Erectile dysfunction is the inability to attain or maintain penile erection sufficient for vaginal intromission. In determining the true incidence of erectile dysfunction as a consequence of prostate cancer therapy, one must consider the total prevalence of erectile dysfunction in the age-matched population. Estimates of all degrees of severity of erectile dysfunction range from 40% in men 40 years of age to 70% in men in their seventies, and are associated with vascular risk factors such as cardiovascular and peripheral vascular disease, hypertension, diabetes, and cigarette smoking. One of the difficulties in isolating the incidence of erectile dysfunction due solely to the complications of prostate cancer therapy, therefore, is the increased incidence of erectile dysfunction associated with aging or concomitant vascular disease. Further, the distinctions between the ability to attain and maintain an erection sufficient for penetration and the patient’s observations that “my erection is not as hard as it used to be” complicate assessment of the actual definition of erectile dysfunction in age-matched cohorts. Despite these limitations, the author’s goal is to understand the treatment-specific etiologies of erectile dysfunction in men undergoing both surgical and nonsurgical treatment for prostate cancer. The different treatment modalities will be examined and the possible mechanisms and incidence of erectile dysfunction discussed as well as potential future therapy.

Erectile Dysfunction following Radical Prostatectomy

Radiation Therapy for Prostate Cancer

The impact of radiation therapy for prostate cancer on the development of erectile dysfunction is unclear, as the widely varying results of various studies indicate. Following external beam radiation, potency is maintained in 40 to 73% of patients. As with other studies, there is considerable variation in results due to patient age, disease status, preoperative potency, definitions of potency, treatment regimens, and length of follow-up.

Potency following three-dimensional conformal radiotherapy is maintained in 30 to 70% of patients, similar to results for conventional external beam radiation. Efforts at distinguishing full and partial potency are made in these studies. Assessing results in relation to those of other studies is difficult.

Radioactive seed implantation caused erectile dysfunction in 6 to 7% of patients and resulted in a 39% chance of a decrease in erectile function at 2 years. The need for studies comparing conformal external beam radiotherapy, interstitial seeding implantation, and nerve-sparing radical prostatectomy cannot be overemphasized. Morbidity associated with prostate cancer treatment is likely to affect the patient’s choice of treatment modality. Earlier studies that report lower rates of erectile dysfunction may be inaccurate due to a lack of standardized reporting of complications. Future studies should implement objective validated instruments specifically designed for outcome analysis.

Cryosurgery

Cryosurgical ablation of the prostate as an established and recommended treatment for prostate cancer is controversial. Considerable patient interest in this alternative has been based in part on the presumption that potency would be maintained. Multiple studies, however, show a significant morbidity associated with cryosurgery. Recent reports show an erectile dysfunction rate of 60 to 90% at 6 and 12 months postoperatively. Although both studies have few patients, the assumption that potency will be maintained appears unfounded. The proposed mechanism of erectile dysfunction was felt to be vascular in origin in one study Men were injected with 10 pg of prostaglandin Ei (PGEi) both prior to and 6 months after cryoablation of the prostate. They demonstrated significant reduction in peak blood flow velocities within the cavernosal arteries and significant increase in the mean time to reach peak flow. Other studies report cavernosal nerve injury as the etiology of cryoablation-induced Erectile dysfunction. In a study by Lue et al, rats underwent cavernosal nerve freezing. Erectile function was assessed by electrostimulation of the cavernous nerves in study and sham-operated controls. They demonstrated substantial recovery of frozen nerve response at 3 months. This was associated with differential gene and protein expression of the growth factors, nerve growth factor, transforming growth factor-a, epidermal growth factor, and insulin-like growth factor (IGF)-I. This suggests a possible molecular mechanism of cryoablation-induced Erectile dysfunction in the rat model.

Hormone Therapy for Prostate Cancer

Hormone therapy for advanced prostate cancer includes surgical treatment (orchiectomy) and nonsurgical treatment (e.g., luteinizing hormone-releasing hormone [luteinizing hormone-releasing hormone] agonists, antiandrogens, estrogens, and combination therapy). Although recent studies suggest a therapeutic effect for hormonal manipulation, the associated morbidity and effect on quality of life must not be overlooked. In an early study of complete androgen blockade with buserelin and flutamide, 15% of 40 patients had loss of libido and potency at 2 months. Combination finasteride and flutamide has been suggested as potency-sparing therapy. This resulted in 18% of patients becoming impotent at their prostate-specific antigen nadir, with 27% impotent at later follow-up. Erectile dysfunction in these patients is secondary to loss of androgen stimulation. Androgen receptors in the sacral parasympathetic cord, hypothalamus, and limbic system suggest androgens play a central role in erectile function. Possible molecular mechanisms are suggested by studies demonstrating decreased nitric oxide synthase (NOS) activity in the penis of castrated rats and androgen-sensitive motor neurons of the spinal nucleus of the bulbocavernosus muscle of adult male rats.

Erectile Dysfunction Evaluation and Treatment

Summary

Advances in both pelvic anatomy and the current concepts of the pathophysiology following radical prostatectomy have led to improved surgical results. In addition, as quality-of-life issues interdigitate with medical and surgical management, the advent of oral, minimally invasive therapies and surgical therapies have resulted in continued and increased patient/partner satisfaction rates. Further progress into outcomes research will establish new inroads into quality-of-life issues for both patient and partner. Use of validated outcome measures such as the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) will allow this data to be accrued.

Erectile dysfunction following radical prostatectomy is a common problem, with the incidence variously estimated at 43, 84, and 100%. The discussion of pelvic anatomy below is helpful in understanding the potential surgical pitfalls that can lead to erectile dysfunction. Modifications in the surgical approach may decrease the incidence of postoperative erectile dysfunction. Nerve-sparing prostatectomy has led to a decrease in the incidence of Erectile dysfunction to as low as 10% in selected patients. The perineal approach for radical prostatectomy is associated with a significant incidence of erectile dysfunction.

Prostatectomy for benign prostatic hyperplasia may also result in erectile dysfunction. Reported rates of erectile dysfunction vary by procedure, with simple perineal prostatectomy at 29%, suprapubic prostatectomy at 13%, and transurethral resection ranging from 5 to 13.3%.

Etiology

Understanding the causes and prevention of prostatectomy-associated Erectile dysfunction requires a thorough understanding of pelvic anatomy. In 1982, Walsh and Donker studied stillborn male neonates to determine the topographic relationship between the pelvic nerve plexus, prostate, urethra, and urogenital diaphragm. The pelvic plexus encompasses both parasympathetic and sympathetic fibers, which innervate the pelvic organs and external genitalia. The parasympathetic nerves provide the primary component of the autonomic nervous system. Parasympathetic visceral efferent preganglionic fibers arise from S2 to S4. This pelvic nerve or nervi erigentes was first named by Eckhard in 1863. The sympathetic fibers arise from the thoracolumbar region Tl 1 to L2 and reach the pelvic plexus predominantly via the hypogastric nerve. The sacral sympathetic chain and branches accompanying the superior hemorrhoidal artery also contribute sympathetic fibers.

The pelvic plexus is located retroperitoneally on the lateral wall of the rectum, forming a fenestrated rectangular plate in the sagittal plane. Its midpoint is in relation with the tip of the seminal vesicles and extend from the sacrum ventrally as high as the pouch of Douglas. The pelvic plexus provides innervation to the rectum, bladder, prostate, seminal vesicles, urethra, and corpora cavernosa. The most caudal fibers of the pelvic plexus travel along the posterolateral aspect of the prostate to innervate the corpora cavernosa. The cavernous branch of the pelvic plexus travels at the posterolateral aspect of the base of the prostate. Here the branches coalesce and travel together with the capsular arteries and veins (neurovascular bundle) in the lateral pelvic fascia outside the prostatic capsule and Denonvillier’s fascia. At the proximal prostatic urethra, the nerves are quite distant from the prostatic capsule. As the nerves approach the apex of the prostate, they are only a few millimeters away from the prostatic capsule at the 5 and 7 o’clock positions.

Cross-section of the membranous urethra demonstrates cavernous nerve bundles at the 3 and 9 o’clock positions external to the striated sphincter muscles.

Some fibers of the cavernous nerve penetrate the tunica albuginia of the corpus spongiosum distal to the membranous urethra. These fibers innervate the vascular and erectile tissue of the corpus spongiosum and glans penis. Other fibers continue outside the corpus spongiosum. At the level at which the paired crura converge, the nerve fibers are found in the 1 and 11 o’clock positions. Some of these bundles will penetrate the corpus spongiosum individually while others travel with the deep artery and cavernous vein. After entering the corpus cavernosum, the terminal branches divide and innervate the helicine arteries and central erectile tissue.

Erectile dysfunction can also result as a complication of inadvertent damage to the pelvic vascular supply during prostate surgery; a discussion of the pelvic vasculature is therefore in order. The arterial supply to the corpus cavernosum may vary from patient to patient. The arterial supply to the penis is classically described as three branches from the internal pudendal. The bulbourethral arteries are the first branches of the internal pudendal reaching the penis, entering distal to the urogenital diaphragm. The cavernous arteries branch next and assume a central location within the corpora. The dorsal arteries represent the third branch and supply the circumflex arteries and glans penis. Significant variation in the blood supply to the penis was found by Breza et al. in a study of adult male cadavers. In their dissections, they found an accessory internal pudendal artery in seven of ten cadavers, predominantly on the left. These traveled along the lower aspect of the bladder and the anterolat-eral surface of the prostate to the dorsal root of the penis. The origin of the accessory pudendal artery varied, including ipsilateral obturator artery, ipsilateral inferior vesical artery, and contralateral superior vesical artery. In five of the patients, the accessory pudendal artery constituted an additional blood supply. In one patient, the accessory pudendal arteries provided the entire blood supply to the left side of the penis. One patient had bilateral accessory pudendal arteries, which supplied the cavernosal artery.

Because of its proximity to the prostate and bladder, the arterial supply to the penis may be compromised during radical pelvic surgery. The prevalence and variable origin of penile arterial supply, the potential dominance of the accessory pudendal arteries, and the importance of preservation of penile blood flow during prostate surgery to recovery of sexual function have all been reported.  Further, it has been shown that trauma to the penile crus leading to penile vascular insufficiency or pudendal artery occlusion may lead to Erectile dysfunction. The presence of cavernosal arterial insufficiency and corporeal veno-occlusive dysfunction have been demonstrated independently and as combined entities following bilateral nerve-sparing retropubic, radical prostatectomy. If vascular insufficiency is present, penile rigidity sufficient for vaginal penetration may not occur. Occasionally, patients with moderate vascular insufficiency following nerve-sparing retropubic, radical prostatectomy will not be amenable to medical or minimally invasive pharmacotherapy and will require a penile prosthesis.

Prevention

With knowledge of pelvic surgical anatomy, the pelvic plexus and cavernous nerves can be identified perioperatively in an attempt to maintain potency. This decision will be influenced by tumor volume, Gleason score, prostate-specific antigen (prostate-specific antigen) status, and other factors. If excision of one neurovascular bundle is required, often the contralateral side can be preserved. The surgical technique for preservation of the neurovascular bundles is described elsewhere.

The correlation between erectile dysfunction and nerve-sparing radical prostatectomy was reported by Quinlan, who found that 68% of men were potent postoperatively. Factors associated with return of sexual function were patient age, clinical and pathologic stage, and surgical technique. Results corrected for age and stage showed a two-fold increase in risk of Erectile dysfunction when one neurovascular bundle was excised.

As with all patients with erectile dysfunction, a complete psychosexual history is critical for evaluation. Focus on duration of dysfunction, level of libido, presence of morning erections, erection quality, and psychologic factors can help direct further work-up and treatment. Comorbid diseases, particularly diabetes mellitus, hypertension, smoking, vascular disease, and psychiatric illness may also contribute to Erectile dysfunction. While less likely in this group, a fair number of men will have underlying psychogenic factors contributing to their erectile dysfunction. Physical examination with attention to testicular size, gynecomastia, and body habitus, as well as a focused neurologic examination, will also aid in identification of associated disorders.

In patients with new onset erectile dysfunction postprostatectomy, the office evaluation is straightforward. Following surgery, patients may have gradual return of some sexual function over 18 months or more. Patients should be made aware of this to help reduce performance anxiety following surgery. With this in mind, patients, partners, and physicians can make decisions about treatment options. Patients should have realistic expectations associated with nonsurgical and surgical treatments.

Alprostadil (Caverject™) injection has also been used in nerve-sparing postprostatectomy patients to improve the recovery rate of erectile function. Montorsi et al. evaluated 30 patients 6 months after prostatectomy. Half of the patients were given intracavernous injections of alprostadil three times per week for 12 weeks. Of the patients receiving injections, 67% reported recovery of spontaneous erections, compared with 20% of the placebo group. The injections were felt to improve cavernous oxy-genation and therefore limit hypoxia-induced tissue damage. This issue, however, remains controversial.

Nonsurgical Treatments

The vacuum erection device is a simple-to-use and inexpensive device. The erection produced is unlike physiologic erection or one produced pharmacologically in that in placing the constriction ring to potentiate the erection, gradual corpus ischemia can result. Further, a hinge effect may be produced because the corpus cavernosum proximal to the constriction device is not rigid. Also, the ring may be uncomfortable or painful and may produce bruising. Nevertheless, satisfaction rates range from 68 to 83%.

Pharmacotherapy includes noninvasive (oral) and minimally invasive (intraurethral suppositories and intracavernosal injections) therapies.

Oral Therapy

Oral agents for treatment of Erectile dysfunction can, by virtue of their systemic administration, have both central nervous system and peripheral effects. Thus, therapy can be targeted to the adrenergic, dopaminergic, and serotoninergic receptors in the brain as well as the nitric oxide pathway and adrenergic or prostanoid receptors in the corpus cavernosum penis.

Phentolamine (Vasomax™) is an a-1 and a-2 adrenergic receptor antagonist also used for injection therapy. There is early evidence that buccal administration may improve erectile function. Three studies have examined its use and have found a response rate of 20 to 42%. Good response was found with psychogenic or mild vascular erectile dysfunction. Very poor responses were reported in those with serious vascular involvement. Food and Drug Administration (FDA) approval of this oral agent is expected in the fall of 1999.

Yohimbine (Yocon™) is an a-2 adrenergic antagonist obtained from the bark of the yohim tree that has been used for centuries as an aphrodisiac. In a recent controlled study of patients receiving 6 mg three times a day, 21% with primary organic Erectile dysfunction had complete recovery of erections. Thirteen percent of the control group also experienced a positive response and no statistical significance was found. In patients with psychogenic Erectile dysfunction, 62% responded versus 16% of the placebo group, which did achieve statistical significance. However, a recent trial of organic Erectile dysfunction patients showed that yohimbine was ineffective in this patient cohort.

Apomorphine is a dopaminergic agonist known to induce yawning, nausea, and penile erections in animals and humans when injected subcutaneously. A subbuccal tablet has been developed that is reportedly successful in inducing erections in patients with minimal disease. Significant side effects include yawning, nausea, vomiting, and hypotension. Studies investigating the utility of this drug are underway, and FDA approval is expected in late 1999 or early 2000.

Trazodone (Desyrel™) is a 5-hydroxytryptamine-receptor agonist prescribed for mild depression. It may also function as an a-adrenergic blocking agent and has been shown to increase nocturnal penile tumescence episodes when administered orally and induce tumescence when injected intracorporeally. In a recent clinical trial, limited efficacy in patients with psychogenic and mild organic Erectile dysfunction was shown. Synergistic effects when used with yohimbine have also been reported.

Sildenafil citrate (Viagra™) is a selective inhibitor of cyclic guanosine monophosphat, specific phosphodiesterase type 5 (PDE5), and is the first FDA-approved oral pharmacotherapeutic for treating Erectile dysfunction. During sexual stimulation, nitric oxide is released from nonadrenergic, noncholinergic nerves in the penile corpus cavernosum. Nitrous oxide diffuses into the trabecular smooth-muscle cells where it activates guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate, which ultimately result in smooth muscle relaxation, corporal expansion, and effective venoocclusion. Sildenafil inhibits the degradation of cyclic guanosine monophosphate by inhibiting PDE5. Two recent studies evaluated the efficacy of sildenafil in postprostatectomy patients. In the first, the effects of bilateral nerve-sparing, unilateral nerve-sparing, and non-nerve-sparing, radical retropubic prostatectomy on efficacy of sildenafil treatment of erectile dysfunction were compared. Sildenafil was efficacious in only the bilateral nerve-sparing cohort of patients, with 80% having sufficient penile rigidity for vaginal intromission. In a second study of patients in a general urology practice, patients were grouped by the severity of erectile dysfunction using the International Index of Erectile Function. Sildenafil was least effective in patients with the most severe erectile dysfunction. Interestingly, radical retropubic prostatectomy patients fell into the most severe group, with only 40% having tumescence on sildenafil. Sildenafil citrate is expected to be a first-line therapy in postprostatectomy patients. However, physician and patient/partner alike should understand that the results may be poor depending on the extent of the nerve and/or vascular damage.

Injection Therapy

Intracavernosal injection therapy stimulates the natural erectile process by stimulating the corporal smooth muscles to relax. The principal drugs used are papavarine, phentolamine, and PGEi.

Papaverine, derived from the opium poppy, is thought to increase intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate by inhibiting cAMP- and cyclic guanosine monophosphate-specific phosphodiesterases. It may also block calcium channels and increase calcium efflux from cells. These actions potentiate smooth-muscle relaxation in the penile arterioles, sinusoids, and veins. Papaverine is metabolized in the liver and has a plasma half-life of 1 to 2 hours. While the advantages of papaverine injection include its low cost and stability at room temperature, associated complications include priapism (0 to 35%), corporeal fibrosis (1 to 33%), and occasional elevation in liver enzymes.

Phentolamine (Regitine™) is an a-1 and a-2 adrenergic receptor antagonist. It causes relaxation of corporeal smooth muscle and increases blood flow. Unlike papavarine, it does not increase resistance to venous outflow. Its plasma half-life is only 30 minutes.

Prostaglandin Ei (alprostadil, Caverject, Edex™) causes smooth-muscle relaxation, dilatation, and inhibition of platelet aggregation. Caverject was the first FDA-approved pharmacotherapy for Erectile dysfunction. This prostaglandin is rapidly metabolized within the trabecular smooth muscle. Also, in studies comparing papavarine and alprostadil, the latter was shown to have a higher response rate and lower incidence of priapism and corporeal fibrosis. Disadvantages include a much higher incidence of painful erections, higher cost, and shorter half-life if not refrigerated. An alprostadil transurethral suppository (MUSE™) has been studied recently in postprostatectomy patients. The overall success rate (the likelihood of active treatment to lead to intercourse at home) was 40.1%. There was no increased incidence of hypotension in postprostatectomy patients but urethral pain/burning was higher. Combination therapies have also been used with good success in patients with different types of erectile dysfunction.

Surgery

Failure of medical therapy, and patient/partner concerns regarding Erectile dysfunction and quality of life will influence surgical therapy for remediating Erectile dysfunction. The use of inflatable penile prosthetic devices provides a natural state of flaccidity and results in rigid, on-demand erection suitable for vaginal penetration. The recent refinement of these mechanical devices has resulted in a lowered mechanical failure and higher patient satisfaction. Discussion with the patient and partner about advantages and disadvantages will guide device selection.

The advent and availability of two-piece mechanical devices has resulted in an increased popularity of these being placed postoperatively; satisfactory results with minimal morbidity have been achieved. These devices provide approximately 95% patient and partner satisfaction.

In one center, placement of a penile prosthesis was performed at the time of radical prostatectomy. Patients elected to undergo non-nerve-sparing prostatectomy and simultaneous placement of penile prosthesis on the basis of grade and extent of disease, apical involvement, and patient preference. These 50 men, when compared to 72 patients undergoing radical prostatectomy alone, had no significant increase in blood loss, hospital stay, or analgesic use. There were no infections in the prosthesis group at 1.7 years mean follow-up. With careful attention to surgical technique and liberal use of antibiotics, the authors of this study were able to perform a combined procedure without increased morbidity. Thus, early return of sexual function after non-nerve-sparing radical prostatectomy can be achieved in select patients. While this may be a novel approach, it overlooks the availability of noninvasive and minimally invasive pharmacotherapeutics and assumes a complete failure rate in recovery of potency following radical prostatectomy.

New Therapies on the Horizon

Evidence of nerve regeneration has recently been described. In work by Costabile et al, regeneration of cavernous nerves that are partially damaged is suggested as the possible cause of delayed recovery of postprostatectomy erectile function. The authors studied the effects of cavernous nerve transection on the nonadrenergic/ noncholinergic   (NANC)   nervous system and erectile function of rats. Nitric oxide is felt to be the main neuro-trasmitter in NANC nerves. Nitric oxide synthase-positive nerve fibers in unilateral transection were found to regenerate almost to the level of the intact side by 6 months. Bilateral transection did not result in nerve regeneration. It was suggested that this was a result of sprouting of intact nerves from the contralateral corpus cavernosum in the unilateral neurotomy group. This suggests that unilateral cavernous nerve sparing is sufficient to preserve erectile function in the rat model. Such a result is in contrast to the results of Zippe et al., who found that sildenafil citrate was only efficacious in bilateral nerve-sparing radical prostatectomy patients.

Klein and colleagues added to the work of Lue by suggesting that apoptosis (programmed cell death) may be the cause of postprostatectomy Erectile dysfunction and/or decrease in penile size. They utilized a rat model of penile denervation by bilateral cavernous neurotomy. Evidence of elevated gene products found in apoptotic tissues was discovered in denervated rats versus sham-operated controls. This interesting study implies a molecular explanation of the mechanism of postprostatectomy Erectile dysfunction.

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.

Pharmacotherapy: Alpha-Adrenergic Blockers

Alpha-1 adrenergic blockers prazosin (Minipress), terazosin (Hytrin) and doxazosin (Cardura) have all been extensively studied in patients with benign prostatic hyperplasia (BPH). These agents relax smooth muscle at the bladder neck and prostatic urethra, offering symptomatic improvement in a relatively short period of time.

Although prazosin has demonstrated efficacy in patients with BPH, it has fallen out of favor since it is short-acting, requiring multiple daily dosing. Terazosin has been studied extensively and has consistently demonstrated efficacy. Patients on terazosin, frequently titrated to doses of 10 mg once daily, show an increase in peak urinary flow rate (PUFR) and a decrease in their symptoms. Doxazosin, although not studied as extensively as terazosin, has also demonstrated similar efficacy in this patient population. Similar agents studied outside the United States, such as tamsulosin and alfuzosin, have demonstrated some efficacy.

The long-acting alpha-1 blockers terazosin and doxazosin are frequently used to treat common comorbid disease states such as hypertension. Occasionally, however, the maximum dose of an alpha-1 blocker necessary to treat benign prostatic hyperplasia (BPH) in normotensive men cannot be achieved due to the risk of hypotension developing. However, studies have demonstrated that alpha-1 blockade will significantly lower blood pressure in patients with BPH who are hypertensive; yet in normotensive BPH patients, the blood pressure is not significantly decreased. Common dosages employed for alpha-1 antagonists in BPH and hypertension can be found in Table 3. Additionally, alpha-1 blockers have a favorable effect on the lipoprotein profile by slightly lowering LDL and VLDL, and increasing HDL, thereby decreasing the risk for coronary artery disease.

Approximately 10%–15% of patients receiving an alpha-1 blocker develop a clinically significant adverse event. Side effects such as dizziness, headache, asthenia, syncope and hypotension have been reported, especially after the first dose. In order to minimize this “first dose” effect, it is important to take the once-daily dose at bedtime, titrating upwards slowly.

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.

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.

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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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).