Health and Prostate

The alternative pharmacological approach to patients with benign prostatic hyperplasia (BPH) is to inhibit androgens that are responsible for prostatic hyperplasia. Androgen deprivation is well known to induce prostatic shrinkage. Trials with antiandrogens have been attempted for many years; however, their use has been limited by the high incidence of adverse effects such as impotence and loss of libido.

The concept of inhibiting dihydrotestosterone (DHT) came from studies involving patients with a deficiency of the 5-alpha reductase enzyme. This autosomal recessive genetic disorder affects males, who at birth have ambiguous genitals but normal male internal testes and structures, and are thus termed pseudohermaphrodites. These patients were raised as females, but at puberty, with the associated surge of testosterone, their penises enlarged and voices deepened. These males had small prostate glands and never developed benign prostatic hyperplasia (BPH).

Finasteride is a potent inhibitor of 5-alpha reductase, decreasing DHT levels by 70%–75%. Since prostatic hyperplasia is contingent on the presence of dihydrotestosterone (DHT), finasteride causes prostate gland atrophy and may decrease prostate size by 30%. The selective nature of this enzyme inhibition to decrease only DHT explains why this treatment is superior to other antiandrogenic hormonal manipulations associated with increased hormonally mediated side effects. Many patients receiving antiandrogenic therapies often experience decreased libido and impotence. Patients receiving finasteride actually have elevated levels of serum testosterone and many retain preservation of the desirable testosterone effects on muscle strength, bone density and sexual function.

Clinical trials evaluating the efficacy of finasteride (5 mg orally daily) have demonstrated significant decreases in prostatic volume, improved peak urinary flow rate and improved symptom scores. However, some investigators have reported only mild improvement in symptomatology and urinary flow rates. Notably, complete clinical effects of finasteride therapy may not be realized for 6 to 12 months.

Finasteride has minimal side effects and its long term safety profile has been well-described. Approximately 5% of patients in two large clinical trials experienced decreased libido, ejaculatory dysfunction or impotence. Finasteride also caused a 50% decrease of serum PSA. A decreased prostate-specific antigen (PSA) level may be disconcerting since PSA is widely used to aid in the detection of early prostate cancer, which develops in men of the same age as those in whom BPH develops. A normal PSA reference range is considered 0 mcg/L–4 mcg/L. It has been proposed that the appropriate prostate-specific antigen (PSA) reference range for patients on 5 mg of finasteride is 0 mcg/L–2 mcg/L.

Recently, a debate regarding finasteride’s clinical efficacy has surfaced. Some investigators state that the relief of urinary symptoms experienced by patients with benign prostatic hyperplasia (BPH) on finasteride is at best moderate, and may not be clinically significant. Conversely, other investigators suggest that finasteride may arrest the progress of BPH, and it may be useful in patients with mild or moderate disease in lieu of watchful waiting, hence preventing the progress of BPH to a more severe state requiring TURP. Perhaps the most appealing feature of finasteride is its side effect profile.

Combination Therapy

Recently the efficacy of terazosin, finasteride and the combination of both agents was evaluated in patients with benign prostatic hyperplasia (BPH). Patients received either placebo, terazosin 10 mg daily, finasteride 5 mg daily, or a combination of both drugs, and were assessed periodically for one year. The study found that terazosin improved urinary symptoms and urinary flow rate while finasteride did not. Combination therapy was no more effective than terazosin alone. Finasteride’s lack of clinical effect may be due to the inclusion criteria, which did not require participants to have a significantly enlarged prostate, since only these men would be expected to respond favorably to finasteride. In conclusion, symptomatic males who do not have a significantly enlarged prostate should be treated with an alpha-1 blocker. Conversely, if the prostate is significantly enlarged, then treatment with either an alpha-1 blocker or finasteride is acceptable.

Conclusion

It is important for pharmacists to develop an understanding of this common disease state in order to inform and guide patients appropriately. Therapy used to treat benign prostatic hyperplasia (BPH) is patient-specific. Transurethral resection of the prostate produces the best overall results in terms of clinical symptoms and urinary flow rate. Transurethral incision of the prostate is an underutilized procedure that offers substantial improvement to the patient, and is associated with less morbidity, particularly ejaculatory disorders. Other less-invasive interventions also offer promising results.

Because of the substantial cost imposed on the health-care system for surgical treatment as well as its associated morbidity and patient dissatisfaction, clinicians often opt for alternative therapies and attempt to hold off surgery unless absolutely indicated. Although intervention may be necessary for many patients, watchful waiting may be appropriate in those with mild prostatism. Long-acting alpha-1-adrenergic blockers such as terazosin and doxazosin have demonstrated consistent efficacy in BPH patients with or without an enlarged prostate, and are considered by many to be the best pharmacological treatment available. These agents not only improve urinary flow rate and decrease symptomatology, but they also selectively lower blood pressure in hypertensive patients and have a favorable effect on the lipid profile. Unfortunately, 10%–15% of patients on alpha-1 blockers may experience adverse effects. Slow-dose titration and administering the once-daily dose at bedtime can minimize the risk of experiencing orthostatic hypotension and related adverse effects.

Finasteride affects the disease process — hyperplasia of the prostate — by preventing the conversion of testosterone to dihydrotestosterone (DHT). Finasteride is probably best indicated for males with a significantly enlarged prostate; it shrinks the prostate gland and has an excellent adverse effect profile. Unlike previous antiandrogenic therapies, finasteride allows most patients to maintain their libido and sexual functioning.

Treatment for benign prostatic hyperplasia (BPH) must be patient specific and includes watchful waiting and monitoring, pharmacotherapy, minimally invasive therapy and surgery. Certain patients may benefit more from surgery than pharmacotherapy based upon results of the clinician’s evaluation and the patient’s subjective assessment of their disease state. When contemplating therapeutic options, it is important for the clinician to realize that 30%–50% of men will experience spontaneous improvement of symptoms. This is also evident when assessing efficacy in clinical trials since there is a significant placebo effect. Additionally, one must be wary of clinical trials evaluating nonsurgical and minimally invasive therapies for BPH since they often have numerous limitations — they may not be properly randomized, double-blinded or placebo controlled. These inconsistencies might explain why a clear consensus in the literature regarding the effectiveness of different treatment options for benign prostatic hyperplasia (BPH) is lacking.

For many years transurethral resection of the prostate (TURP) was the standard of care for patients with BPH and is still considered the most effective treatment by many experts. Unfortunately, many patients have complications related to this surgical procedure and are dissatisfied with the results. Therefore, there is an increased interest in finding effective nonsurgical therapies for patients with benign prostatic hyperplasia (BPH). One option for patients with mild prostatism is simply watchful waiting. Watchful waiting may be appropriate when symptoms are not affecting the patient’s activities of daily living and there is no evidence of bladder or upper urinary tract deterioration. With this approach, patients are continually reevaluated and are assessed for complications or worsening of symptoms. Although this may be viewed as a nonaggressive approach, it is important to remain cognizant that a significant number of patients not receiving treatment will either improve or have no change in their symptomatology. For those patients who experience bothersome symptoms, medical intervention is indicated since watchful waiting may result in unnecessary complications.

Surgical Treatment of Benign Prostatic Hyperplasia (BPH)

Surgical intervention is considered the gold standard for the treatment of benign prostatic hyperplasia (BPH) and offers the best chance for symptom improvement. Surgical management is recommended for patients who have failed either pharmacological or minimally invasive therapy (e.g., balloon dilatation, transurethral microwave hyperthermia) for obstructive symptoms, and in patients with more advanced disease (e.g., serious urinary retention).

Surgical prostatectomy refers to the surgical removal of the enlarged portion of the prostate. This can be performed either through the urethra (TURP) or an open prostatectomy. Twenty-five percent of appropriately aged men undergo TURP, and it is second only to cataract removal as the most common surgery reimbursed by Medicare. Transurethral resection of the prostate costs approximately $10,000 including hospitalization per procedure; total expenditures to the health care system are approximately $5 billion annually.

The probability of symptomatic improvement is greatest with surgical options; however, there are a plethora of significant adverse effects. Approximately 20% of patients will experience procedure complications, and mortality is estimated at 0.2%. Typical perioperative complications include urinary retention, thrombus formation, hemorrhage requiring transfusion, urethral stricture and bladder neck contracture. Retrograde ejaculation (failure of the bladder neck to close during ejaculation) occurs in over 70% of patients after TURP or open prostatectomy. Another 5%–10% of patients will suffer from impotence postoperatively. Urinary incontinence is common and may be subclassified as stress urinary incontinence (involuntary urine loss during physical activity), urge urinary incontinence (involuntary urine loss associated with an uncontrollable urge to void), or total urinary incontinence (complete loss of the voluntary control of voiding). In addition, patients frequently will complain of bladder irritability.

Post-TURP syndrome occurs perioperatively in 2% of patients undergoing TURP. Post-TURP syndrome is a dilutional hyponatremia that occurs secondary to absorption of large quantities of hypotonic fluid used for irrigation during the procedure. It is manifested by mental confusion, nausea, vomiting, hypertension, bradycardia and visual disturbances. Despite the success associated with TURP, many patients will need a repeat procedure in the following years and 20%–25% of patients do not have satisfactory long-term outcomes. Some investigators have also suggested that men who undergo TURP have a shorter lifespan than those who do not; however, this data has been refuted. Due to the associated morbidity of TURP and patient discontent, interest in other treatment modalities has emerged.

Transurethral incision of the prostate (TUIP) is a minimally invasive procedure ideal for men with small prostates. TUIP’s indications are analogous with those of TURP and prostatectomy. Deep incisions are made through the prostate gland to the level of the capsule, relieving bladder outlet obstruction. Studies have demonstrated that TUIP can significantly improve patients’ symptom scores and objective parameters. Comparative studies reveal lower complication rates with TUIP than TURP. Duration of surgery, hospitalization and onset of convalescence are all shorter. Notably, there is a lower incidence of impotence, retrograde ejaculation and incontinence. Transurethral incision of the prostate (TUIP) is ideal for many surgical candidates; however, it is markedly underutilized.

In addition to transurethral incision of the prostate (TUIP), other minimally invasive procedures include the use of prostatic stents, microwave therapy delivered to the prostate trans-rectally or transurethrally,laser ablation of the prostate or laser prostatectomy, and prostatic balloon dilation. These are promising procedures that will need to be investigated further.

The patient’s initial evaluation should consist of a complete history, physical examination (including digital rectal examination (DRE)), urinalysis and assessment of his renal function (serum creatinine and blood urea nitrogen level). In addition, a urine culture is recommended in order to aid in ruling out a urinary tract infection. All medications the patient is currently taking should be scrutinized since drugs such as anticholinergics (e.g., disopyramide, tricyclic antidepressants, neuroleptics), alpha-adrenergic agonists and calcium channel blockers can cause obstructive symptoms as well. Prostatic enlargement can be identified by DRE (although not very reliably), as well as the more reliable ultrasound and other imaging studies. However, there is little correlation between prostate size and degree of voiding symptomatology. A prostate gland that feels small on palpation may cause a significant degree of bladder outlet obstruction if the area around the urethra, which cannot be palpated, is enlarged. Conversely, an enlarged prostate gland may produce no symptoms if it does not constrict the urethra.

Measuring the patient’s prostate-specific antigen (PSA) level is irrelevant in the evaluation of benign prostatic hyperplasia (BPH). However, since occult prostate cancer may be present in 10%–20% of patients with BPH symptoms, many clinicians recommend contemporaneous PSA measurements. Notably, prostate infection and benign prostatic hyperplasia (BPH) can cause a falsely elevated PSA value — transrectal ultrasound may be necessary to evaluate the significance of an elevated prostate-specific antigen (PSA) level in these settings.

A urologist usually selects a battery of other tests in order to determine the significance of the benign prostatic hyperplasia (BPH) symptoms. A urinary flow test (uroflowmetry) is routinely done in which the patient voids into a flowmeter to assess how efficiently the patient is evacuating urine. The peak urinary flow rate and voiding pattern (continuous or intermittent) is a useful indicator of outflow resistance. Measurements of postvoid residual volume (PVR) and pressure flow studies can also be done. Cystometry, urethrocystoscopy and intravenous urography are usually not part of an initial evaluation but are reserved for individuals with more complicated cases.

Patients with benign prostatic hyperplasia experience symptoms of prostatism which are considered either irritative or obstructive in nature (Table 1). The symptomatology of benign prostatic hyperplasia (BPH) often varies, and significant intra- and interindividual variation in symptoms exists. Nocturia, urinary urgency and frequency and pain or burning on urination are typical irritative symptoms, while obstructive symptoms manifest with urinary hesitancy, straining or dribbling during micturition, and a weak or interrupted stream of urine. Initially, the bladder can expel urine past the prostatic blockage. Eventually the bladder is no longer able to compensate, which results in incomplete emptying and stasis of urine within the bladder. Patients may present with severe symptoms that are hallmarks of advanced disease, such as urinary retention, urinary tract infections, nephrolithiasis, hydronephrosis, gross hematuria and compromised renal function.

The Multidisciplinary Measurements Committee of the American Urological Association (AUA) published its Urinary Symptom Index for Prostatism (Table 2) which is an accepted and validated patient questionnaire. In order to eliminate any bias from interviewer technique, the patient administers a seven-question test to himself. The AUA symptom score is an indicator of symptom severity from mild to severe prostatism. However, the AUA symptom index may not be BPH-specific, and significant interindividual variation is often seen. A recent study compared the scores obtained from the AUA index in an unselected group of men and a parallel group of women between 55 and 79 years of age. The prevalence and severity of symptoms of prostatism as defined by the AUA symptom index was identical between groups. These findings suggest that the development of urinary symptoms termed “prostatism” is probably a multifactorial process and not exclusively related to benign prostatic hyperplasia (BPH).

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Benign prostatic hyperplasia (BPH) is the most common cause of voiding dysfunction, and one of the most frequent causes of disability in aging men. BPH is a nonmalignant neoplasm of prostatic epithelial and stromal tissue. Often inappropriately termed “benign prostatic hypertrophy,” the disease process involves hyperplasia rather than hypertrophy. Benign prostatic hyperplasia is a rare occurrence in men less than 40 years of age. After age 40 the prevalence of BPH is age-dependent and approximately 50% of men greater than 50 years of age have moderate urinary difficulties due to the disease process. By age 85, approximately 90% of men will have BPH. Men of all races and cultures are afflicted, suggesting the etiology of BPH may not be environmentally or genetically influenced.

Often benign prostatic hyperplasia (BPH) is present prior to the fifth decade of life; however, it is benign and unnoticed since patients are usually asymptomatic. Generally BPH becomes symptomatic commencing with the fifth decade of life. Identified risk factors for BPH are aging and normal testicular function. Since the prostate surrounds the urethra, urinary symptoms are the signs of prostatic hyperplasia. Although benign prostatic hyperplasia (BPH) and prostate cancer often coexist, there is no evidence that men with BPH are more likely to develop prostate cancer.

Pathogenesis of benign prostatic hyperplasia (BPH)

Aging and androgens are all that is required for the development of benign prostatic hyperplasia (BPH). The disease is not seen in men who are castrated early in life, and castration actually promotes regression of BPH. Testosterone, the major circulating androgen, diffuses into the prostate cells, and is predominantly converted to dihydrotestosterone (DHT) by the enzyme 5-alpha reductase. More than 90% of testosterone in the prostate is of testicular origin with the remainder produced by the adrenal glands. Testosterone and DHT bind to androgen receptors and result in increased protein biosynthesis and hyperplasia. Thus, prostatic hyperplasia is dependent directly on androgen stimulation.

Prostatic obstruction consists of two elements: the static and dynamic components. The static component is related to enlargement of the prostate gland, which requires the presence of dihydrotestosterone (DHT). Thus, the use of antiandrogens and more recently the 5-alpha reductase inhibitor finasteride (Proscar), approved in 1992 by the Food and Drug Administration (FDA) to treat BPH, are therapeutic options. The dynamic component originates from the tone of the prostatic smooth muscle and is under the influence of the sympathetic nervous system. Smooth muscle contraction in the urethra, prostate and bladder neck contribute to the voiding symptoms of benign prostatic hyperplasia (BPH). Research in the animal model demonstrated that the rat prostate contracts in the presence of norepinephrine, an adrenergic agonist. Alpha-adrenergic receptors are abundant in the prostatic adenoma, prostatic capsule, and bladder neck, and these adrenergic receptors are primarily the alpha-1 type. On the basis of these findings, the nonselective alpha-adrenergic antagonist phenoxybenzamine was studied as an agent to decrease muscular resistance to urinary outflow, and proved to be beneficial in the treatment of BPH. Consequently, the selective alpha-1 adrenergic antagonists (prazosin, terazosin and doxazosin) have been advocated for use in patients with benign prostatic hyperplasia (BPH).