Melvin Blanchard
Prostate Cancer Screening
GENERAL PRINCIPLES
· Prostate cancer is the most common noncutaneous malignancy in older men and is the second most common cause of cancer mortality after lung cancer.
· Approximately 239,000 men will be diagnosed in 2013, and 29,000 will die from this malignancy.1
· The introduction of screening tests has led to intense debate and varying recommendations (also see Chapter 5).
o The variable course of prostate cancer makes screening for the presence of disease a complicated decision. Some men have subclinical prostate cancer that progresses slowly and never contributes to mortality, whereas others have disease aggressive enough to cause premature death.
o The American Cancer Society recommends screening and early detection programs for men at high risk for prostate cancer (first-degree relative diagnosed prior to age 65 or African American) starting as early as 40 to 45 years of age. The American Urological Society recommends an individualized approach for men 54 to 71 years old. However, the U.S. Preventive Services Task Force (USPSTF), Canadian Task Force on Preventive Health Care, and United Kingdom National Screening Committee all recommend against screening.
· Unfortunately, neither highly sensitive screening tests that detect cancers likely to be clinically significant nor highly specific tests that identify low-grade disease unlikely to cause death are available.
· Early detection and treatment are the only ways to decrease mortality from prostate cancer since it is incurable once spread beyond the capsule. Screening has effectively increased the identification of organ-confined and potentially curable cancer. However, the apparent gain in survival resulting from early detection may be due to lead-time bias, as men who would otherwise never be diagnosed or have any sequelae of prostate cancer are having it detected earlier.
· The benefit of treatment in clinically localized prostate cancer has not been definitively proven.
o In observational studies of men with well- and moderately differentiated cancers, active surveillance or observation alone is associated with high prostate cancer–specific survival rates.2–5
o The primary treatment modalities, radical prostatectomy and radiation therapy, are associated with significant rates of complications, including erectile dysfunction (ED), urinary incontinence, and urethral or rectal injury.
· Controversy persists as to whether screening for prostate cancer decreases its morbidity or mortality. Two large multicenter randomized prospective clinical trials, one conducted in Europe and another in the United States, reported conflicting results on this question.6,7
o The European study reported a 20% decline in mortality, whereas the US study found no significant difference in death rate.
o The initial results of the US study reported at 9 years persisted in follow-up analysis after 10 and 13 years.8
DIAGNOSIS
Digital Rectal Examination
· The digital rectal examination (DRE) is a nonstandardized examination of the prostate that reveals abnormalities in 3% to 12% of patients.9 In fact, the interrater agreement among urologists for detecting prostate abnormalities is poor.10
· An abnormal DRE (asymmetric, nodular, or indurated) has a positive predictive value for cancer of 18% to 28%.11 When abnormal, it necessitates a transrectal ultrasound-guided prostate biopsy. Therefore, 72% to 82% of patients with an abnormal DRE will have a prostate biopsy that is negative for malignancy.
Prostate-Specific Antigen
· Prostate-specific antigen (PSA) is a 240-amino-acid serine protease secreted by prostatic epithelial cells that lyses the clotted ejaculate to enhance sperm motility. Some PSA naturally leaks into blood and does so to a greater extent in prostate cancer.
· Ejaculation and prostate manipulation raise PSA levels; however, a routine DRE does not clinically change the results of PSA testing.12
· Finasteride, a 5-α-reductase inhibitor, reduces total PSA (tPSA) by about 50% in 6 to 12 months.13
· The positive predictive value of a tPSA >4.0 ng/mL is about 30%, but it is a continuum, as the risk of prostate cancer increases significantly even within the normal range.14 The sensitivity of this cutoff is 70% to 80%, but the specificity is low, as multiple conditions besides cancer can elevate tPSA (Table 4-1).
TABLE 4-1 Processes That Affect Prostate-Specific Antigen (PSA) besides Prostate Cancer
Prostate-Specific Antigen Velocity
· PSA velocity (PSAV), the rate of change in PSA over time, is abnormal when it is >0.35 ng/mL/year (for tPSA <4 ng/mL) or >0.75 ng/mL/year (for tPSA >4).
· It correlates with prostate cancer diagnosis and is most reliable when three values are obtained at the same laboratory over at least 18 months. High PSAV, however, may be indicative of prostatitis.
· One study suggests that PSAV may be prognostic when obtained in the year before the diagnosis of prostate cancer.15
Free Prostate-Specific Antigen
· Percent-free PSA (fPSA), the ratio of free circulating to bound PSA in serum, is lower in men with prostate cancer than in those with benign prostatic diseases.
· It is most useful in deciding which patients with a mildly elevated PSA (4 to 10 ng/mL) should undergo biopsy.
· An upper cutoff of 30% significantly decreases the number of false-positive biopsies while maintaining a high level of sensitivity.16
· The complexed PSA (cPSA) is also measurable, but has no significant advantage over fPSA.
Prostate-Specific Antigen Density
· Defined as the PSA divided by prostate volume (measured by transrectal ultrasound or MRI) and compared with age-/race-specific reference ranges
· More costly and has less clear benefit on cancer detection rates. Not currently a part of routine guidelines
Screening
· The decision as to whether to screen for prostate cancer must be individualized, as the lack of evidence from clinical trials has led to very different recommendations on screening. Patients who request screening must be educated about the risks and benefits involved. (Fig. 4-1).
Figure 4-1 Prostate cancer screening algorithm. BPH, benign prostatic hyperplasia; DRE, digital rectal examination; PSA, prostate-specific antigen.
· The USPSTF 2012 update concludes that there is moderate certainty that the benefit of screening does not outweigh potential harm and recommends against PSA-based screening for prostate cancer. Men who request screening should be educated to enable an informed choice.
· The American Cancer Society recommends screening for men at age 50 if life expectancy is at least 10 years. The frequency should be annual if PSA is >2.5 ng/mL and every 2 years if PSA is <2.5 ng/mL. Men at high risk (African American men or men with one or more first-degree relatives with prostate cancer prior to age 65) should be offered screening starting at age 40 to 45.
· The American Urological Association recommends an individualized approach and shared decision making for men 55 to 69 years old.
Benign Prostatic Hyperplasia
GENERAL PRINCIPLES
· Benign prostatic hyperplasia (BPH) is defined histologically as hypertrophy of glandular and stromal tissue.
· It is present primarily in older men with functioning testicles. The prevalence of BPH increases with age from 8% among men in their fourth decade of life to 80% among those >80 years of age, with lower urinary tract symptoms (LUTS) in about 25% to 45% of men >70 years of age.17
· BPH may be complicated by recurrent urinary tract infections (UTIs), urinary bladder stones, and acute urinary retention.
DIAGNOSIS
Clinical Presentation
History
· Patients with LUTS complain of urgency, frequency, nocturia, weak stream, hesitancy, and incomplete emptying.
· The American Urological Association Symptom Index (AUA-SI) (Table 4-2), a standardized questionnaire that quantifies these symptoms, should be administered to all men with BPH.18 The AUA-SI score is used to classify symptom severity, guide treatment recommendations, and follow response to therapy.
· The history should also assess for sexual dysfunction, neurogenic bladder; prior urethral trauma or urethritis; diabetes; hematuria; family history of BPH or prostate cancer; and drugs that decrease bladder function or increase tone at bladder neck (anticholinergics, sympathomimetic amines).
TABLE 4-2 American Urological Association Symptom Index
0–7 points = mild symptoms8–19 points = moderate symptoms20–35 points = severe symptomsModified from Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association Symptom Index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148:1549.
Physical Examination
The prostate should be palpated for nodules and an estimation of its size. Men with oversized prostates are at increased risk of experiencing complications and undergoing prostate surgery.
Diagnostic Testing
Laboratories
· Urinalysis should be obtained to rule out infection and assess for complications (hematuria, UTI) and glycosuria.
· Serum creatinine should be obtained as it may indicate underlying kidney disease, which could contribute to LUTS.
· Screening for prostate cancer is optional, as its prevalence is not increased despite the fact that PSA is elevated in 25% to 30% of men with BPH.
· PSA is predictive of prostate size, as PSA values of >1.6, 2.0, and 2.3 correlate with 70% sensitivity and specificity to prostates >40 mL in size in men in their 50s, 60s, and 70s, respectively.19
Imaging
Renal imaging (ultrasound or intravenous pyelography) should be performed in patients with complications such as hematuria, recurrent UTIs, or unexplained chronic kidney disease.
Diagnostic Procedures
Urodynamic testing (peak flow rate and pressure volume studies) should be reserved for patients with an unclear diagnosis, suspected neurogenic bladder dysfunction, or moderate to severe disease that fails to respond to initial therapy.
TREATMENT
· The major factors to consider in selecting a therapy are AUA-SI score and prostate size. The other factors to consider are age, concomitant hypertension, current medications, sexual history, and the degree to which the symptoms affect quality of life.
· Watchful waiting without treatment is recommended for patients with mild symptoms (AUA-SI ≤7) and is an option for those with moderate symptoms who do not want to initiate lifelong medical therapy and do not have BPH complications (urinary retention, renal insufficiency, or UTI).
· Patients should minimize fluids before bedtime and avoid medications with anticholinergic or sympathomimetic properties (including antihistamines, tricyclic antidepressants, and decongestants), caffeinated beverages, and alcohol.
· Many patients with mild symptoms have no change or improve without treatment; however, there is some concern that delay in treatment may result in bladder decompensation.20
Medications
Pharmacologic therapy is recommended for patients with moderate symptoms who request treatment and for those with severe symptoms.
First-Generation α-Blockers
· Terazosin and doxazosin are α1-adrenergic blockers that relax smooth muscle cells in the prostate and lead to an improvement of symptoms (decrease of 4 to 6 points on AUA-SI) within weeks of initiating therapy.21
· Symptomatic improvement is maintained with long-term therapy, but α1-blockers do not decrease prostate size, the rate of urinary retention, the need for surgery, or PSA.
· α1-Blockers are effective in men with small and large prostates.
· These agents are possible choices for men with concomitant hypertension that requires treatment. Terazosin and doxazosin decrease blood pressure (BP) by approximately 10 to 15/10 to 15 mm Hg in men with elevated BP but have no clinically significant effect on BP in normotensive patients.22 However, they should not be used at the expense of other drugs for overriding indications (see Chapter 6).
· Treatment is initiated at night with dose titration over 2 to 3 weeks to minimize side effects.
o Terazosin is titrated weekly from 1 to 2 to 5 mg PO nightly and can subsequently be increased to 10 to 20 mg PO nightly.
o Doxazosin is titrated from 1 to 2 to 4 mg PO nightly and can be subsequently increased to 8 to 16 mg PO nightly.
· Common side effects are dizziness, orthostatic hypotension, and fatigue. Hypotension and orthostasis are exacerbated with concomitant use of phosphodiesterase inhibitors for ED (e.g., sildenafil, vardenafil, tadalafil).
· The Food and Drug Administration (FDA) has posted a drug safety alert indicating that α1-blockers increase the risk of floppy iris syndrome in patients with cataract surgery.
Second-Generation α-Blockers
· Alfuzosin, silodosin, and tamsulosin are uroselective α1a-blockers with pharmacologic activity that is limited to the prostate with minimal systemic effects on BP. They are good choices for men who want rapid symptom relief and who are prone to orthostasis.
· The dose for alfuzosin is 10 mg PO daily, silodosin is 8 mg PO daily, and tamsulosin is 0.4 to 0.8 mg PO daily.
o Dose titration and nocturnal dosing are unnecessary for these three agents.
o The dose of silodosin should be halved for patients with a creatinine clearance of 30 to 49 mL/minute.
o Both silodosin and alfuzosin should be avoided in patients with a creatinine clearance of <30 mL/minute.
· Common side effects of these agents are ejaculatory problems and dizziness.
· The FDA has posted a drug safety alert indicating that tamsulosin and other α1-blockers increase the risk of floppy iris syndrome in patients with cataract surgery.
5α-Reductase Inhibitors
· Finasteride and dutasteride are 5α-reductase inhibitors that inhibit conversion of testosterone to dihydrotestosterone (DHT), reverse epithelial glandular hyperplasia, and shrink the prostate by approximately 15% to 30% within several months.
· Symptomatic improvement is sustained long term, and they are the only drug class that have been shown to decrease the rate of urinary retention and need for prostate surgery.23–25
· These agents are more effective in men with prostates >40 mL in size.26
· PSA can predict which patients are candidates for treatment with finasteride (see the Prostate-Specific Antigen section).
· The symptomatic response to these agents is delayed for 6 to 12 months.
· The dose for finasteride is 5 mg PO daily, and for dutasteride, it is 0.5 mg PO daily.
· The only common side effects are sexual, including ED, decreased libido, and ejaculatory dysfunction.
· After 6 months of therapy, finasteride decreases PSA by approximately 50%.
o PSA may still be used as a screening test for prostate cancer provided that the PSA value is doubled.27
o Free PSA is unchanged by treatment.
· Questions have been raised about the safety of these agents in the Prostate Cancer Prevention Trial. This 7-year study showed that, compared with placebo, finasteride reduced the risk of prostate cancer. However, participants who developed prostate cancer while on study drug were more likely to develop higher-grade cancers.28,29 The FDA recommends that patients be assessed for prostate cancer before starting this class of drugs.
Combination Therapy
· Combination therapy with an α1-blocker and finasteride makes theoretical sense for men with large prostates and is frequently attempted, but research study results are mixed.
· It is a general practice among many to use combination therapy in symptomatic men with large prostate and monotherapy (α1-blockers) in patients with small gland size.30,31
Herbal Treatment
· Several different forms of herbal therapy, including saw palmetto (Serenoa repens), Pygeum africanum, Cernilton, and β-sitosterols, are available and self-prescribed by patients to treat BPH.
· These agents have been shown to be effective in the short term, but their mechanism of action and long-term efficacy are unknown.32
· Saw palmetto (160 mg PO bid) is the most commonly used herb in the United States, but is not FDA approved.
Surgical Management
· Indications for referral to urology include refractory LUTS, complications such as recurrent hematuria or recurrent UTIs, bladder stones, acute urinary retention and renal insufficiency with hydronephrosis, a rectal examination or PSA suspicious for prostate cancer, and an unclear diagnosis when urodynamic testing may be helpful.
· Transurethral resection of the prostate (TURP), the “gold standard” for BPH treatment, has a much greater benefit in reducing symptoms than medical therapy.
o TURP results in retrograde ejaculation and ED in a significant percentage of patients, and approximately 20% have unsatisfactory results and require further therapy.
o As TURP removes only central prostatic tissue, it does not eliminate the chance of developing prostate cancer.
o Several new minimally invasive surgical procedures have been introduced as alternatives to TURP.
Prostatitis
GENERAL PRINCIPLES
· Prostatitis is the most common urologic complaint among men <50 years of age.
· The prostatitis syndromes are classified by the acuity of presentation and findings on urinalysis and culture before and after prostatic massage.
· Prostatitis is classified as follows:
o Acute prostatitis
o Chronic bacterial prostatitis
o Chronic prostatitis/chronic pelvic pain syndrome:
§ Inflammatory
§ Noninflammatory
· Asymptomatic inflammation of the prostate
· Only 5% to 10% of cases are due to bacterial causes.33
DIAGNOSIS
Acute Bacterial Prostatitis
· Patients present with symptoms of a UTI (e.g., dysuria, frequency, urgency) and systemic symptoms such as fever, malaise, and lower abdominal or back pain. Risk factors include instrumentation and HIV.
· A gentle prostate examination might reveal an enlarged, warm, and very tender prostate. Vigorous massage is contraindicated as this could cause bacteremia and sepsis.
· Urinalysis and culture are positive, most often for Escherichia coli or other gram-negative organisms.
· An abdominal ultrasound or CT scan to rule out a prostatic abscess should be considered if initial treatment fails.
Chronic Prostatitis Syndromes
· Patients with the three chronic prostatitis syndromes present with similar symptoms, classically a triad of recurrent voiding symptoms, pain (pelvic, perineal, inguinal, back, penile, or scrotal), and ejaculatory symptoms (pain, hematospermia).
· Patients with chronic bacterial prostatitis are usually older, frequently have recurrent UTIs with the same organism, and may have a history of acute prostatitis.
· Patients with the two chronic nonbacterial prostatitis syndromes are often younger and do not have a history of recurrent UTIs.
o The predominant symptom of pain and predilection to occur in younger men distinguish it from BPH.
o Chronic nonbacterial prostatitis is the most common urologic diagnosis in men <50 years of age.
· The prostate examination is often normal in men with each of the chronic prostatitis syndromes. A diagnostic prostate massage comparing a midstream urine specimen (the second 10 mL of urine voided) with one after a vigorous prostate massage is the test of choice to correctly diagnose the three syndromes (Table 4-3). However, this is usually done after presumptive diagnosis fails to respond to treatment.
TABLE 4-3 Diagnostic Prostate Massage Results
aA positive urinalysis is >10 to 15 WBCs/high-power field.
bA positive culture has a colony count that is at least 10-fold greater than the premassage culture.
TREATMENT
Acute Bacterial Prostatitis
· Patients should be treated initially with broad-spectrum parenteral antibiotics followed by oral agents if they respond.
o Potential oral regimens include trimethoprim-sulfamethoxazole, 1 DS tablet PO bid; doxycycline, 100 mg PO bid; ciprofloxacin, 500 mg PO bid; or levofloxacin, 500 mg PO daily for 4 to 6 weeks.
o Severely ill patients with suspected bacteremia require admission for IV antibiotics.
· Supportive care with analgesics, stool softeners, and vigorous oral hydration may be beneficial.
· Because of the relatively high risk for urinary retention, bladder scanning should be done to assess the postvoid residual. For patients who require short-term drainage, a small urethral catheter may be sufficient; those who require long-term drainage will need a suprapubic catheter.
Chronic Bacterial Prostatitis
· Prolonged courses of antibiotics (4 to 6 weeks), preferably with a fluoroquinolone (excellent prostate penetration), are recommended.
· α1-Adrenergic blockers (see the “Benign Prostatic Hyperplasia” section above) may provide additional symptomatic relief.
· Recurrences require retreatment.
Chronic Nonbacterial Prostatitis
· Treatment of both types of chronic nonbacterial prostatitis is difficult and often prolonged. Recommendations are based primarily on clinical experience, as controlled trial data are limited.34
· Patients with inflammatory chronic nonbacterial prostatitis should receive a trial of 4 to 6 weeks of antibiotics (fluoroquinolone or trimethoprim-sulfamethoxazole). This should be continued for 12 weeks if improvement occurs due to anecdotal evidence that links the syndrome to atypical pathogens. Doxycycline and azithromycin can be used to treat Chlamydia trachomatis.
· Treatment options for noninflammatory chronic nonbacterial prostatitis (prostatodynia) include α1-adrenergic blockers, nonsteroidal anti-inflammatory drugs, “muscle relaxants” such as diazepam, and anticholinergic agents.35
Erectile Dysfunction
GENERAL PRINCIPLES
· ED is the consistent inability to attain or maintain an erection that is satisfactory for successful intercourse.36
· The prevalence increases with advancing age, and the impact on quality of life is substantial.37
· Many men are embarrassed to raise the subject, so it is important that primary care physicians initiate the conversation with their patients.
· The risk factors for ED are presented in Table 4-4.
TABLE 4-4 Common Risk Factors for Erectile Dysfunction
CNS, central nervous system; COPD, chronic obstructive pulmonary disease; LHRH, luteinizing hormone–releasing hormone; MAO, monoamine oxidase; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
DIAGNOSIS
Clinical Presentation
History
· A detailed sexual history should assess the severity, onset, duration, progression, and situational nature of the problem to confirm that the patient has erectile failure and not a problem with libido or ejaculation.
· A gradual progressive onset of ED with absence of nocturnal or morning erections suggests an underlying medical cause.
· ED that develops suddenly is likely either psychogenic or due to a medication.
· Risk factors for ED should be reviewed (Table 4-4).
· The potential cardiovascular risk of intercourse to the patient should be assessed, given the strong association between ED and coronary artery disease. Sexual activity is equivalent to walking 1 mile in 20 minutes, climbing two flights of stairs in 10 seconds, or 3 metabolic equivalents (METs) of activity.38
· Patients who can safely exercise to a level of five METs (see Chapter 2, Table 2-3) are at low risk for coronary ischemia during intercourse. Stress testing should be considered, before the initiation of therapy or resumption of intercourse, in sedentary men with multiple cardiac risk factors who cannot safely exercise to this level. Patients should complete 4 minutes on the Bruce treadmill protocol (5 to 6 METs) without symptoms, arrhythmias, or fall in blood pressure.38
Physical Examination
The physical examination should assess for evidence of vascular or neurologic disease, stigmata of hypogonadism (small testicles, gynecomastia), prostate abnormality (with DRE), and penile anatomic abnormalities (Peyronie disease).
Diagnostic Testing
· Routine laboratory evaluation should include serum glucose, renal function, complete blood count, and lipid analysis.
· A PSA should be considered if testosterone therapy needs to be initiated.
· Thyroid-stimulating hormone and liver function tests should be performed if the initial history or physical examination is suggestive of thyroid or liver disease.
· Routine testosterone assessment in patients with ED is controversial.
o Hypogonadism is the cause of ED in 5% to 10% of patients, but only approximately one-third of these patients improve with testosterone replacement.39
o Testing with morning total and free serum testosterone is initially recommended only for patients with low libido or evidence of hypogonadism.
o Testing should otherwise be deferred until patients have failed oral pharmacologic therapy.
o Abnormal initial testosterone levels should be repeated for confirmation along with serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin to determine the source of hypogonadism.
· Urologic testing with nocturnal penile tumescence or vascular studies is unnecessary in the primary care setting.
TREATMENT
· In 80% to 90% of men, erectile function should be restored with some form of therapy.
· Attempts should be made to improve uncontrolled risk factors, such as diabetes and hypertension, and to decrease the use of tobacco, alcohol, and other illicit substances.
· If possible, potentially contributing medications should be stopped or have their doses decreased.
· Reassurance may be curative in young men with psychogenic ED. Referral to a psychologist for marital or couples counseling may be helpful as an adjunctive form of therapy for psychogenic ED that has failed to respond to oral pharmacologic therapy.
Medications
Phosphodiesterase Inhibitors
· Phosphodiesterase inhibitors include sildenafil, tadalafil, and vardenafil (Table 4-5).
· These agents are the treatment of choice for ED and work by selectively inhibiting PDE5, which is found in high concentrations within the corpus cavernosum.
· They require sexual stimulation to precipitate an erection and are effective in all forms of organic and psychogenic ED, but response rates are lower in patients with complete ED and diabetes and after radical prostatectomy.40
· They do not increase libido.
· The three agents available are thought to have similar efficacy (no head-to-head trials yet done).
· Side effects include headaches, flushing, dyspepsia, visual disturbance, rhinitis, priapism, and dizziness.
· Patients with symptoms of cardiac disease should be referred for cardiac evaluation before initiation of these agents.
· The PDE5 inhibitors potentiate the effect of nitrates causing severe and refractory hypotension, so the combination of these agents with nitrates in any form (oral, transdermal, IV) is absolutely contraindicated.41
· The combination with α1-adrenergic blockers can also cause orthostatic hypotension and even severe hypotension. Alcohol potentiates the hypotensive effects of these agents.
· They are metabolized in the liver by cytochrome P450 CYP3A4, and thus, caution must be exercised when prescribing with inhibitors such as ketoconazole, itraconazole, protease inhibitors, and cimetidine.
TABLE 4-5 Phosphodiesterase Inhibitors for Erectile Dysfunction
Testosterone Replacement
· Testosterone replacement is only indicated for men with documented hypogonadism.
· Currently, there are no oral preparations of testosterone sold in the United States.
· Since prostate cancer is hormone sensitive, before initiating testosterone, it is necessary to ensure that the patient does not have prostate cancer. After starting testosterone replacement, PSA, prostate examination, testosterone levels, liver function tests, and cholesterol should be monitored.42
· Intramuscular injections of testosterone enanthate or testosterone cypionate are initiated at dosages of 150 to 200 mg IM every 2 to 3 weeks.
· Testosterone patches provide physiologic doses of hormone replacement. Androderm, 2.5 to 7.5 mg, is applied daily to clean, dry, non–hair-bearing areas.
· Several testosterone gels are available (AndroGel, Testim, Foresta, Axiron). They are applied to clean, dry skin via metered-dose device in a dosage range of 5 to 10 g/day.
· One buccal form of testosterone is available (Striant). It is dosed as 30 mg every 12 hours and applied to the gum area above the upper incisors.
· A subcutaneous testosterone pellet (Testopel), which is implanted under the skin, is administered every 3 to 6 months.
· Patients on testosterone replacement need to be monitored upon initiation, around dose changes (q2 to 3 months), and every 6 to 12 months while on a stable regimen.
· Adverse effects of testosterone include erythrocytosis, worsening of sleep apnea, and enlargement of the prostate.
Other Nonpharmacologic Therapies
· More invasive nonsurgical treatment options include intracorporeal and intraurethral injections of alprostadil and external vacuum constriction devices.
· Intracorporeal injections and vacuum devices are very effective but suffer from high dropout rates.
· These forms of therapy should be deferred to a urologist unless the primary care physician has undergone appropriate training in the administration of these modalities, which require significant office-based patient education and training.
REFERRAL
· Indications for referral to urology include a history of pelvic trauma, abnormal genital examination, contraindications to or intolerable side effects from oral pharmacologic therapy, and failure of oral therapy in patients who wish to try a more invasive modality.
· Priapism is an indication for an emergent urology consult.
Testicular Masses
GENERAL PRINCIPLES
· Patients with testicular masses may present with a painless lump or scrotal discomfort, ranging from a dull ache that worsens with exercise to severe testicular pain.
· Benign causes include fluid collections, infection (e.g., acute orchitis, focal or subacute orchitis, or postinflammatory scarring), infarction (idiopathic or secondary to torsion), and cysts.
o A hydrocele is a collection of peritoneal fluid between the parietal and visceral layers of the tunica vaginalis, a potential space surrounding the testicle. A communicating hydrocele allows peritoneal fluid to pass between the peritoneal cavity and the layers of the tunica vaginalis. A noncommunicating hydrocele represents an imbalance in the secretory and absorptive capacities of the layers of the tunica vaginalis. This is most often due to injury or infection with resultant inflammatory reaction. A hydrocele may also accompany a testicular neoplasm or torsion. Hydroceles transilluminate, but hernias or other mass lesions do not. Ultrasound can be helpful, when the cause of the hydrocele is unclear. Simple aspiration of hydrocele usually leads to reaccumulation.
o A varicocele is an abnormal tortuosity and dilation of the pampiniform venous plexus and internal spermatic vein. Varicoceles are found in 20% of men, more frequently on the left (because of the drainage of left gonadal vein). Patients are usually asymptomatic, but may report achy, dull pain exacerbated by standing. Varicoceles constitute the most common surgically correctable cause of male factor infertility (15% to 30% of infertile men), although the benefit of surgery is controversial.
o A spermatocele is a painless cystic mass (2 to 5 cm) separate from the testis (<2 cm; this is called an epididymal cyst). These are located at the superior pole of the testes and can be diagnosed by physical examination, but ultrasound may be used to confirm the diagnosis if there is uncertainty.
· Malignant causes include primary testicular cancer and extratesticular malignancies such as leukemia or lymphoma.
o Testicular cancer accounts for only 1% of all cancers in men but is the most common cancer in men 15 to 34 years of age.
o A significantly increased number of testicular cancers are found in patients with cryptorchidism, with neoplasms developing in the undescended and the contralateral descended testis.43–45 Other risk factors include family history (6- to 10-fold for first-degree relative), tobacco use (doubles risk), white race, and infertility.
o Lymphomas and leukemia are the most common extratesticular malignancies to involve the testicles. Lymphoma accounts for 1% to 7% of all testicular tumors and is a frequent cause of testicular enlargement in men >50 years of age. Involvement is bilateral in 50% of cases either simultaneously or successively. Leukemic infiltration (50% have bilateral involvement) is usually seen in children, and the testis is the most common site of relapse of acute leukemia.
DIAGNOSIS
Clinical Presentation
History
· Men with hydrocele present with a painless scrotal swelling that can be transilluminated. The swelling may be small and soft on awakening but worsens during the day, becoming large and tense.
· Most varicoceles occur on the left side as the left testicular vein drains into the left renal vein, whereas the right testicular vein drains directly into the large inferior vena cava. Patients generally report a mass that lies posterior to and above the testis. The sudden onset of a left-sided varicocele in an elderly man may be indicative of a renal cell carcinoma and should be evaluated with a renal ultrasound. Sudden development of a right-sided varicocele may occur with inferior vena cava obstruction. The venous dilation is commonly decreased when the patient is supine and increases when he is upright.
· A painless testicular mass is suggestive of a primary testicular tumor but occurs only in a minority of patients. Most present with diffuse testicular pain, swelling, hardness, or some combination of these findings.46
Physical Examination
· The testes should be palpated for masses, volume, tenderness, and cryptorchidism.
· A testicle that is <4 cm long is considered small.
· All masses and swellings should be transilluminated. Solid tumors do not transmit light, whereas a hydrocele glows a soft red color.
· If a testicle cannot be palpated within the scrotum, the inguinal canals and lower abdomen should be examined.
· The epididymis, spermatic cord, and vas deferens are examined next.
o The epididymis is located posterior to the testicle.
o Have the patient perform the Valsalva maneuver while standing.
o Palpate for a mass of dilated testicular veins in the spermatic cord, forming a varicocele above and behind the testis.
· The inguinal canals should be explored for hernias or cord tenderness. Inflammation of the cord structures can cause inguinal or scrotal pain, with a normal testis.
· Classically, a varicocele feels like a “bag of worms” above the testicle. Examine the patient in both upright and supine positions. Have him perform the Valsalva maneuver when standing, which accentuates the dilation.
· Spermatoceles are typically located superior and posterior to the testis, freely movable, and transilluminate easily. Aspiration of the contents usually reveals dead sperm.
· Evaluate men for the presence of gynecomastia, as 30% of Leydig cell tumors produce testosterone, which is converted to estrogen.
· Rarely, testicular tumors present with disseminated disease, such as supraclavicular lymphadenopathy or abdominal masses from retroperitoneal lymph node spread or as a result of a tumor that arises within an undescended intra-abdominal testis.
Diagnostic Testing
Laboratories
· α-Fetoprotein is produced by nonseminomatous germ cell tumors (embryonal carcinomas and yolk sac tumors). An elevated α-fetoprotein may be seen at any stage, although 40% to 60% of patients with metastases have increased serum concentrations.
· β-Human chorionic gonadotropin is increased in seminomatous and nonseminomatous tumors. Elevations occur in 40% to 60% of patients with metastatic nonseminomatous germ cell tumors and 15% to 20% of patients with metastatic seminomas.
· Lactate dehydrogenase elevation is nonspecific but has prognostic value in patients with advanced germ cell tumors. It is increased in 60% of patients with nonseminomatous germ cell tumors and 80% of those with seminomatous germ cell tumors.
Imaging
· Testicular ultrasound is a highly reliable way of differentiating intratesticular from extratesticular lesions and should be the initial imaging study of choice.
· Gray-scale sonography of lymphomatous and leukemic testicular involvement reveals diffuse or multifocal decreased echogenicity, which can be more subtle and ill defined than the typical well-circumscribed hypoechoic mass of primary testicular cancer.
· Germ cell tumors are typically intratesticular and may produce one or more hypoechoic masses or show diffuse abnormalities with microcalcifications.
· CT scans and MRI of malignancy demonstrate a mass that is relatively isointense to the surrounding normal testicular parenchyma on T1-weighted images and exhibits brisk and early enhancement after IV gadolinium.
TREATMENT
Benign Masses
Hydrocele
· Management of hydrocele may require aspiration of the fluid (by a urologist) to be able to palpate the testis carefully.
· A scrotal ultrasound should always be considered if the diagnosis is in question, as a reactive hydrocele may occur with a testicular neoplasm.
· Generally, no therapy is needed except in the setting of discomfort from either a bulky mass or a tense hydrocele, which decreases circulation to the testis.
· Tense or uncomfortable hydroceles should always be aspirated.
Varicocele
· Not all varicoceles are associated with infertility and not all need to be corrected.
· If the patient has an abnormal semen analysis and is infertile or if the patient is symptomatic with a dull ache or feeling of heaviness in the testicle, the varicocele should be treated.
· Therapy consists of surgical ligation or sclerotherapy of the pampiniform plexus.
Malignant Masses
· Management of suspicious masses should be with urologic consultation.
· For lesions that are likely malignant, a radical orchiectomy with ligation of the spermatic cord at the internal ring is required.
· The primary lymphatic and vascular drainage of the testis is to the retroperitoneal lymph nodes and the renal or great vessels, respectively. Therefore, direct testicular biopsy through the scrotum is contraindicated.
· The staging workup includes CT scans of the abdomen and pelvis and a chest x-ray.
Priapism
· Priapism is a prolonged (>4 hours), usually painful, erection that is not initiated by sexual stimuli. It results from a disturbance in the normal regulatory mechanisms that initiate and maintain penile flaccidity.
· Low-flow, or ischemic, priapism is due to decreased penile venous outflow. The etiologies include hematologic dyscrasias (sickle cell disease, thalassemia, G6PD deficiency), tumor infiltrates, vasoactive erectile agents (papaverine, phentolamine), infectious (toxin mediated) such as scorpion sting and spider bites, hormones (testosterone), recreational drugs (alcohol, cocaine, marijuana), neurogenic (cauda equina compression, autonomic neuropathy, spinal cord injury), or idiopathic.
· Low-dose, or arterial, priapism produces painless, persistent semirigid to rigid erections that may still increase in tumescence in response to sexual stimuli. It results from increased arterial inflow into the cavernous sinusoids, which overwhelms venous outflow. The etiology is usually groin or straddle trauma that causes injury to the internal pudendal artery or its branches. This establishes a direct arterial-to-cavernous shunt that bypasses the normally regulatory helicine arteries. A growing cause is vasoactive erectile agents/drugs.
· Patients with priapism should be emergently managed in consultation with a urologist. Evaluation may include blood gas assessment of cavernosal aspirate.
· Therapeutic options range from aspiration to embolization and surgical intervention.47,48
Androgenetic Alopecia
GENERAL PRINCIPLES
· Androgenetic alopecia is a hereditary thinning of the hair that is induced by androgens in genetically susceptible men. DHT, produced by action of the enzyme 5α-reductase on testosterone, is the most important androgen responsible for induction and promotion of alopecia. It is also known as male pattern hair loss or common baldness.
· Thinning of the hair usually begins between 12 and 40 years of age, and approximately 50% of men express this trait to some degree before the age of 50 years.
· The pattern of inheritance is polygenic.
· The onset is gradual, and the condition slowly develops over years.
· It is important to rule out other causes of alopecia, such as has hypo- or hyperthyroidism, iron deficiency, acute illness, and effects of drugs such as anticonvulsants.
TREATMENT
Medications
Topical Minoxidil
· Topical minoxidil, a potassium channel agonist and vasodilator, is able to increase survival time and delay senescence of cultured keratinocytes in vitro.
· After topical application, minoxidil increases the duration of the anagen phase, leading to production of hairs that are progressively thicker and longer. Cessation of the drug leads to loss of hair growth resulting from the treatment.
· Minoxidil lotion 2% or 5%, 1 mL should be applied twice per day to the affected scalp. Twice-daily application has no significant systemic side effects.
· The percentage of patients who show cosmetically acceptable hair regrowth after 1 year ranges from 40 to 60, depending on patient selection.
· Adverse effects include allergic contact dermatitis and reversible hypertrichosis.
Finasteride
· Low-dose oral finasteride, 1 mg/day, is FDA approved for androgenic alopecia.
· It is an oral 5α-reductase isoenzyme 2 inhibitor, which decreases DHT levels in scalp and blood by 60%.
· It may take 6 to 12 months to see the full effect of the drug, and it must be continued to maintain the new hair growth.
· Patients taking finasteride for androgenic alopecia have about 50% reduction in PSA. The FDA has issued warnings regarding the risk of high-grade prostate cancer among men who develop prostate cancer while taking finasteride.
· There is minimal effect on libido at the dose for alopecia when compared with effects seen at the higher BPH dose.49–53
Other Nonpharmacologic Therapies
Surgical options including hair transplantation, scalp flaps, and excision of bald scalp with or without tissue expansion are options to treat advanced androgenetic alopecia.
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