Cryptorchidism
Mumps orchitis
Orchiectomy
Irradiation of testes
Traumatic injury to the testes
5-α reductase deficiency
Aging
Autoimmune disorders (e.g., Hashimoto thyroiditis or Addison disease)
Medications: high dose ketoconazole, cytotoxinsKallmann syndrome
Pituitary adenoma or infarction
Prolactinoma
Medications: estrogens, LHRH agonists (e.g., leuprolide, goserelin), LHRH antagonists (e.g., degarelix), prolonged course of high dose corticosteroids, megestrol acetate, medroxyprogesterone, long-acting opioidsInfectious or infiltrative diseases of the hypothalamus (e.g., tuberculosis, sarcoidosis, infectious abscess) Serum testosterone levelDecreasedDecreasedDecreased LH levelIncreased DecreasedDecreased GnRH levelIncreased Increased Decreased

GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone ; LHRH = luteinizing hormone–releasing hormone.

Late-Onset Hypogonadism

Late-onset hypogonadism, also known as andropause or androgen deficiency in aging males (ADAM), refers to the biochemical changes associated with age-related alterations in the hypothalamic-pituitary-gonadal axis, which may or may not be associated with clinically significant symptoms and signs.^4,5 As testosterone levels decline, some men develop symptoms including decreased libido, erectile dysfunction, mood changes, difficulty in coping with stress, lack of motivation, inability to concentrate, a diminished sense of well-being, generalized muscle aches, decreased muscle strength, increased body fat, gynecomastia, and decreased bone mineral density.⁴ However, other men with decreased testosterone levels do not complain of their symptoms or have vague, nonspecific symptoms (e.g., malaise or decreased energy) for which they do not seek medical treatment.⁵ Although late-onset hypogonadism is often compared to the menopause in aging females, these conditions are different (Table 22-3). In males gonadal function decreases over decades, and symptoms develop slowly and often are not attributed to decreasing hormone levels. In females, gonadal function decreases over a comparatively shorter time period of 4–6 years, and symptoms are closely associated with decreasing hormone levels.

Hormonal Changes Associated with Late-Onset Hypogonadism^4–6

Low serum testosterone levels in patients with late-onset hypogonadism are due to multiple physiologic changes including^4,5

1. Increased sensitivity of the hypothalamus and pituitary gland to negative feedback. Thus, even low circulating testosterone levels stimulate the negative feedback loop.
   
2. Irregular, nonpulsatile secretion pattern of LH
   
3. Loss of usual circadian secretion pattern of testosterone from Leydig cells; smaller difference in peak and trough serum concentrations during the day when compared to young adult males
   
4. Increased production of SHBG, which increases the plasma concentration of physiologically-inactive SHBG-bound testosterone³
   
5. Decreased number of functioning Leydig cells, which results in an age-related decrease in testicular production of testosterone. As mentioned previously, the decrease in testicular production occurs over decades. Starting at age 40, serum testosterone levels decrease by 1% to 2% annually. At age 80, the mean serum testosterone declines by approximately 40% of that typically observed in men at age 40.⁷

Of importance, late-onset hypogonadism was once thought to be a type of primary hypogonadism. However, multiple alterations in the hypothalamic pituitary gonadal axis suggest that late-onset hypogonadism can present as either primary or secondary hypogonadism in individual patients. This phenomenon occurs in the face of a wide range of serum (total) testosterone and bioavailable testosterone levels among elderly males. Whereas some symptomatic elderly males have levels that are below the normal physiological range, others have levels that are decreased but are still within the normal range.⁸

A male patient, age 50 years or older, who presents with symptoms of hypogonadism (e.g., decreased libido, unexplained mood changes) or signs of hypogonadism (e.g., gynecomastia, testicular atrophy) should undergo evaluation for late-onset hypogonadism. However, this is a diagnosis of exclusion, which is made after all other causes of low serum concentrations of testosterone have been ruled out. To assess symptom severity, the patient is commonly asked to complete a validated self-assessment questionnaire at baseline and at regular intervals after treatment is started. For example, the St. Louis University Androgen Deficiency in Aging Males questionnaire includes 10 questions to which the patient responds either “yes” or “no.”^9,10 An affirmative response to at least three questions on the survey is considered significant. A similar alternative self-assessment instrument is the Aging Male Symptom Scale.¹¹ These surveys are sensitive but not specific for hypogonadism. Rather than being used for diagnostic purposes, they are used prior to and during treatment to monitor the effectiveness of treatment.^2,4,5

Late-onset hypogonadism should be treated with testosterone supplements if the patient has both symptoms of hypogonadism and an unequivocal serum testosterone level of 230 ng/dL or less, based on at least two separate serum testosterone measurements on different days, and provided that the patient has no contraindications for androgen supplementation.^5,12 In addition to relieving symptoms and potentially preventing osteoporosis and bone fracture from long-term hypogonadism, treatment may decrease the prevalence of prostate cancer, which tends to occur more frequently in men with hypogonadism.¹³ For a patient with symptoms of hypogonadism and a serum testosterone level of 230–350 ng/dL, the treatment of late-onset hypogonadism should be decided after assessing the benefits versus the risks of androgen supplementation by the physician and patient. Controversy exists on the value of testosterone replacement in this subset of patients.^12,14 As long as the serum testosterone level is in the normal physiologic range, some physicians will not prescribe testosterone supplements. This is because some evidence suggests that administration of exogenous androgens to increase the serum testosterone level from one end of the normal range to a higher point within the normal range does not improve or increase sexual drive or energy.^15,16 Rather than prescribe testosterone supplements, the physician will treat individual symptoms with specific nonandrogen treatments. For example, if the patient is moody or depressed, psychotherapy may be beneficial. If the patient has erectile dysfunction, then a phosphodiesterase inhibitor may be indicated. On the other hand, there is evidence that suggests that signs and symptoms of hypogonadism respond to different levels of serum testosterone; libido may be restored at the lower end of the normal physiologic range, whereas increased bone mineralization is observed when serum testosterone is at the higher end of the normal physiologic range.^4,16 For this reason, some physicians will prescribe testosterone replacement to patients who have serum testosterone levels at the low end of the normal range. Patients with symptoms of hypogonadism and a serum testosterone level of 350 ng/dL or more should not receive testosterone supplements.

Once a testosterone replacement regimen is initiated, the patient should return for assessment of the efficacy and safety of treatment every 3 or 4 months during the first year.^14,16 A minimum clinical trial of a testosterone supplement is 3 months.^4,5 Within the normal serum testosterone range, an adult male will generally have appropriate sexual drive and feel energetic.

Assessments of efficacy should include serum testosterone levels, which should return to the normal range by the third month. The target serum testosterone level when the patient is receiving testosterone replacement is 400–500 ng/dL.⁴ Other assessments include a persistent reduction of symptoms of hypogonadism as assessed by medical history and the patient’s responses to the self-assessment questionnaire. Since testosterone can theoretically stimulate prostate enlargement and is a cocarcinogen in the development of prostate cancer, the patient should also annually undergo a digital rectal exam of the prostate and PSA testing. Finally, since excess androgen is converted to estrogen, which can induce breast cancer or gynecomastia, the patient should also undergo breast examination prior to the start of and periodically during treatment.

Testosterone, Total

Normal range, adult male: 280–1100 ng/dL or

9.7–38.14 nmol/L

Normal range, age-related:

Male, 6–9 yr old: 3–30 ng/dL or 0.10–1.04 nmol/L

Male, pubertal: 265–800 ng/dL or 9.19–27.74 nmol/L

A routine serum testosterone level reflects the total concentration of testosterone in the bloodstream, in all three of its forms: free, albumin-bound, and SHBG-bound. Testosterone secretion follows a circadian pattern such that morning levels are approximately 20% higher than evening levels, which is a difference of approximately 140 ng/dL between the peak and nadir serum levels. In addition, intrapatient variability in measured testosterone levels is characteristic from day to day, from week to week, and seasonally.¹⁷ Thus, when obtaining serum testosterone levels, it is recommended that blood samples be obtained between 8:00 a.m. to 11:00 a.m. Furthermore, to confirm a low serum testosterone level, it is also recommended that a second sample be obtained usually at least 1week apart. If the patient has a medical disorder or is taking medication that can alter serum testosterone levels, it is recommended that testing for serum testosterone levels be deferred until the medical disorder resolves or the medication is discontinued. Common causes of decreased and increased serum testosterone levels are listed in Table 22-4.

LHRH = luteinizing hormone-releasing hormone.

The normal range is wide for serum testosterone levels and is based on lab results for young adult males. Although this normal range is applied to interpretation of serum testosterone levels in elderly males, no single threshold serum testosterone value has been identified to be pathognomonic for hypogonadism in this age group.^16,18 When treating patients with prostate cancer with LHRH agonists or antagonists, medical castration is induced. The target serum testosterone level is 50 ng/dL or less.

Testosterone levels are commonly determined using radioimmunoassay, nonradioactive immunoassays, or chemiluminescent detection methods. However, these methods exhibit significant performance variability in the normal range.^19,20 Thus, some experts recommend that a normal range of serum testosterone be determined for each clinical laboratory that runs the assay.²¹ Such a determination would require measurement of serum testosterone in approximately 40 normal, healthy men, aged 20–40 years.^4,6 The U.S. Centers for Disease Control and Prevention has initiated a program to standardize testosterone assays, which involves providing reference material to calibrate immunoassays. This should reduce the variability of testosterone lab results among laboratories.¹⁵ Alternatively, stable isotope dilution liquid chromatography using benchtop tandem mass spectrometry has improved accuracy over radioimmunoassay and is simple and fast.²²

Free Testosterone

Normal age-related range, adult male:

10–15 ng/dL, age 20–29 yr

9–13 ng/dL, age 30–39 yr

7–11 ng/dL, age 40–49 yr

6–10 ng/dL, age 50–59 yr

5–9 ng/dL, age >60 yr

Free testosterone levels are the best reflection of physiologically-active androgen. When compared to young adult males, elderly males experience an almost 20% decrease in albumin-bound testosterone and an almost 20% increase in SHBG-bound testosterone in the circulation. Since free testosterone is in equilibrium with albumin-bound testosterone, the amount of bioavailable testosterone is decreased in elderly males, and therefore, elderly males may develop symptoms of hypogonadism despite having serum total testosterone levels near the normal range (Table 22-5).

SHBG = sex hormone-binding globulin.

Free testosterone levels are altered by the concentration of SHBG. Thus, free testosterone levels are preferred in patients with diseases or taking medications, which increase or decrease levels of SHBG (Table 22-6), or when the patient has symptoms of hypogonadism but has a serum total testosterone in the normal physiologic range.²³

HIV = human immunodeficiency virus; SHBG = sex hormone-binding globulin.

The most accurate assay method to measure free testosterone is by centrifugal ultrafiltration or equilibrium dialysis technique. However, such assays are not routinely available and are expensive. Thus, many laboratories offer radioimmunoassay for free testosterone levels. Although inexpensive, this method is associated with less accurate results.²⁴ Saliva specimens using a direct luminescence immunoassay can be used to measure free testosterone but is rarely done.²⁵

If free testosterone levels cannot be measured using an assay, the level may be estimated (a commonly used calculator is available at http://www.issam.ch/freetesto.htm; last accessed March 2, 2012). By inserting serum levels of albumin, SHBG, and total testosterone into the online calculator, the patient’s free testosterone level is derived. Estimated values are comparable to measured values by equilibrium dialysis.²³

Bioavailable Testosterone

Normal age-related range, adult male:

83–257 ng/dL, age 20–29 years

72–235 ng/dL, age 30–39 years

61–213 ng/dL, age 40–49 years

50–190 ng/dL, age 50–59 years

40–168 ng/dL, age 60–69 years

Not established, age greater than 70 years

Also expressed as percentage of total serum testosterone

Normal range, adult male: 12.3% to 63%

Bioavailable testosterone levels measure the concentration of free testosterone and albumin-bound testosterone in a serum sample. Since albumin has low affinity for testosterone, reversible binding of testosterone to albumin allows an equilibrium to be established between free and albumin-bound testosterone fractions. Thus, these two forms of circulating testosterone are considered bioavailable and physiologically-active.^4,6 As men age, bioavailable testosterone levels decrease as serum SHBG levels increase. Similar to free testosterone levels, which are dependent on SHBG levels, bioavailable testosterone levels may be preferred when assessing testosterone activity in patients with significant alterations of SHBG (Tables 22-5 and 22-6).

An ammonium sulfate precipitation assay is used to measure bioavailable testosterone. It is expensive and technically challenging to perform. For this reason, this test is not commonly available in clinical labs. If bioavailable testosterone levels cannot be measured using an assay, the level may be estimated. (A commonly used calculator is available at http://www.issam.ch/freetesto.htm; last accessed March 2, 2012.) By inserting serum levels of albumin, SHBG, and total testosterone into the online calculator, the patient’s bioavailable testosterone level is derived.

ERECTILE DYSFUNCTION

Erectile dysfunction is the consistent inability over a minimum duration of 3 months to achieve a penile erection sufficient for sexual intercourse.²⁶ The prevalence of erectile dysfunction increases with increasing patient age. According to the Massachusetts Male Aging Study, the prevalence of moderate erectile dysfunction increases in men from the 4th decade of life to the 6th decade of life, from 12% to 46%, respectively.²⁷ In the health professional study of men, age 50 years or older, the overall prevalence of erectile dysfunction was 33%, with an increased prevalence in patients with risk factors, including cigarette smoking, excessive alcohol intake, sedentary lifestyles, and obesity.^28,29 However, advancing age is not considered an independent risk factor for erectile dysfunction.

The causes of erectile dysfunction are broadly divided into two types: organic and psychogenic.^26,30 Most patients with erectile dysfunction have the organic type, in which concurrent medical illnesses interfere with one or more physiologic components essential for a penile erection (Table 22-7).³⁰ That is, the patient has one or more medical illnesses that impairs vascular flow to the corpora cavernosa; impairs central or peripheral innervation necessary for a penile erection; or is associated with testosterone insufficiency, in which case the patient develops erectile dysfunction secondary to a decreased libido (Table 22-8). Psychogenic erectile dysfunction is commonly situational in that the patient is unable to have an erection with a particular person, has performance anxiety, or is recovering from a major life stress (e.g., loss of a job, divorce, death in the family, etc.) (Table 22-7).³⁰

LHRH = luteinizing hormone–releasing hormone.

Because current first choice treatment for erectile dysfunction is effective in up to 70% of treated patients, independent of the etiology, the diagnostic assessment of these patients has been streamlined. These patients are commonly diagnosed in primary care clinics with a comprehensive sexual history to identify the particular type of sexual dysfunction that the patient has (e.g., decreased libido, erectile dysfunction, or ejaculation disorder). Details on onset of symptoms are obtained, a patient’s self-assessment of the severity of the problem using a validated, reliable questionnaire (e.g., International Index of Erectile Function, Sexual Health Inventory for Men [SHIM], Brief Male Sexual Function Inventory) is completed, and information on the patient’s expectations for improved sexual function are collected from the patient and from the spouse or significant other.^31,32

A comprehensive medical history is then performed to identify treatable underlying diseases, which may be contributing to erectile dysfunction (Table 22-8).²⁶ In addition, because erectile dysfunction may be the first presenting symptom of underlying cardiovascular or metabolic diseases, the clinician will investigate thoroughly for such conditions.³³ Blood pressure is measured and, if elevated, is treated. The patient is instructed to discontinue smoking, if applicable. A physical exam is completed to check for signs of hypogonadism (e.g., gynecomastia, small testes, decreased body hair). Peripheral pulses are palpated to assess vascular integrity (which would suggest adequate blood flow to the corpora cavernosa). A thorough urological examination to evaluate the integrity of the lower urinary tract and functional status of the bladder, urethra, and external genitalia is mandatory. A digital rectal exam is conducted on patients who are 50 years of age or older. This checks for anal sphincter tone, which indicates adequacy of sacral nerve innervation to the corpora cavernosa; prostate enlargement, which could obstruct urinary flow and lead to incontinence (which has been linked to erectile dysfunction); and a nodular or indurated prostate, which is suggestive of prostate cancer. Finally, an examination of the external genitalia identifies the presence of penile deformity or tissue scarring, which may contribute to erectile dysfunction.

For those patients who are over the age of 50 years and who have a life expectancy of at least 10 years, a blood test for prostate specific antigen (PSA) is obtained. If the medical or medication history suggests that the patient has concurrent medical illnesses that may contribute to erectile dysfunction, laboratory tests should be obtained to determine if these medical illnesses require more aggressive treatment. Such laboratory tests include a fasting blood glucose for diabetes mellitus, a lipid profile for hypercholesterolemia, a urinalysis to check for genitourinary tract disorders, serum testosterone levels for hypogonadism, a serum prolactin level if the patient has erectile dysfunction, decreased libido, and gynecomastia. Specialized clinical testing to identify surgically correctable causes of erectile dysfunction is reserved for those patients who do not respond to drug therapy, which includes oral phosphodiesterase inhibitors (e.g., sildenafil), intracavernosal alprostadil, intraurethral inserts, and vacuum erection devices (Table 22-9).

CIS = combined intracavernous injection and stimulation.

International Index of Erectile Function

The International Index of Erectile Function (IIEF) is a validated self-assessment questionnaire that includes 15 questions. The patient assesses the presence and severity of decreased libido, erectile or ejaculatory dysfunction, diminished orgasm, and his overall satisfaction with his sexual performance for the past month.³¹ The questionnaire takes approximately 10–15 minutes to complete. Total scores can range from 0–25 and various score ranges are associated with symptom severity (Table 22-10).

Two shorter self-assessment questionnaires that are also used include the abridged IIEF, which includes four of the 15 questions from the original survey that focus on erectile dysfunction and the last question concerning the patient’s overall satisfaction with his sexual performance and the Male Sexual Function Scale.^32,33 Some clinicians consider these shorter questionnaires to be more practical to use than the original IIEF. The IIEF is used at baseline to assist the physician in determining the severity of erectile dysfunction. Once treatment is initiated, the patient is asked to complete the IIEF questionnaire again so that the physician can assess the level of improvement in erectile function.

Prolactin

Normal range, adult males: 0–15 ng/mL or 0–15 mcg/L

Prolactin is secreted by the anterior pituitary gland in multiple pulses during the day. The normal daily production rate is 200–536 mcg per m² total body surface area. Although some prolactin circulates in inactive dimeric form (also known as “big prolactin”) or in a less active form complexed to immunoglobin (also known as “big, big prolactin”), the majority exists as active hormone. Its pulsatile secretion is predominately controlled by prolactin inhibitory factor, which is believed to be a dopamine₂-like substance secreted by the hypothalamus in response to high levels of prolactin in the systemic or hypophyseal portal circulation. A prolactin stimulatory factor may also regulate prolactin secretion; however, its chemical structure still needs to be identified. Prolactin follows a diurnal pattern of secretion with highest serum levels occurring when the patient sleeps at night. Nadir levels occur between 10:00 a.m. and 12:00 p.m. The precise role of prolactin in males is unclear; however, it has been hypothesized that high circulating prolactin levels suppress LH and FSH, thereby decreasing testosterone production and spermatogenesis. Prolactin is excreted renally.

Hyperprolactinemia occurs in 1% to 2% of men who present with erectile dysfunction and is typically associated with symptoms of hypogonadism. Medical conditions and medications that can produce hyperprolactinemia are included in Table 22-11. They can be broadly classified as disorders of the hypothalamus or pituitary gland, neoplastic conditions, metabolic disorders, or drug causes. Whereas hypothalamic (e.g., craniopharyngioma), pituitary (e.g., prolactinoma), and neoplastic conditions (e.g., paraneoplastic syndromes) can cause significant increases in serum prolactin levels exceeding 250 ng/mL, physiologic and pharmacologic factors, including medications, sleep, pain, or meals, cause only smaller increases in serum prolactin level that rarely exceed 200 ng/mL. It should be noted that decreased prolactin levels in men is a rare condition. The clinical significance of this finding is unknown as it is associated with no symptoms or disease.

Indications for assessing serum prolactin levels include (1) a patient who is less than 50 years of age who complains of decreased libido and gynecomastia, or who has low serum testosterone levels; (2) a patient who is more than 50 years of age who complains of gynecomastia; or (3) a patient with late-onset hypogonadism and erectile dysfunction, whose symptoms are not corrected with a testosterone replacement regimen that restores serum testosterone to the normal range. Prolactin levels should not be routinely obtained in patients who present with erectile dysfunction. (See Minicase 1.)

Assay techniques for prolactin measurement include immunoassays using chemiluminescent, fluorescent, or radioactive labels. To minimize interference of prolactin assays by meals and stress, both of which can cause increased prolactin levels, it is recommended that blood specimens be collected 3 or 4 hours after the patient has awakened and fasted overnight. Prior to the blood draw, it is recommended that the patient rest for at least 20 minutes. Big prolactin and big, big prolactin, which are the less active forms of prolactin, crossreact with prolactin in immunoassays. To eliminate this interference, polyethylene glycol extraction and centrifugal ultrafiltration assay methods can be employed.³⁶ Extremely high serum levels of prolactin may saturate the ability of immunoassays to measure correct levels. Therefore, in patients with prolactinomas, it may be necessary to dilute the specimen to 1:100 before assaying.

BENIGN PROSTATIC HYPERPLASIA

Benign prostatic hyperplasia (BPH) is an enlargement of the prostate gland that occurs in all males as they age. The histologic disease prevalence is 80% in men aged 70–79 years.³⁷ Furthermore, 50% of men with a histologic diagnosis of BPH develop clinical symptoms of at least moderate severity.³⁸ Beginning at approximately age 40 years in males, the prostate gland undergoes a second growth spurt and the prostate grows from a normal adult size of 15–20 g to a much larger size that can exceed 100 g. The local complications of BPH include obstructive and irritative voiding symptoms. Collectively, these symptoms are often referred to as lower urinary tract symptoms (LUTS); however, LUTS are not specific for BPH and may be due to other genitourinary tract disorders (e.g., neurogenic bladder, prostate cancer, urethral stricture, prostatitis, and urinary tract infection).³⁸ Obstructive symptoms include a slow urinary stream, difficulty emptying urine out of the bladder, hesitancy, dribbling, a sensation of incomplete bladder emptying, and straining to void. Such symptoms can be due to the enlarged prostate, which produces an anatomical block of the bladder neck. Irritative symptoms include urinary frequency, nocturia, and urgency, which may progress to urinary incontinence. Such symptoms are due to the long-term effects of obstruction on the detrusor muscle of the bladder. That is, an enlarged prostate results in partial obstruction of the bladder outlet. In time this causes hypertrophy of the bladder muscle and increased intravesical pressure, which translates to urgency, frequency, nocturia, and urge incontinence. If untreated, progressive increased resistance at the bladder outlet will result in decompensation and residual urine, and then total urinary retention and overflow incontinence. Other complications of untreated, severe BPH include recurrent urinary tract infection, urosepsis, urolithiasis (primarily bladder stones), and chronic renal disease.

The symptoms of BPH are most often the driver that brings the patient to medical attention. Nocturia (which interferes with sleeping) and urgency-associated incontinence (which curbs social activity) can significantly reduce quality of life. Thus symptom assessment is crucial in evaluating the disorder. Symptom assessment is typically completed by having the patient use a validated questionnaire such as the American Urological Association Symptom Score or the International Prostate Symptom Score instrument.

Signs of disease are evaluated by the physician using clinical procedures that can be performed easily in the outpatient setting. A careful medical history is taken to identify any concurrent medical illnesses or medications that may be causing LUTS or worsening LUTS. A physical examination should be performed to check for bladder distention and neurologic innervation of the lower urinary tract. A digital rectal exam is performed to assess prostate gland size, shape, and consistency, and anal sphincter tone. The latter is maintained by the pudendal nerve, which is also responsible for bladder contraction and emptying. In addition, to rule out other common causes of urinary frequency and urgency, physicians should obtain a urinalysis. Microscopic examination of the spun sediment for white blood cells and bacteria, and a dipstick check for leukocyte esterase and nitrite help identify urinary tract infection as a cause for the patient’s symptoms. If gross or microscopic hematuria is present and the patient has a past or current history of smoking, urine is sent for cytological assessment. Bladder neoplasms typically shed cancer cells into the urine. For patients in whom the urinalysis is suspicious for renal impairment (e.g., casts are detected on microscopic examination) or in whom surgical treatment of BPH is being considered, specialized testing is performed. Serum creatinine may be assessed to check for evidence of chronic renal disease. If present, such patients have a higher risk of postoperative complications than patients with normal renal function, 25% versus 17%, respectively, and of worsening renal function due to radiographic contrast media, if used during intravenous pyelography to assess renal function and anatomy.³⁸ In such high-risk patients, a renal ultrasound would be a better test for evaluation of renal anatomy.

Other specialized tests include uroflowmetry, postvoid residual urine volume, transrectal ultrasound of the prostate, and cystoscopy. Uroflowmetry and postvoid residual urine volume, which are quantitative tests, are discussed below. Transrectal ultrasound of the prostate entails insertion of an ultrasound probe into the rectum. Ultrasound waves are bounced off the prostate through the rectal mucosa and images are produced. These images allow identification of stones, abscesses, or other changes in echogenicity in the prostate, and also provide an estimate of prostate size, which is more accurate than digital rectal exam. During cystoscopy an endoscope is passed transurethrally so that the urologist can visualize the urethra, bladder neck, and bladder. In patients with BPH, the classic findings are changes in the bladder mucosa secondary to prolonged bladder neck obstruction, and obstruction of the urethral lumen and bladder neck by an enlarged prostate. This gives the appearance that the three side-walls of the prostatic urethra bulge out and appear to kiss each other.

American Urological Association (AUA) Symptom Score and International Prostate Symptom Score (IPSS)

This validated survey instrument is administered to the patient, who responds to a series of seven questions about the severity of his obstructive and irritative voiding symptoms. For each question, the patient rates symptom severity on a scale of 1 to 5, where 0 is not bothersome and 5 is severely bothersome. Thus, the lowest total score is 0 and the maximum total score is 35. Scores are interpreted according to the following ranges:

• Mild symptoms, score of 0–7
  
• Moderate symptoms, score of 8–19
  
• Severe symptoms, score of 20–35

The AUA Symptom Score Survey is administered to establish a baseline and then is repeated at regular intervals for patients with mild symptoms to determine if symptoms are worsening over time and deserve medical or surgical treatment. Similarly, once specific treatment for BPH is initiated, the AUA Symptom Score Survey is repeated several weeks after treatment is started to determine if the treatment is effective in relieving symptoms. An effective treatment should reduce the AUA Symptom Score by 30% to 50% or decrease the score by at least three points.

The International Prostate Symptom Score Survey is a symptom survey instrument, which includes all seven questions in the AUA Symptom Score survey plus one additional question about the impact of the patient’s voiding symptoms on overall quality of life. The last question is not included in the total score. Therefore, the total score ranges from 0 to 35, with 0 suggesting that the patient has no symptoms and 35 suggesting that the patient has severe symptoms.

Both the AUA and the International Prostate Symptom Score may not correlate with the actual severity of the patient’s obstruction. This is partly because some patients deny the presence of LUTS and attribute their symptoms to getting older. Furthermore, the AUA and International Prostate Symptom Score do not always correlate with prostate gland size, urinary flow rate, or postvoid residual urine volume. However, patients with high AUA and International Prostate Symptom Scores generally show significant improvement with surgical treatment for BPH.⁴²

Digital Rectal Exam of the Prostate

Because of its location below the urinary bladder, the prostate is difficult to examine directly. Instead, it must be examined indirectly by having a physician insert a gloved index finger into the anus and then digitally palpating the prostate through the rectal wall. This is a simple physical examination procedure, which can be performed without any local anesthetic or bowel preparation. The prostate is assessed for its size, shape, consistency, and mobility. A normal prostate is 15–20 g in size, is heart-shaped and symmetric, has a soft consistency similar to the thenar eminence of the hand with no areas of nodularity or induration, and should be moveable when pushed with the finger. Patients with BPH have an enlarged, symmetric, rubbery, mobile gland with a smooth surface. In contrast, a patient with prostate cancer could have a variable size (normal-sized or enlarged), asymmetric gland with a nodular or indurated surface on palpation. If the cancer has locally extended to surrounding periprostatic tissue, the prostate becomes fixed in place and is no longer mobile.

The physician will estimate the size of the gland based on the degree to which the examiner’s finger can reach up to the base and over the border of the prostate gland. The accuracy of the prostate size assessment by digital rectal exam is dependent on the expertise of the physician who is conducting the exam. Due to skill variability among clinicians for this physical assessment technique, a transrectal or transabdominal ultrasound is often performed to better assess the size of an enlarged gland.⁴³

An accurate prostate size assessment is useful for identifying patients at high risk for developing complications of BPH, who would most benefit from treatment with finasteride and dutasteride. These agents are most effective in patients with prostates that are least 40 g in size and treatment can reduce the risk for acute urinary retention, slow BPH progression, and delay the need for surgery. In addition, the size of the prostate helps determine the best surgical approach for large prostate glands.^44,45

Estimated prostate size does not correlate with the severity of voiding symptoms, degree of bladder neck obstruction, or the need for treatment.^38,46 This can be explained by the existence of at least two mechanisms for obstructive voiding symptoms in patients with BPH. In some patients, the obstructive voiding symptoms are due to the anatomic blockade of the urethra caused by the enlarged prostate gland. However, in other patients, obstructive voiding symptoms may be due to excessive alpha adrenergic stimulation of receptors in the smooth muscle fibers of the prostate and bladder neck, which decreases the caliber of the urethral lumen. In these patients, despite the absence of a significantly enlarged prostate gland, the patient may develop significant symptoms. Alternatively, some patients with BPH have enlargement of the median lobe of the prostate, which grows inside the bladder and produces a ball-valve obstruction of the bladder neck. In this case, the enlarged gland is not palpable on digital rectal exam, but must be identified by transrectal ultrasound of the prostate or cystoscopy.

Peak Urinary Flow Rate

Peak urinary flow rate, normal range:

≥25 mL/sec, in young male

≥10–15 mL/sec, minimum, in older males

The urinary flow rate refers to the speed with which urine is emptied out of a full bladder. Urinary flow rate is assessed as a simple outpatient procedure. The patient is instructed to drink water until his bladder is full, and then is instructed to urinate into the uroflowmetry measuring device until he feels empty. The peak urinary flow rate is the maximum flow rate using the time period limited to the interval when the bladder volume was at least 150 mL.⁴⁶ The average urinary flow rate is calculated from the total volume (mL) of urine collected divided by the total time (seconds) that it took to empty his bladder.

A low peak urinary flow rate is suggestive of bladder outlet obstruction, particularly when the peak urinary flow rate is less than 10–12 mL/sec. In addition, a patient with a peak urinary flow rate of less than 10 mL/sec is more likely to benefit from surgical correction of BPH than a patient with a higher flow rate.³⁸ However, there is no direct correlation between voiding symptom severity and urinary flow rate. Again, this is likely due to patient’s attribution of voiding difficulty to advancing age (and not due to a prostate disorder), or a patient’s denial of the presence of symptoms.³⁸

There is no standardized cutoff point for urinary flow rate that identifies a patient with clinically significant urinary obstruction requiring medical or surgical treatment.⁴⁷ In patients with BPH, the urinary flow rate is typically used along with the patient’s AUA symptom score and the absence or presence of complications secondary to bladder neck obstruction to assess the severity of the patient’s disease.⁴⁶ As mentioned, a patient may have a low urinary flow rate, but may not consider his symptoms severe. In this case, the perceived severity of the patient’s symptoms will impact on the ultimate choice of therapy for the patient rather than the urinary flow rate.

A limitation of uroflowmetry testing is that there is intrapatient variability of results from test to test. That is, even if repeated on the same day, the urinary flow rate may not be the same in the same patient.³⁸ Also a low flow rate is not specific for BPH. Low flow rates may be due to urethral stricture, meatal stenosis, or neurogenic bladder secondary to detrusor muscle hypotonicity.^46,47 The latter occurs in patients with diabetes mellitus, peripheral neuropathy, or spinal cord injury.⁴⁷ Finally, the uroflowmetry test requires a minimal urine volume of 150 mL, which may be difficult for some patients to attain (i.e., they balk at consuming so much fluid in a short period of time).

Postvoid Residual Urine Volume

Normal range: <50 mL

Postvoid residual urine volume refers to the amount of urine left in the bladder after a patient empties his bladder and voids a minimum volume of 120–150 mL. In a normal person, the postvoid residual urine volume should be zero, range 0.09–2.24 mL. However, in patients with BPH, the enlarged prostate at the bladder neck causes an obstruction that makes it difficult to empty urine completely from the bladder. Chronic retention of large volumes of urine increases the risk of urinary tract infections in men with BPH and can lead to decompensation of the detrusor muscle fibers of the urinary bladder, which can result in urinary frequency, overflow incontinence, or acute urinary retention.

Traditionally to assess the postvoid residual urine volume, the patient is asked to empty his urinary bladder. Then a small bore urethral catheter is inserted up the urethra and into the urinary bladder to drain any residual urine. The urine is collected and the volume is measured. This method is invasive and is associated with some risk of urethral injury and pain secondary to catheter insertion. More recently, noninvasive determination of the postvoid residual urine volume with abdominal ultrasonography is commonly used.

A specific postvoid residual urine volume has not been identified as a critical value that necessitates treatment, although in clinical practice, a persistent postvoid residual urine volume of 50 mL or more is cause for concern.³⁸ Although a high postvoid residual urine volume correlates with decreased peak urinary flow rate, the former may not correlate with the patient’s reported symptom severity.^48,49 However, effective drug or surgical treatment that improves symptoms of BPH generally reduces a high postvoid residual urine volume. As a result, clinicians generally evaluate elevated postvoid residual urine volumes in the context of the patient’s medical history of recurrent urinary tract infections.

A high postvoid residual urine volume is not specific for BPH. An enlarged prostate due to prostate cancer can be associated with an increased postvoid residual urine volume. Also, a hypotonic detrusor muscle, which lacks contractile force to empty the bladder, as occurs in patients with peripheral neuropathies secondary to severe diabetes mellitus, spinal cord injury, or chronic alcoholism, can be associated with a high postvoid residual urine volume.

Transrectal Ultrasound of the Prostate

Normal prostate size: <15–20 cm³

In this outpatient procedure, after application of a local anesthetic jelly to the rectal mucosal surface, biplanar ultrasound probes are inserted into the rectum. Ultrasound waves are bounced through the rectal wall to assess the size, shape, and echogenicity of the prostate. Transrectal ultrasound of the prostate is more accurate in estimating prostate size than digital rectal exam and helps inform the urologist of the best approach for surgical removal of an enlarged prostate gland.

Transrectal ultrasound of the prostate is also used to assess indurated or nodular areas of the prostate or an elevated PSA, which are suspicious for prostate cancer. A transrectal ultrasound of the prostate may reveal hyper-, hypo-, and isoechoic areas of the prostate. By so doing, different sites for prostate needle biopsy can be better identified.⁵⁰

PROSTATE CANCER

Prostate cancer is the most common cancer of American men, and the second leading cause of cancer-related death among American men. The prevalence is highest in males aged 50 years or more. Approximately 11% of men present with advanced disease at the time of first diagnosis, and unfortunately, there is no cure for advanced disease at this time. The clinical presentation of prostate cancer is heterogeneous. In some patients, prostate cancer is slow growing and may or may not be associated with localized symptoms, such as voiding difficulty. Such patients are more likely to die from other concurrent medical illnesses, and not prostate cancer. In other patients, prostate cancer spreads quickly, follows a progressive course, and produces many systemic symptoms. Such patients are more likely to die from complications of prostate cancer and its treatment.

The symptoms of prostate cancer are associated with cancer invasion of the prostate gland or tumor spread to metastatic sites. Tumor in the prostate gland generally causes hardness, nodularity, induration, asymmetry, and may also be associated with glandular enlargement, which can lead to obstructive voiding symptoms (e.g., decreased force of urinary stream, inability to completely empty the bladder, and overflow urinary incontinence, similar to BPH). Tumor spread to the lungs can cause dyspnea; to the bone it can cause bone pain and anemia; to the vertebral bodies it can cause peripheral neuropathies, urinary or fecal incontinence, or difficulty walking; to the lymph nodes it can cause lymphadenopathy, lower extremity peripheral edema, or ureteral obstruction; and to the rectum it can cause rectal bleeding.⁵¹

As recommended by the American Cancer Society and the American Urological Association, screening for prostate cancer is recommended for a patient age 50 years or older and who has a life expectancy of at least 10 years. Screening includes both a digital rectal exam (described above in the section on BPH) and a blood test for PSA. In patients with risk factors for prostate cancer, including African Americans and those with a family history of first-degree relatives with prostate cancer, screening with a digital rectal exam and PSA is recommended beginning at age 45 and 40 years, respectively.⁵² Four common scenarios may result (Table 22-12).

PSA = prostate specific antigen.

It should be noted that the value of PSA screening for prostate cancer has been questioned by the American College of Preventative Medicine and the U.S. Preventative Services Task Force.^53,54 PSA has several limitations as a screening tool. Despite the widespread use of PSA for screening, only a 20% decrease in prostate cancer-related mortality has been attributed to PSA screening alone. Although PSA has produced a 70% increase in the diagnosis of patients with prostate cancer, many of these patients are at low risk of significant morbidity or mortality from their disease but yet are treated aggressively with surgery, radiation therapy, or medically.^55,56 Treatment is expensive and is associated with many adverse effects. Finally, there is no threshold PSA which guarantees the absence of prostate cancer. In the Prostate Cancer Prevention Trial, men with PSAs <0.5 ng/mL, 0.6–1.0 ng/mL, 1.1–2.0 ng/mL, 2.1–3.0 ng/mL, and 3.1–4.0 ng/mL had a 6.6%, 10%, 17%, 23.9%, and 26.9% prevalence of histologically confirmed prostate cancer, respectively. Of these cases, 10% to 25% had high-grade tumors, which generally carry a worse prognosis than low grade ones.⁵⁷ For these reasons, the U.S. Preventative Services Task Force recommends that physicians candidly discuss with each patient the option of routine screening versus not screening with PSA and give full consideration to the patient’s age, the patient’s willingness to live with cancer, the risk of side effects of treatment if prostate cancer is diagnosed, and the patient’s overall health in determining the use of PSA for screening.⁵⁴

In scenarios where the patient undergoes a prostate needle biopsy and it yields a positive pathologic result, the tissue-diagnosis of prostate cancer confirms the presence of the tumor. Based on the Gleason score of the tumor specimen, PSA, digital rectal exam, and transrectal ultrasound of the prostate, a clinical stage of disease can be determined and a risk assessment can be performed. If the patient is thought to have disease confined to the prostate and is considered to be at low risk of tumor recurrence, no further testing is done. If the patient is thought to have disease that has spread locally or is metastatic, and is considered to be at intermediate or high risk of tumor recurrence, the patient will undergo clinical staging to determine the presence and the location of tumor spread. A variety of clinical tests are performed. If initial tests are positive, additional tests are run to assess tumor burden and degree of spread of the cancer in the patient, and hence, to determine the stage of disease (Table 22-13). Current clinical tests to stage prostate cancer fail to identify approximately one-third of patients with prostate cancer that has spread outside of the prostate gland.⁵¹ Thus, the search continues for improved diagnostic tools. For example, ProstaScint^® is a type of scan that uses indium-111 capromab pendetide, a monoclonal antibody against prostate specific membrane antigen, to detect prostate cancer cells, which may have spread to soft tissue outside of the prostate gland.⁵⁹ Initial evaluation shows that ProstaScint may be useful for detecting tumor recurrence or for identifying those patients with disease which has spread locally outside the prostate. However, its role as a tumor marker must be further defined.

CT = computerized axial tomography; PSA = prostate specific antigen.

Prostate Specific Antigen

Non-age-related normal range: <4 ng/mL

Age-related normal ranges:

Men, age 40–49 yr, 0–2.5 ng/mL

Men, age 50–59 yr, 0–3.5 ng/mL

Men, age 60–69 yr, 0–4.5 ng/mL

Men, age 70+yr, 0–6.5 ng/mL

Prostate specific antigen (PSA) is a glycoprotein produced by the glandular epithelial cells in the transition zone of the prostate gland. Small amounts are also produced by breast tissue, parotid gland, and periurethral glands. In normal, healthy males, 20–45 years of age, mean plasma PSA levels are undetectable or at the low end of the normal range, usually less than 1.14 ng/mL in Caucasians and less than 1.37 in African Americans. This is because PSA is carried out of the prostate through ducts to the urethra, where it is passed out of the body in the ejaculate during coitus. Prostate specific antigen liquefies semen after ejaculation. However, once the prostate gland becomes cancerous, the duct system in neoplastic tissue is inadequate. As the gland grows, PSA production increases and leaks into the circulation; this results in elevated plasma PSA levels.

In the bloodstream, PSA exists in two forms: free PSA (fPSA) and complexed PSA (cPSA). Of the total PSA in plasma, 30% to 40% is fPSA, and 50% to 70% of the total PSA is complexed to alpha 1-antichymotrypsin (ACT) and alpha 2-macroglobulin (A2M).⁶⁰ Free PSA is renally excreted, while cPSA is hepatically catabolized. The plasma half-life of PSA is 2–3 days. Because of daily intrapatient variation in PSA measurements, it is recommended to confirm an increased PSA value by repeating it. ⁶⁰ A PSA level measures both fPSA and PSA complexed to ACT. Prostate specific antigen complexed to A2M is not detected by immunoassay.

In the bloodstream, fPSA exists in several forms. ProPSA is the inactive precursor of PSA and is associated with prostate cancer.⁶¹ It may be modified or clipped to produce two different inactive forms; however, most of it is converted to active PSA. Active PSA can be converted to inactive PSA (iPSA) or benign PSA (BPSA), which is produced by BPH tissue, as opposed to normal prostate tissue. High levels of BPSA are associated with high-volume BPH and obstructive voiding symptoms.⁶¹ Preliminary studies are being conducted to evaluate the diagnostic usefulness of measuring ProPSA, clipped forms of ProPSA, and BPSA. Currently, these forms of fPSA are largely used as research tools. Whether these will replace PSA as a tumor marker is not known at this time.

Prostate specific antigen serum levels are affected by several patient factors.^62,63 Decreased PSA levels are associated with obesity. It has been postulated that obese patients have larger circulating plasma volumes, which dilutes PSA concentrations in the bloodstream.⁶⁴ Decreased PSA is also seen with hypogonadism. This is probably because hypogonadism results in shrinkage of the prostate gland, the major site of PSA production. Increased PSA levels are observed in elderly patients probably because BPH occurs with a high prevalence. Also, increased PSA normal range levels are reported in African-American patients less than 60 years of age.⁶⁵ The reason for this is unknown.

As a tumor marker, PSA has several uses: as a diagnostic screening test for prostate cancer; to determine the spread of the disease; and to assess the patient’s response to treatment. As a diagnostic screening test, PSA has high sensitivity (70% to 80%), but low specificity (50%) for prostate cancer when used alone. The positive predictive value of PSA to diagnose prostate cancer is directly related to the PSA value such that the higher the PSA value, the higher the positive predictive value. In the range of 2.5–4 ng/mL, PSA has a positive predictive value of 18%. In the range of 4–10 ng/mL, PSA has a positive predictive value of 20%. Above 10 ng/mL, PSA has a positive predictive value of 42% to 64%.⁶⁶ Prostate specific antigen should be used in combination with a digital rectal examination of the prostate for prostate cancer screening because either test alone has inadequate sensitivity and specificity as a diagnostic test. When used in combination with a digital rectal exam, the sensitivity of PSA is increased to 85% to 90%, and the positive predictive value of a PSA cutoff of 4 ng/mL to diagnose prostate cancer is increased from 32% to 49%.⁶⁷ With the use of PSA screening, patients with prostate cancer are diagnosed 5–13 years earlier in the course of their disease when the tumor burden is less. Thus, fewer patients present with advanced stage disease at the time of initial diagnosis.⁶⁸

When used for prostate cancer screening, a common interpretation of test results follows if the PSA normal range is assumed to be <4 ng/mL:

Prostate specific antigen can be used as a laboratory test to determine the spread of prostate cancer. Although the amount of PSA produced increases with the size of the tumor, there is a poor correlation between the PSA level and the actual size of the prostate tumor. However, a semiquantitative relationship exists between the PSA level and the degree of prostate cancer spread such that a PSA level less than 10 ng/mL suggests that tumor is confined to the prostate, a PSA level of greater than 20 ng/mL suggests the possibility of extracapsular spread, and a PSA level of greater than or equal to 80 ng/mL suggests advanced disease.

When used to assess the patient’s response to treatment for prostate cancer, an elevated PSA prior to treatment should be reduced to the normal range, or at least exhibit a two-fold reduction in PSA level, with effective treatment. In addition, pretreatment PSA is used along with the Gleason score of prostate tissue and the clinical stage of disease to predict the prognosis of patients in terms of their low-, medium-, or high-risk of post-treatment disease recurrence.⁶⁹ This information is then used to guide treatment selection for individual patients.²⁹ Although multiple risk stratification schemes have been devised, no one system is considered the standard.⁷⁰

As previously mentioned, using a cutoff value of 4 ng/mL, PSA is 70% to 80% sensitive in screening for prostate cancer but has low specificity. Many noncancerous conditions can increase PSA (Table 22-14), which could trigger a clinical decision for an unnecessary prostate biopsy. For example, almost 30% of men with BPH have PSA values of 4 ng/mL or higher. Also, as previously mentioned, some high-grade prostate tumors do not produce PSA. Thus, this cutoff value for PSA potentially misses up to 27% of patients with prostate cancer confined to the prostate gland, which is curable.⁶⁰ Therefore, various alternative strategies have been employed to improve the usefulness of PSA as a tumor marker for prostate cancer screening including the following:

BPH = benign prostatic hyperplasia; PSA = prostate specific antigen.

^aProcedures that have minimal effect on (total) PSA: digital rectal exam, transrectal ultrasound of the prostate, cystoscopy, and urethral catheterization.⁷¹

1. Consider the normal value of total PSA to be less than 2.5 ng/dL, particularly in men less than 60 years of age. Thus, patients with a total PSA of 2.5 ng/dL or greater would undergo a prostate needle biopsy. This should avoid missing that subgroup of patients with organ confined prostate cancer who have PSA values in the range of 2.5–4.0 ng/dL.^72,73 However, lowering the normal value of PSA also is likely to increase the number of biopsies that are negative.^52,74
   
2. Consider age-related normal value ranges.⁷⁵ Using the current cutoff value of 4 ng/mL, the specificity of PSA decreases as men age.⁶⁷ This is because PSA normally increases as men age and develop BPH. Thus, to minimize the risk of interpreting an increased PSA as due to prostate cancer, when it is due to BPH, age-related normal value ranges, which have been further delineated for Asians and African Americans, as listed below, are often provided by clinical laboratories (Table 22-15).^76,77 An advantage of age-related normal value ranges is that they increase the likelihood of disease detection in young men. However, a disadvantage is that they delay biopsies in older men, which can delay the diagnosis of prostate cancer.^60,77

The total PSA range of 4–10 ng/mL is considered to be a gray-zone range because the increase in PSA in many cases is due to BPH and not prostate cancer. Thus, to improve the usefulness of total PSA in the range of 4–10 ng/mL as a screening test or to assess prognosis of patients, the following strategies have been recommended by some investigators:

1. PSA density (PSAD). The PSAD is thought to be increased in patients with prostate cancer as compared to patients with BPH. The PSAD is calculated by dividing the total PSA by the prostate volume as determined by transrectal ultrasound of the prostate (TRUS). A normal PSAD is less than 0.15 ng/mL/cm³. If the PSAD is 0.15 ng/mL/cm³ or more, it suggests that the patient’s increased PSA is due to prostate cancer, and this patient should undergo additional diagnostic testing. However, this cutoff value has only 50% sensitivity, and it misses many patients with prostate cancer.^77,78 In addition, to derive PSAD, a TRUS must be performed. This adds an extra cost to the patient and is uncomfortable for the patient. Finally, a TRUS measurement of prostate volume is difficult to reproduce in the same patient.⁶⁰
   
2. PSA velocity. The PSA velocity refers to the rate of increase in PSA values over time and is based on the concept that a faster rate of rise is suggestive of the presence of prostate cancer. To determine PSA velocity, the patient must have three PSA values performed, each one is at least 1 year apart; or alternatively the patient must have three PSA values performed over a 1.5-year period.⁷⁸ If the PSA velocity is greater than 0.75 ng/mL/year, this suggests that the patient has prostate cancer and should undergo additional diagnostic testing. Prostate specific antigen velocity has 95% specificity as a screening test for prostate cancer, which is much better than total PSA. In men less than age 60 years, whose lifespans are potentially more severely impacted by aggressive prostate cancer, it is suggested that a PSA velocity greater than 0.4 ng/mL/year be used as a threshold value.⁷⁹ Prostate specific antigen velocity is affected by the intrapatient variation of PSA values. That is, a PSA value may fluctuate 10% to 25% from day-to-day in the same patient. For this reason, it may be difficult to derive a consistent PSA velocity value for a patient. Thus, some recommend that the trend of an increase in PSA values over a 1.5-year period should be considered as suggestive of prostate cancer in place of the 0.75 ng/mL/yr cutoff.⁶⁰ In addition, the long period of time needed to collect enough PSA measurements to determine PSA velocity is a significant disadvantage of using this parameter.
   

   A related alternative strategy is to evaluate PSA doubling time or the length of time it takes for the PSA level to double. The preoperative PSA doubling time has been used to predict cancer recurrence after surgical intervention for the disease. A preliminary study suggests that a PSA doubling time of less than 10 months indicates that the patient probably has tumor recurrence.⁸⁰ A disadvantage to using PSA doubling time is that there is no accepted standard for the minimum number of PSA values to use or the time interval between PSA values.

   
   
3. Percentage of free PSA (% fPSA). Prostate cancer is associated with an increased fraction of cPSA as opposed to fPSA in the plasma. Therefore, the fPSA level is inversely related to the risk of prostate cancer in a patient. Thus, if the percentage of fPSA is less than 25% of the total PSA, and depending on the actual percentage of fPSA, the patient has up to a 56% probability of having prostate cancer (Table 22-16).^81,82 The use of fPSA to screen for prostate cancer when the total PSA is less than 4 ng/mL has not been well-studied, but preliminary evaluation suggests that the percentage of fPSA may be a good screen for prostate cancer.⁶⁰ One study showed that in the (total) PSA range of 2.5–10 ng/mL, the fPSA cutoff of 25% had greater than 90% sensitivity for screening for organ-confined prostate cancer.⁸²
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   

   TABLE 22-16. Estimated Probability of Prostate Cancer Depending on the Percentage of Free PSA81,82
   % FREE PSA RANGE	% PROBABILITY OF PROSTATE CANCER
   0–10	56
   10–15	28
   15–20	20
   20–25	16
   >25	8

   
   

   Assessing the percentage of fPSA helps the clinician determine if the elevated PSA is due to prostate cancer or BPH. Thus, prostate needle biopsy would be reserved for those patients with an fPSA less than 25%. Free PSA is renally excreted; therefore, in patients with renal failure, the fPSA level will be increased, and the percentage of fPSA will increase.⁸³ Free PSA increases after digital rectal exam of the prostate, prostate needle biopsy, and after ejaculation. Finasteride and dutasteride also decrease free and complexed PSA but do not affect the ratio of the two; therefore, fPSA percentages are not affected by these medications. Free PSA blood specimens are subject to degradation if stored for long periods of time at ambient temperature. It is recommended that specimens for fPSA be stored at –70^oC or assayed within 3 hours of specimen collection.

   
   
4. cPSA. As previously mentioned prostate cancer is associated with an increased fraction of cPSA. With this assay, the concentration of PSA complexed to ACT is measured. Using the PSA normal value of 4 ng/mL, the cPSA normal value is 3.1 ng/mL. Although cPSA assays appear to be comparable in sensitivity and specificity to PSA assays, cPSA assays have not replaced PSA assays.⁸⁴

Medications may alter PSA levels. Of importance, the 5-alpha reductase inhibitors (e.g., finasteride (Proscar^®) and dutasteride (Avodart^®), generally produce an average 50% reduction in PSA after 6 months of continuous treatment. This has been reported with usual daily doses of both drugs (5 mg finasteride daily and 0.5 mg dutasteride daily) for treatment of BPH, and also with 1 mg finasteride (Propecia^®) daily used for androgenetic alopecia.^85–87 To preserve the usefulness of PSA as a tumor marker in patients who are taking 5-alpha reductase inhibitors, it is essential to obtain a pretreatment PSA as a baseline. After at least 6 months of treatment, when PSA levels are repeated, it is recommended to double the measured PSA level before interpreting it. If a patient has a PSA level that is significantly higher than baseline after 6 months of treatment, it is recommended that the patient be evaluated for causes of the abnormal PSA level, including prostate cancer. If the patient has not experienced a 50% decrease in measured PSA level after 6 months of treatment, it is recommended that the patient be questioned as to his adherence with the prescribed regimen. These agents cause a variety of adverse effects, including sexual dysfunction, which may be a reason for a patient to discontinue the drug against medical advice.

Another interesting aspect of the effect of finasteride on PSA levels is that when finasteride was used to prevent prostate cancer, it appeared to increase the sensitivity of PSA as a screening test for prostate cancer, and to improve the ability of the prostate needle biopsy to detect prostate cancer.^84,88 To minimize the impact of noncancerous conditions on PSA (Table 22-14), it is recommended to allow an adequate interval after the condition has resolved before measuring PSA. Consideration of the 2–3 day plasma half-life of PSA along with the time it takes the condition to resolve affects the time interval to allow. For example, following transurethral prostatectomy, it is recommended to wait 6 weeks before obtaining a PSA, whereas, following ejaculation, it is recommended to wait only 2 days. Also, in a patient with PSA levels in the gray zone of 4–10 ng/mL who has a normal digital rectal exam and no evidence of infection on urinalysis, a short 3-week treatment course of antibiotics (to treat a presumptive prostate infection) has been used before repeating the PSA. In some cases, the PSA returns to the normal range. This strategy has been used to avoid unnecessary biopsy of the patient; however, it is considered a controversial measure at this time.⁸⁹

A 20% biological variation in measured PSA levels has been documented when the PSA ranges from 0.1–20 ng/mL. For this reason, it is common practice to repeat a single elevated PSA and not to take action based on a single elevated value.⁸⁶

A radioimmunoassay is commonly used to measure total and free PSA levels. Assays are quick to perform and commonly available. Newer commercially available assay kits allow for measurement of PSA concentrations that are less than 0.1 ng/mL. Several different immunoassays are available and results are not interchangeable among them. Therefore, it is recommended that the same assay methodology be used when interpreting serial PSA results.⁹¹

Prostate Needle Biopsy

A needle biopsy of the prostate is used to establish a tissue diagnosis of prostate cancer. It may be performed transrectally in one of two ways: digitally guided or guided by TRUS.

As a digitally-guided procedure, a biopsy needle is passed over the index finger of the urologist into the rectum and is directed to the site in the prostate where induration or a nodule was palpated. The needle is inserted through the rectal mucosa into the prostate to obtain a core of suspicious tissue. In addition, the urologist obtains four to six other biopsy specimens from the base, lateral mid portion, and apex of the prostate gland. The false-negative rate with this technique is 20% to 25%.⁹² Alternatively, a biopsy gun is used along with transrectal ultrasound for guidance. Local anesthesia is required. To reduce the false-negative rate, the number of random biopsy specimens is increased from 6 or 8–20.^93,94 With the increase in tissue sampling, the false-negative rate is only 4%.⁹⁵

All biopsy specimens are sent to the pathologist for examination. If prostate cancer is detected microscopically, the sample is graded histologically. The Gleason scoring system is used to grade the pattern of glandular differentiation of the prostate tumor. Two grades are assigned: one for the dominant pattern of glandular differentiation and a second for the less prevalent pattern. Uniform, round well-formed glands would be graded as 1 or 2, whereas solid sheets of tumor cells without gland formation would receive a grade of 5. Transition between these two extremes would be graded as 3 or 4. Two grades are assigned if two patterns of infiltration are identified; or, if only one pattern of infiltration is evident, the same number is assigned twice. The two numbers are then added to give the Gleason score, which can range from 2–10. The Gleason score correlates with progression of the tumor and the patient’s prognosis; the higher the score the worse the prognosis. A single, tissue specimen score of 4 or more, or a total score of 7 or higher suggests that the patient is at intermediate or high risk of developing metastatic disease.⁹⁶ Along with other parameters, the Gleason score has been incorporated into various formulae to predict the prognosis of patients. (See Minicase 2.)

MINICASE 2

Interpreting PSA in a Patient with Prostate Cancer

ROBERT R. IS A 60-YEAR-OLD WHITE MALE with newly diagnosed adenocarcinoma of the prostate cancer. He is undergoing cancer staging and risk assessment to determine the next step in his management.

Cc: Robert R. is anxious and concerned about his diagnosis. He has a 10-year-old daughter and an 8-year-old son and expresses fear that he “will not be around” as they grow older.

HPI: On a routine annual physical exam, Robert R. had an abnormal digital rectal exam. The prostate was enlarged and symmetric. A small nodule was palpated and subsequently biopsied, which showed adenocarcinoma, Gleason grade 8 in 60% of the biopsy specimens. Two PSA tests, which were conducted 1 week apart before the prostate needle biopsy, were 25 ng/mL and 28 ng/mL. Liver function tests, BUN, and serum creatinine were all normal.

PMH: Hypertension; leg cramps occasionally at night

Medications: Lisinopril 20 mg orally once a day; aspirin 325 mg orally once a day

Allergies: None

Vital signs: BP 140/85, HR 80, RR 16, weight 200 lb

Question: What does Robert R.’s PSA suggest about the stage of Robert R.’s disease? What additional tests should be performed to confirm the stage of prostate cancer in him?

Discussion: Because Robert R.’s PSA is >20 ng/mL and the prostate cancer is a Gleason grade 8 in a majority of the specimen, he is at high risk of tumor recurrence, and his cancer has likely spread outside of the prostate. To determine the sites of tumor spread, additional testing should include a bone scan, transrectal ultrasound of the prostate, computerized axial tomography (CT) scan of the pelvis, and chest radiograph.

Question: Let us assume that the bone scan shows no boney metastatic sites, the chest radiograph shows no lung metastases, and the CT scan of the pelvis shows no lymphatic invasion. However, the digital rectal exam PSA and the transrectal ultrasound of the prostate suggest direct extension of the prostate through the prostatic capsule to the periprostatic tissues, including the seminal vesicles. Robert R. has clinical stage T3 prostate cancer. How would this information be used in a risk assessment?

Discussion: Assessment of the risk of tumor recurrence is used to guide treatment selection. Although no single risk assessment tool has been accepted as a standard, most risk assessments are similar in that they are based on the prostate cancer disease stage, PSA, and Gleason score of the tumor. One commonly used risk assessment is depicted below.³⁹

As an example, for the low-risk category, a patient with stage T1C or T2A disease, a PSA less than 10 ng/mL or a Gleason score <6, could be offered active surveillance if his life expectancy is less than 10 years, or radiation therapy or radical prostatectomy if his life expectancy is 10 years or more. The selection of a particular treatment should be individualized based on Robert R.’s life expectancy, patient’s preference, and patient’s ability to deal with potential adverse effects or complications of various treatment options. Active surveillance has no adverse effects and entails PSA monitoring every 6 months and an annual prostate needle biopsy. Such close monitoring will allow the physician to detect early tumor progression to a higher stage or higher grade. Radiation therapy can be delivered as external beam or internally with seed implants into the prostate. As an adjuvant to external beam radiation therapy, androgen deprivation therapy with a combination of an LHRH agonist and an antiandrogen has been shown to be more effective in prolonging tumor-free survival over external beam radiation therapy alone for stage T2 and T3 prostate cancer.^40,41 A radical prostatectomy, which includes removal of the prostate, prostatic urethra, pelvic lymph nodes, and periprostatic tissues is an effective treatment modality for localized prostate cancer and lowers the likelihood of disease recurrence and decreases cancer-related mortality. However, perioperative complications include bleeding and infection. Late complications include urinary incontinence and erectile dysfunction.

Based on Robert R.’s disease stage, Gleason score, and PSA, he is considered at high risk of tumor recurrence and the best treatment option would be external radiation with adjuvant androgen deprivation therapy.

RISK CATEGORY	STAGE OF PROSTATE CANCERa	PSA (ng/mL)	GLEASON SCORE	TREATMENT OPTIONS
Low	T1C or T2A	<10	6 or less	Active surveillance if life expectancy <10 yr; radiation therapy or surgery if life expectancy >10 yr
Intermediate	T2B	10–20	7	Active surveillance if life expectancy <10 yr; radiation therapy with or without androgen deprivation therapy or surgery if life expectancy >10 yr
High	T2C or T3A or T3B or T3C	>20	8–10	External radiation with androgen deprivation therapy; or surgery in selected cases

^aStage T1 and T2 are localized to the prostate. Stage T3 refers to cancer that has directly extended to periprostatic tissue. Stage T4 is metastatic to lymph nodes, bone, or soft tissues distant from the prostate. The alphabetic letter refers to the volume of the prostate cancer tissue. A refers to one focus; B refers to two foci; and C refers to multiple foci of tumor.

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