of micturition, a considerable amount of residual urine is left. This residual urine provides a static fluid that is vulnerable to infection. On this basis, catheterization or surgical manipulation provides a real danger of the introduction of organisms and the development of pyelonephritis. Many secondary changes occur in the bladder, such as hypertrophy, trabeculation, and diverticulum formation. Hydronephrosis or acute retention, with secondary urinary tract infection and even azotemia or uremia, may develop. Nodular hyperplasia is not considered to be a premalignant lesion. Mild cases of BPH may be treated without medical or surgical therapy, such as by decreasing fluid intake, especially prior to bedtime; moderating the intake of alcohol and caffeine-containing products; and following timed voiding schedules. The most commonly used and effective medical therapy for symptoms relating to benign hyperplasia are -blockers, which decrease prostate smooth muscle tone via inhibition of 1-adrenergic receptors. Another common pharmacologic therapy aims to decrease symptoms by physically shrinking the prostate with an agent that inhibits DHT. Various plant extracts are also in wide use as a treatment (phytotherapy) for this condition, although their efficacies have not been well documented. For moderate to severe cases that are recalcitrant to medical therapy, a wide range of more invasive procedures exists. Transurethral resection of the prostate (TURP) is effective in reducing symptoms, improving flow rates, and decreasing postvoid residual urine. It is indicated as a first line of therapy in certain circumstances, such as recurrent urinary retention. Owing to its morbidity and cost, alternative procedures have been developed. These include high-intensity focused ultrasound, laser therapy, hyperthermia, transurethral electrovaporization, intraurethral stents, and transurethral needle ablation using radiofrequency. Background Benign prostatic hyperplasia (BPH) is a noncancerous enlargement of the prostate gland that may restrict the flow of urine from the bladder. BPH is a proliferative process of the cellular elements of the prostate (ie, an enlarged prostate). Cellular accumulation and gland enlargement may be due to epithelial and stromal proliferation, impaired preprogrammed cell death (apoptosis), or both. More recently, the voiding dysfunction that ensues from prostate gland enlargement and bladder outlet obstruction (BOO) has been generically termed lower urinary tract symptoms (LUTS). It has also been commonly referred to as prostatism, although this term has decreased in popularity. These entities overlap; not all men with BPH have LUTS, and, likewise, not all men with LUTS have BPH. The same can be said for BOO. BPH involves both the stromal and epithelial elements of the prostate arising in the periurethral and transition zones of the gland; the condition is considered a normal part of the aging process in men and is hormonally dependent on testosterone and dihydrotestosterone (DHT) production. Pathophysiology The prostate is a walnut-sized gland that forms part of the male reproductive system. The gland is composed of several regions or lobes that are enclosed by an outer layer of tissue (capsule). The different zones are the peripheral, central, anterior fibromuscular stroma, and transition. The transition zone, which surrounds the urethra, enlarges with age in a hormonally dependent manner. Castrated males do not develop BPH. The prostate is located in front of the rectum and just below the urinary bladder. It can be examined or felt by inserting a gloved finger into the rectum. Only the posterior superficial surface of the gland can be examined this way. For a short distance, the prostate surrounds the urethra, the tube that carries urine from the bladder to the outside of the body. Its main function is primarily secretory; it produces alkaline fluid that comprises approximately 70% of the seminal volume. It is a conduit for semen to pass, and it prevents retrograde ejaculation (ejaculation resulting in semen being forced backwards into the bladder) by closing off the bladder neck during sexual climax. The fluid (semen) helps to neutralize the acidic vaginal environment and provides carbohydrates and nutrients for the sperm. Ejaculation involves a coordinated contraction of many different components, including the smooth muscles of the seminal vesicles, vasa deferentia, ejaculatory ducts, and the ischiocavernosus and bulbocavernosus muscles. The traditional theory is that as the prostate enlarges, the surrounding capsule prevents it from readily expanding, and this subsequently results in urethral compression. The notion that clinical symptoms are simply due to mass-related increases in urethral resistance is too

simplistic. Current thinking holds that obstruction-induced bladder dysfunction contributes significantly to symptoms. The bladder wall becomes thickened, trabeculated, and irritable when it is forced to hypertrophy and increase its own contractile force. This increased sensitivity (detrusor instability), even with small volumes of urine in the bladder, is believed to cause ensuing urinary frequency and LUTS. The bladder may gradually weaken and lose the ability to empty completely, thus leading to increased residual urine volume and, sometimes, acute or chronic urinary retention. History As with many disease states, the diagnosis can often be suggested based on history findings alone. Special attention to the onset and duration of symptoms, general health issues (including sexual history), fitness for any possible surgical intervention, severity of symptoms and how they are affecting QOL, medications, and previously attempted treatments is essential to making the correct diagnosis. Symptoms often attributed to BPH can be caused by neurogenic bladder, carcinoma in situ of the bladder, urethral stricture from trauma or sexually transmitted disease, cystitis, and prostatitis. Excluding these entities based on findings from a thorough history and appropriately directed diagnostic studies is essential. The prostate is a chestnut- or walnut-sized gland that produces lubrication and nutrition for sperm. It also adds alkaline fluid to the ejaculate, resulting in liquefaction. The prostate rests just below the bladder, as a collar around the urethra. When the prostate enlarges, it may act similar to a clamp on a hose, constricting the flow of urine. Nerves within the prostate also may have a role in causing the following common symptoms: Urinary frequency o The need to urinate frequently during the day or night (nocturia), usually voiding only small amounts of urine with each episode o Interrupted sleep to urinate at night Urinary urgency o The sudden urgent need to urinate quickly o The sensation of imminent loss of urine without control Hesitancy o Hesitant, interrupted, weak urinary stream o Difficulty initiating the urinary stream o Having to stand at or sit on the toilet for some time prior to producing a urinary stream Incomplete bladder emptying o The sensation of incomplete evacuation of urine from the bladder o The feeling of persistent residual urine regardless of the frequency of urination Straining - The need strain or push (Valsalva maneuver) to initiate and maintain urination in order to more fully evacuate the bladder Decreased force of stream - The subjective loss of force of the urinary stream over time Dribbling - Dribbling small amounts of urine due to a poor urinary stream Physical: Conduct a focused physical examination to assess the suprapubic area for signs of bladder distention and a cursory neurological examination for overall sensory and motor deficits. The digital rectal examination (DRE) is an integral part of the evaluation for men with presumed BPH. o During this portion of the examination, prostate size and contour can be assessed, nodules can be evaluated, and areas suggestive of malignancy can be detected. The normal prostate volume in a young adult is approximately 20 g. o A more precise volumetric determination can be made using transrectal ultrasound (TRUS). o In general, an estimation of the number of index finger pads that one can sweep over the rectal surface of the prostate during a DRE is a useful way for nonurologists to communicate estimated gland size. Anecdotally, each fingerbreadth correlates to approximately 15-20 g of tissue. For example, one can report the prostate size as 2-3 fingerbreadths wide when charting in the medical record or communicating with a colleague. Most asymptomatic men have glands less than or equal to 2 fingerbreadths. o In addition, pelvic floor tone, the presence or absence of fluctuance (ie, prostate abscess), and pain sensitivity of the gland (prostatodynia) can be assessed. o The prostate is examined using the index finger of the dominant hand. The finger is placed through the anus after relaxation of the anal sphincter, and the prostate is palpated circumferentially (analogous to a windshield wiper movement). Lab Studies: Urinalysis: Examine the urine using dipstick methods and/or via centrifuged sediment evaluation to assess for the presence of blood, leukocytes, bacteria, protein, or glucose.

 Prostate-specific antigen (PSA): Although BPH does not cause prostate cancer, men in the age range for BPH are at risk for cancer and should be screened accordingly. Men with larger prostates may have slightly higher PSA levels. Discuss the risks and benefits of screening PSA levels with the patient. Urine culture: This may be useful to exclude infectious causes of irritative voiding and is usually performed if the initial urinalysis findings indicate an abnormality. Electrolytes, BUN, and creatinine: These evaluations are useful screening tools for chronic renal insufficiency if patients have high postvoid residual urine volumes. Imaging Studies: Ultrasound (abdominal, renal, transrectal) and intravenous urography are useful for helping determine bladder and prostate size and the degree of hydronephrosis (if any) in patients with urinary retention or signs of renal insufficiency. Generally, they are not indicated for the initial evaluation of a patient with uncomplicated LUTS. Imaging of the prostate using TRUS is recommended in selected patients. The success of certain minimally invasive treatments may depend on the anatomical characteristics of the gland. o For patients with elevated PSA levels, a TRUS-guided biopsy may be indicated. o Imaging of the upper tracts is indicated if patients present with concomitant hematuria, history of urolithiasis, elevated creatinine level, high postvoid residual volume, or history of upper urinary tract infection. Other diagnostic studies, such as CT scanning or MRI, have no role in the evaluation and treatment of patients with uncomplicated BPH. Rationale for alpha1-receptor blockade in BPH A significant component of the BPH complex and its associated symptoms is believed to be related to the smooth muscle tension in the prostate stroma, urethra, and bladder neck. The smooth muscle tension in these areas is mediated by the alpha1-adrenergic receptors; therefore, alpha-adrenergic receptor-blocking agents should theoretically decrease resistance along the bladder neck, prostate, and urethra by relaxing the smooth muscle and allowing passage of urine. BPH is predominantly a stromal proliferative process, and a significant component of prostatic enlargement is due to smooth muscle proliferation. The stromal-to-epithelial ratio is significantly greater in males with symptomatic BPH relative to those with asymptomatic BPH. The 3 subtypes of the alpha-1 receptor are 1a, 1b, and 1c. Of these, the alpha-1a receptor is most specifically concentrated in the bladder neck and prostate. Provided that the alpha-1a subtype is predominant in the prostate, bladder neck, and urethra, but not in other tissues, drugs that are selective for this receptor (eg, tamsulosin) may have a potential therapeutic advantage. Tamsulosin is considered the most pharmacologically uroselective of the commercially available agents because of its highest relative affinity for the alpha1a-receptor subtype. Alpha-adrenergic receptor blockers o The alpha-blocking agents administered in BPH studies can be subgrouped according to receptor subtype selectivity and the duration of serum elimination half-lives. o Nonselective alpha-blockers include phenoxybenzamine. o Selective short-acting alpha-1 blockers include prazosin, alfuzosin, and indoramin. o Selective long-acting alpha-1 blockers include terazosin and doxazosin. o Partially subtype (alpha-1a)selective agents include tamsulosin. Nonselective alpha-blockers o Phenoxybenzamine was the first alpha-blocker studied for BPH. Its nonselective nature causes it to antagonize both the alpha1- and alpha2-adrenergic receptors, resulting in a higher incidence of adverse effects. o Because of the availability of more alpha1-receptorspecific agents, it currently is not often used for the treatment of BPH.