OBJECTIVES

After completing this chapter, the reader should be able to

  • Distinguish when serum free testosterone levels are preferred over serum total testosterone levels in selected patients

  • Develop a laboratory monitoring plan for testosterone supplementation for the treatment of late-onset hypogonadism

  • Explain why minimal laboratory testing is used to evaluate a patient with new-onset erectile dysfunction

  • Explain the expected impact of benign prostatic hyperplasia on peak urinary flow rate and postvoid residual urinary volume

  • Argue for and against the use of prostate-specific antigen screening for prostate cancer

  • Describe the alteration of prostate-specific antigen levels in patients being treated with 5α-reductase inhibitors

  • Describe the rationale for using age-related normal value ranges for prostate-specific antigen, percent free prostate-specific antigen, prostate-specific antigen doubling time, and prostate-specific antigen density levels in evaluating patients with prostate cancer

  • Explain the advantages and disadvantages of using PCA3, PHI, and the 4K score over prostate-specific antigen for a patient with a prostate-specific antigen value of 4 to 10 ng/mL

  • Explain the role of histologic Gleason scoring in managing patients with prostate cancer

  • Contrast the four-glass versus the two-glass method for diagnosis of prostatitis

This chapter focuses on laboratory and clinical tests used to evaluate several common medical disorders in aging men—hypogonadism, erectile dysfunction, benign prostatic hyperplasia (BPH), prostate cancer, and prostatitis. Tumor markers for assessing testicular cancer and lab tests for diagnosis of urinary tract infection and venereal diseases are discussed in other chapters.

HYPOGONADISM

Hypogonadism refers to medical conditions in which the testes or ovaries fail to produce adequate amounts of testosterone or estrogen in men or women, respectively, to meet the physiologic needs of the patient. For the purposes of this chapter on men’s health disorders, hypogonadism refers to conditions in which testicular production of testosterone is inadequate. Increasing patient age is associated with a greater percentage of men with serum testosterone levels that are below the normal range. Out of approximately 900 men in the Baltimore Longitudinal Study, the calculated incidence of hypogonadism was 12%, 19%, 28%, and 49% in men in their fifth, sixth, seventh, and eighth decade of life, respectively.1

Testosterone Production and Physiologic Effects

Testosterone secretion is principally regulated by the hypothalamic-pituitary gonadal axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH). This hormone acts on anterior pituitary receptors to stimulate the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH acts on testicular Sertoli cells to stimulate spermatogenesis, whereas LH stimulates testicular Leydig cells to produce testosterone. Once the serum level of testosterone increases to within the normal physiologic range, it triggers a negative feedback loop, which inhibits GnRH release from the hypothalamus. Pituitary LH release is inhibited, too, but generally less so than GnRH. The testes secrete 95% of all androgens in men.2

In young men, 4 to 10 mg of testosterone is produced each day. Testosterone secretion follows a circadian pattern, such that the highest secretion occurs at 7:00 a.m. and the lowest secretion occurs at 8:00 p.m.

Testosterone is responsible for various age-related physiologic effects in men, but most notably, it is responsible for development of secondary sexual characteristics in men. The physiologic effects of testosterone and dihydrotestosterone (DHT) during the stages of life are included in (Table 25-1).

TABLE 25-1.

Physiologic Effects of Testosterone and DHT3,5

STAGE OF LIFE OF MALE

PHYSIOLOGIC EFFECT

In utero

Differentiation of male internal and external genitalia

At puberty

Male body habitus; deepening of voice; male hair distribution; enlargement of testes, penis, scrotum, and prostate; increased sexual drive and bone growth

Adulthood

Sexual drive, muscle strength and mass, bone mass, prostate enlargement, male hair growth and distribution, spermatogenesis

DHT = dihydrotestosterone

In nontarget tissue, including the liver and adipose tissue, aromatase enzyme can convert excess androgen to estrone and estradiol. In men, excess estrogen or a higher ratio of serum estrogen to androgen can result in gynecomastia or decreased libido and cause negative feedback to the hypothalamus and pituitary, which further suppresses serum testosterone production.5

Adrenocorticotrophin stimulates the adrenal gland to produce three androgens: dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione. DHEA and DHEA-S are secreted at a daily rate of 15 to 30 mg, whereas androstenedione is secreted at a daily rate of 1.4 mg. All three adrenal androgens are weak androgens compared with testosterone. DHEA and DHEA-S combined only contribute to 1% of circulating androgens, so the clinical effect of adrenal androgens is considered minor in healthy men.

Testosterone comprises approximately 90% to 95% of circulating androgens. Of circulating testosterone, 55% (range, 44% to 60%) is bound tightly to sex hormone binding globulin (SHBG); 30% (range, 38% to 54%) is bound loosely to albumin, corticosteroid-binding globulin, and orosomucoid; and 1% to 3% is free and physiologically active.24 At its targets in skeletal muscle, bone, brain, and Sertoli cells, testosterone itself appears to be physiologically active.4 However, in the prostate and hair follicles of the scalp, where 5α-reductase enzyme is expressed, testosterone must be activated intracellularly by 5α-reductase to DHT, an androgen with at least twice the potency of testosterone. Two separate forms of 5α-reductase enzymes exist: type I and type II. Each enzyme type tends to predominate in a particular tissue. Type I enzyme concentrates in the skin, liver, and sebaceous glands of the scalp. Type II 5α-reductase predominates in the prostate and hair follicles of the scalp, and DHT in these tissues contributes to the development of BPH and alopecia, respectively.3

The level of physiologically active testosterone is directly related to multiple factors that affect SHBG production and serum levels. Factors that alter SHBG concentrations are included in Table 25-2. Measurement of free testosterone levels is essential in patients when the serum total testosterone level is inconsistent with the clinical symptoms of the patient and the patient has a concurrent medical illness that can alter the level of SHBG.

TABLE 25-2.

Medical Conditions and Drugs That Alter SHBG Concentrations

INCREASED SHBG

DECREASED SHBG

Medical conditions that produce an alteration of SHBG concentration

Hepatic cirrhosis

Hepatitis C

HIV disease

Anorexia nervosa

Hyperthyroidism

Aging men

Prolonged stress

Hypothyroidism

Nephrotic syndrome

Obesity

Acromegaly

Cushing syndrome

Diabetes mellitus

Drugs that produce an alteration of SHBG concentration

Estrogens

Phenytoin and other anticonvulsants

Thiazolidinediones (eg, pioglitazone, rosiglitazone)

Ethanol, chronic use

Testosterone supplements, excessive doses

Corticosteroids

Progestins

Tyrosine kinase inhibitors (eg, imatinib)

HIV = human immunodeficiency virus.

Source: Adapted with permission from references 4,6.

Hormonal Changes Associated with Primary, Secondary, and Tertiary Hypogonadism

Primary hypogonadism occurs when the testicles are absent or surgically removed or when they are nonfunctional secondary to an acquired disease (eg, mumps orchitis). Secondary hypogonadism occurs when the pituitary fails to release adequate amounts of LH; thus, the testes are not stimulated to produce adequate amounts of testosterone. Tertiary hypogonadism refers to a disorder of the hypothalamus such that there is inadequate release of GnRH, and a subsequent decrease in release of LH from the pituitary and testosterone from the testes. Table 25-3 contrasts serum testosterone, LH, and GnRH levels in patients with primary, secondary, and tertiary hypogonadism.

TABLE 25-3.

Etiology of and Laboratory Test Results in Patients with Primary, Secondary, and Tertiary Hypogonadism

PRIMARY

SECONDARY

TERTIARY

Common causes

Klinefelter syndrome

Cryptorchidism

Mumps orchitis

Orchiectomy

Irradiation of testes

Traumatic injury to the testes

5α-reductase deficiency

Noonan syndrome

Autoimmune disorders (eg, Hashimoto thyroiditis or Addison disease)

Systemic disorders: HIV, hemochromatosis, cancer, liver cirrhosis

High-dose radiation therapy

Medications: high-dose ketoconazole, cytotoxins

Kallmann syndrome

Pituitary adenoma or infarction

Prolactinoma

Sleep apnea

Obesity

Metabolic syndrome

Type 2 diabetes mellitus

Chronic renal failure

Hepatic cirrhosis

Hypothyroidism

Anorexia nervosa

Medications: estrogens, LHRH agonists (eg, leuprolide, goserelin), LHRH antagonists (eg, degarelix), abiraterone, digoxin, prolonged course of high-dose corticosteroids, megestrol acetate, medroxyprogesterone, long-acting opioids

Infectious or infiltrative diseases of the hypothalamus (eg, tuberculosis, sarcoidosis, infectious abscess)

Isolated gonadotropin deficiency

Chronic opioid abuse

Serum testosterone level

Decreased

Decreased

Decreased

LH level

Increased

Decreased

Decreased

GnRH level

Increased

Increased

Decreased

HIV = human immunodeficiency virus; LHRH = luteinizing hormone–releasing hormone.

Source: Adapted with permission from references 3,5,6.

Late-Onset Hypogonadism

Late-onset hypogonadism, also known as andropause or androgen deficiency in aging men (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 signs and symptoms.79 Some men with decreased testosterone levels do not complain of their symptoms or have vague, nonspecific symptoms (eg, malaise or decreased energy) for which they do not seek medical treatment.5,7,9 Although late-onset hypogonadism is often compared with menopause in aging women, these conditions are different. In men, gonadal function decreases over decades, and symptoms develop slowly and often are not attributed to decreasing hormone levels. In women, gonadal function decreases over a comparatively shorter time period of 4 to 6 years, and symptoms are closely associated with decreasing hormone levels. Table 25-4 contrasts physiologic changes associated with late-onset hypogonadism in men versus menopause in aging women.

TABLE 25-4.

Characteristics of Late-Onset Hypogonadism in Aging Men Versus Menopause in Aging Women

LATE-ONSET HYPOGONADISM

MENOPAUSE

Time period over which gonadal function decreases

Decades, beginning at age 30–40 yr

4–6 yr, beginning approximately at 50–52 yr

Fertility is maintained

Yes

No

Signs and symptoms

Decreased libido, erectile dysfunction, gynecomastia, weight gain, visceral obesity, moodiness, decreased sense of well-being, muscle aches, decreased muscle mass and strength (sarcopenia), weight gain, osteopenia, osteoporosis, hot flashes, reduced body hair, decreased testicular size, infertility

Menstrual cycles become progressively heavier and lighter, shorter and longer, and then stop; hot flashes, weight gain, vaginal dryness, dyspareunia, and hair loss

Symptoms and signs are linked to serum level of gonadal hormone

No

Yes

Source: Adapted with permission from references 7,8.

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 is a mixed type of hypogonadism. This phenomenon occurs in the face of a wide range of serum (total) testosterone and bioavailable testosterone levels among elderly men.7 Whereas some symptomatic elderly men have serum testosterone levels that are below the normal physiologic range, others have levels that are decreased but are still within the normal range.8,9

Hormonal Changes Associated with Late-Onset Hypogonadism

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 407,8; however, the serum testosterone level may remain in the normal range in elderly men because the normal range is wide. The symptoms of late-onset hypogonadism include physical weakness, decreased muscle mass, obesity, fatigue, psychologic depression, decreased libido, and erectile dysfunction. The incidence of clinically symptomatic hypogonadism is low and approximates 2.1% to 5.6% in men aged 40 to 70 years.5 Low serum testosterone levels in patients with late-onset hypogonadism are due to multiple physiologic changes:

  • Increased sensitivity of the hypothalamus and pituitary gland to negative feedback; thus, low circulating testosterone levels stimulate the negative feedback loop9

  • Irregular, nonpulsatile secretion pattern of LH10

  • Increased production of SHBG resulting in higher concentrations of physiologically inactive SHBG-bound testosterone and a reduced concentration of free active testosterone in plasma7

  • Fewer functioning Leydig cells, which results in an age-related decrease in testicular production of testosterone7

A male patient age ≥50 years who presents with symptoms or signs of hypogonadism should undergo laboratory evaluation for late-onset hypogonadism. However, this is a diagnosis of exclusion that 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. Because of the lack of specificity, these questionnaires are used to monitor a patient’s treatment response, as opposed to diagnosing disease. For example, the St. Louis University ADAM questionnaire includes 10 questions that can be categorized into three symptom domains (psychologic, somato-vegetative, and sexual), and to which the patient responds either “yes” or “no.”11,12 An affirmative response to at least three questions on the survey is considered significant. The ADAM questionnaire has a sensitivity of 88% and a specificity of 60% and is considered to have the greatest reliability of the currently available questionnaires.

A similar alternative self-assessment instrument is the Aging Males’ Symptoms (AMS) scale, which comprises 17 questions focused on symptoms associated with low testosterone. The patient rates the severity of each symptom on a scale of 1 (none) to 5 (extremely severe). It has a sensitivity of 83% and a low specificity of 39%.13 Finally, a third tool, the Massachusetts Male Aging Survey comprises eight multiple-choice questions. Each response is assigned a certain number of points. Once all of the points are tallied, the total score has implications about the likelihood that the patient has hypogonadism. For example, a total score of 10 or higher suggests that the patient has a 50-50 chance of having hypogonadism, whereas a score of 4 or below suggests that the patient probably does not have hypogonadism. The Massachusetts Male Aging Survey is considered the least sensitive of the three tools. It has a sensitivity of 60% and a specificity of 59%.11

Testosterone, Total

Normal range, adult men: 280 to 1,100 ng/dL (9.7 to 38.17 nmol/L)

Normal range, age-related: boys, 6 to 9 years old: 3 to 30 ng/dL (0.1 to 1.04 nmol/L)

Boys, pubertal, 10 to 18 years old: 265 to 800 ng/dL (9.2 to 27.76 nmol/L)

Men, 19 to 39 years old: 264 to 916 ng/dL (9.2 to 31.8 nmol/L)

A routine serum testosterone level reflects the total concentration of testosterone in the bloodstream in all three of its forms: free; loosely bound to albumin, corticosteroid-binding globulin, and orosomucoid; and tightly bound to SHBG.4 Testosterone secretion follows a circadian pattern in younger men such that morning levels are approximately 15% to 20% (but can range up to 50%) higher than evening levels, which is a difference of approximately 140 ng/dL between the peak and nadir serum levels.2 In addition, variability in measured testosterone levels is characteristic from day to day, from week to week, and seasonally.2 This can result in a 20% to 25% difference in measured serum testosterone levels from the same patient.2 Thus, when obtaining serum testosterone levels, it is recommended that blood samples be obtained between 7:00 a.m. and 11:00 a.m. in a patient who has fasted.2,7,14 Furthermore, a single low serum testosterone level should be confirmed with a second sample usually at least 1 week later.5,15 This is necessary because 30% of men with initial serum testosterone levels that are in the hypogonadal range have levels in the normal range when the laboratory test is repeated.2 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.15 Common causes of decreased (Table 25-3) and increased serum testosterone levels are listed in Table 25-5.

TABLE 25-5.

Common Causes of Increased Total Testosterone Levels

Hyperthyroidism

Adrenal tumors

Adrenal hyperplasia

Testicular tumors

Precocious puberty

Excessive exogenous testosterone use (usually seen with parenteral, but not transdermal use)

Anabolic steroids

Source: Adapted with permission from Qaseem A, Horwitch CA, Vijan S, et al. Testosterone treatment in adult men with age-related low testosterone: a clinical guideline from the American College of Physicians. Ann Intern Med. 2020;172(2):126–133.

The normal range is wide for serum testosterone levels and is based on laboratory results for young adult men. Although this normal range is applied to interpretation of serum testosterone levels in elderly men, no single threshold serum testosterone value has been identified to be pathognomonic for hypogonadism or low serum testosterone in this age group.16,17 As an example, the U.S. Food and Drug Administration uses a serum testosterone of <300 ng/dL as an inclusion criterion for patients with hypogonadism in controlled clinical trials. However, some clinicians view that using a threshold serum testosterone value of <300 ng/dL results in excessive or unnecessary treatment of hypogonadism in asymptomatic men. As a result, the International Society for the Study of the Aging Male, the International Society of Andrology, the European Association of Urology, the European Association of Andrology, and the American Society of Andrology collectively have taken the position that a serum testosterone level of <230 ng/dL may be treated if the patient is symptomatic with decreased libido or inadequate response to type 5 phosphodiesterase inhibitor.18 Furthermore, a serum testosterone level >350 ng/dL generally should not be associated with symptoms, nor should it be treated.19 Generally, the following interpretation of serum testosterone levels is used:

  • Serum testosterone <230 ng/dL: Most likely the patient has symptomatic hypogonadism and requires testosterone replacement.

  • Serum testosterone 250 to 360 ng/dL: This level is equivocal for hypogonadism. The patient should be treated only if a low serum testosterone, free testosterone, or bioavailable testosterone level is confirmed and if the patient is symptomatic.19

  • Serum testosterone >600 ng/dL: The patient does not have hypogonadism and requires no testosterone replacement.

  • After instituting a testosterone replacement regimen, the goal of treatment is to increase the serum testosterone level between 400 and 700 ng/dL.19 The onset of symptomatic improvement after initiating a testosterone replacement regimen is variable. An increase in libido and an improved perception of quality of life is evident in 3 weeks; signs of decreased mental depression may first appear at 3 to 6 weeks; increased muscle strength and decreased fat mass are observable at 12 to 16 weeks; and improved erectile dysfunction and bone density occur at 6 months.20 Patients should be monitored for the effectiveness and safety of testosterone supplementation every 3 to 4 months for the first year of treatment and then annually thereafter.

  • When treating patients with prostate cancer with luteinizing hormone–releasing hormone (LHRH) agonists or antagonists, medical castration is induced. The target serum testosterone level is ≤50 ng/dL.

Testosterone levels are commonly determined using radioimmunoassay, nonradioactive immunoassays, or chemiluminescent detection methods, which are relatively easy to perform and inexpensive. However, these methods exhibit significant performance variability in the normal range and are limited in detecting serum testosterone levels <300 ng/dL.21 That is, these assays may produce results that are significantly different than the true value. Thus, it is recommended that a physician try to ensure that a single patient’s serum testosterone levels be assayed by the same clinical laboratory over time and that a normal range of serum testosterone be determined for each clinical laboratory that runs the assay.21 The latter determination would require measurement of serum testosterone in approximately 40 normal, healthy men, age 20 to 40 years.7 The Centers for Disease Control and Prevention initiated a program to standardize testosterone assays, which involves providing reference material to calibrate immunoassays. This reduces the variability of testosterone laboratory results among laboratories.21 Despite the availability of more sensitive and specific antibodies for radioimmunoassays, stable isotope dilution liquid chromatography using benchtop tandem mass spectrometry (LC-MS) is generally considered the gold standard method for assaying serum testosterone.22 Although both assays detect serum testosterone levels <300 ng/dL, LC-MS has greater accuracy and precision than radioimmunoassay22 (Minicase 1).

Free Testosterone

Normal age-related ranges are as follows for adult men:

  • 20 to 29 years, 10 to 15 ng/dL

  • 30 to 39 years, 9 to 13 ng/dL

  • 40 to 49 years, 7 to 11 ng/dL

  • 50 to 59 years, 6 to 10 ng/dL

  • >60 years, 5 to 9 ng/dL

Free testosterone levels are the best reflection of physiologically active androgen. Free testosterone levels measure the concentration of testosterone not bound to any plasma protein in the circulation. When compared with young adult men, elderly men experience an almost 20% increase in SHBG-bound testosterone in the circulation. Therefore, elderly men may develop symptoms of hypogonadism despite having serum total testosterone levels near the normal range.

Free testosterone levels are altered by the concentration of SHBG. Thus, free testosterone levels are preferred to assess testosterone adequacy in patients with concurrent illnesses known to alter SHBG, when patients are taking medications that increase or decrease levels of SHBG (Table 25-2), or when a patient has symptoms of hypogonadism but has a serum total testosterone in the equivocal range.2,7,9 A free testosterone level that is <6.5 ng/dL in the presence of symptoms of hypogonadism strongly suggests that the patient would benefit from testosterone replacement.19,20

Free testosterone levels are subject to the same diurnal patterns of total testosterone levels. Therefore, samples should be drawn in the morning.2,23 The most accurate assay methods for free testosterone are centrifugal ultrafiltration and an equilibrium dialysis technique. However, such assays are not routinely available, are time-consuming, and are expensive. Thus, many laboratories offer radioimmunoassay for free testosterone levels. Although inexpensive, this method is associated with less accurate results.24 Also, saliva specimens using a direct luminescence immunoassay can be used to measure free testosterone.25

Erectile Dysfunction and Low Serum Testosterone Levels

John A. is a 60-year-old white man who reports erectile dysfunction and no sexual drive. He feels like he is disappointing his sexual partner because he has no desire for sexual intercourse and cannot seem to perform adequately. He attributes all of this to getting older and wonders if a pill can “make him better.”

Cc: John A. has erectile dysfunction and decreased libido.

HPI: John A. reports that the problem has been getting worse over the past 2 years. Initially, he had periodic erectile dysfunction. Now, he has no nocturnal erections and cannot get an erection when he needs it. He still has morning erections.

PMH: Essential hypertension and hypercholesterolemia

Medications: hydrochlorothiazide, valsartan, and atorvastatin

Allergies: None

Physical exam:

  • ROS: Well-developed, well-nourished man with mild nocturia and some urinary hesitancy, particularly in the morning

  • Vital signs: blood pressure (BP) 140/87 mg Hg; heart rate (HR) 65 beats/min; respiratory rate (RR) 16 breaths/min; temperature 98.6°F; weight 75 kg; height 5′11″; BMI 23 kg/m2

  • Genitourinary tract: Normal penis, no curvature; testes, mildly atrophic; anal sphincter tone intact and within normal limits; digital rectal exam reveals mildly enlarged prostate; pedal pulses, PSA 1.2 ng/mL from 1 month ago

  • Assessment: Suspect late-onset hypogonadism with erectile dysfunction and BPH

QUESTION: A serum total testosterone level is ordered. The result is 200 ng/dL. Is testosterone supplementation indicated?

DISCUSSION: The patient’s decreased libido and erectile dysfunction are consistent with late-onset hypogonadism. His serum testosterone is also significantly below the normal range. He is a candidate for testosterone supplementation once the low serum testosterone level is confirmed with a repeat serum testosterone level.

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). By inserting the values for measured 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.26

Bioavailable Testosterone

Normal age-related ranges for adult men as are follows:

  • 20 to 29 years, 83 to 257 ng/dL

  • 30 to 39 years, 72 to 235 ng/dL

  • 40 to 49 years, 61 to 213 ng/dL

  • 50 to 59 years, 50 to 190 ng/dL

  • 60 to 69 years, 40 to 168 ng/dL

  • >70 years, not established

It is also expressed as a percentage of total serum testosterone.

  • Normal range, adult men: 12.3% to 63%

Bioavailable testosterone levels measure the concentration of free testosterone and testosterone loosely bound to albumin, corticosteroid-binding globulin, or orosomucoid in a serum sample.4,7 Because these plasma proteins have low affinity for and reversibly bind to testosterone, an equilibrium is established between free testosterone and the fraction that is loosely bound to these plasma proteins. Thus, testosterone loosely bound to these proteins is considered bioavailable and physiologically active.4,7

As men age, bioavailable testosterone levels decrease as serum SHBG levels increase. Bioavailable testosterone levels may be preferred when assessing testosterone activity in patients with significant alterations of SHBG or albumin (Table 25-6).

TABLE 25-6.

Comparison of the Percentage of Serum Bioavailable Testosterone in Young Versus Old Men

YOUNG MEN

OLDER MEN

% of total testosterone, which is free testosterone

2

2

% of total testosterone, which is bound to albumin

38

20

% of total testosterone, which is bound to SHBG

60

78

% of bioavailable testosterone (% free + % albumin-bound)

40

22

Source: Adapted with permission from Lombardo F, Lupini C, Meola A, et al. Clinical and laboratoristic strategy in late onset hypogonadism. Acta Biomed. 2010;81(suppl 1):85–88.

An ammonium sulfate precipitation assay or the concanavalin A method is used to measure bioavailable testosterone.4 It is expensive and technically challenging to perform. For this reason, this test is not commonly available in clinical laboratories. 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). By inserting the values for measured 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 that is sufficient for satisfactory sexual intercourse and sexual performance and is sexually satisfying.27,28 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 fourth decade of life to the sixth decade of life, from 12% to 46%, respectively.29 In the health professional follow-up study of men age ≥50 years, 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, obesity, diabetes mellitus, or cardiovascular disease.3032 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.27,28 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 That is, the patient has one or more medical illnesses that impair vascular flow to the corpora cavernosa, impair central or peripheral innervation necessary for a penile erection, or are associated with testosterone insufficiency, in which case the patient develops erectile dysfunction secondary to decreased libido. Other hormonal disorders, including increased estrogen or hyperprolactinemia, may also cause organic erectile dysfunction. Table 25-7 shows common causes of organic erectile dysfunction.28,30,32 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 (eg, loss of a job, divorce, death in the family).30 Table 25-8 contrasts differences in the clinical presentation of organic and psychogenic erectile dysfunction.

TABLE 25-7.

Common Causes of Organic Erectile Dysfunction

IMPAIRMENT

HOW IT CAUSES ERECTILE DYSFUNCTION

EXAMPLE DISEASES/CONDITIONS ASSOCIATED WITH THIS TYPE OF IMPAIRMENT

Vascular

Decreased arterial flow to the corpora cavernosa

Hypertension

Congestive heart failure

Coronary artery disease

Arteriosclerosis

Smoking

Obesity

Peripheral vascular disease

Chronic, heavy smoking

Drugs that cause hypotension: antihypertensives, central and peripheral sympatholytic agents

Neurologic

Decreased central processing of sexual stimuli or impaired peripheral nerve transmission, which decreases erectogenic reflex responses to tactile stimuli

Stroke

Diabetes mellitus

Chronic alcoholism

Postradical prostatectomy in which pelvic nerve injury has occurred

Epilepsy

Multiple sclerosis

Parkinson disease

Psychosis

Major depression

Pelvic trauma with nerve injury

Spinal cord injury

Drugs with anticholinergic effects: antispasmodics, phenothiazines, tricyclic antidepressants, first-generation antihistamines, etc.

Hormonal

Decreased serum testosterone, increased serum estrogen, increased ratio of serum estrogen to serum testosterone, or hyperprolactinemia results in decreased libido; erectile dysfunction is secondary to the decrease in libido

Late-onset hypogonadism

Primary or secondary hypogonadism

Hypothyroidism/hyperthyroidism

Hyperprolactinemia

Adrenal gland disorders

Drugs with estrogenic effects or that decrease androgen production or action: diethylstilbestrol, LHRH agonists, LHRH antagonists

Anatomic

Penile deformity or curvature when erect

Peyronie disease

Traumatic injury to the penis

Source: Adapted from references 28,30,32.
TABLE 25-8.

Comparison of Organic and Psychogenic Erectile Dysfunction

ORGANIC

PSYCHOGENIC

Patient age

Older male

Younger male

Onset

Gradual, unless erectile dysfunction is due to traumatic injury

Sudden and complete loss of erectile function

Linked to a particular event in the patient’s life

No

Yes (eg, divorce, job-related stress, financial stress)

Patient has a normal libido

Yes

No

Patient has nocturnal erections, which are reflex reactions

No

Yes

Patient has erections on awakening

No

Yes

Patient has erections with masturbation

No

Yes

Patient has erections with foreplay

No

Yes

Patient has concurrent medical illnesses that could contribute to erectile dysfunction

Yes

No

Patient’s partner is perceived to be a problem in the relationship prior to the onset of erectile dysfunction

No

Yes

Patient has performance anxiety prior to the onset of erectile dysfunction

No

Yes

Source: Adapted with permission from references 27,30,32.

Because type 5 phosphodiesterase inhibitors (eg, sildenafil) are effective in up to 70% of patients independent of the etiology of erectile dysfunction, 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 (eg, decreased libido, erectile dysfunction, or ejaculation disorder). Details on onset of symptoms are obtained along with a patient’s self-assessment of the severity of the problem using a validated, reliable questionnaire (eg, International Index of Erectile Function) and information on expectations for improved sexual function from the patient and from the spouse or significant other.33,34

A comprehensive medical history is then performed to identify treatable underlying diseases that may be contributing to erectile dysfunction (Table 25-7).28,30,32 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.35 For example, 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. Peripheral pulses are palpated to assess vascular integrity. 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. 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); or 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 patients age ≥50 years who have a life expectancy of at least 10 years, prostate cancer screening is conducted. 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, HbA1c for diabetes mellitus, a lipid profile for hypercholesterolemia, a urinalysis to check for genitourinary tract disorders, serum testosterone levels for hypogonadism, and a serum prolactin level if the patient has erectile dysfunction, decreased libido, and gynecomastia. Specialized clinical testing is reserved for patients who developed erectile dysfunction at a young age, patients with a family history of cardiovascular disease who cannot be treated with first-line oral erectogenic drugs, patients with a history of pelvic trauma with damage to the vascular supply or neurologic innervation to the corpora cavernosa, or patients who are candidates for vascular correction of erectile dysfunction because of lack of response to drug therapy or noninvasive medical devices. Table 25-9 provides a brief description of some less commonly used tests for erectile dysfunction that require specialists to perform them and interpret results.28

TABLE 25-9.

Specialized Diagnostic Testing for Erectile Dysfunction

TEST

DESCRIPTION

PURPOSE OF TEST

Nocturnal penile tumescence and rigidity testing

Two strain gauges are placed circumferentially on the penile shaft to measure erectile hardness and frequency of erections when the patient is sleeping.

This test is used to distinguish organic from psychogenic erectile dysfunction. If the patient has organic erectile dysfunction, the test should show that the patient gets no erections when sleeping, whereas a patient with psychogenic erectile dysfunction does get erections when sleeping.

Intracavernosal injection (ICI) testing

A single dose of alprostadil, papaverine, and phentolamine is administered as an intracavernosal injection.

If a penile erection is induced by ICI, this allows visual assessment of vascular integrity of penile arterial and venous flow

Penile duplex ultrasonography

ICI is performed, then ultrasound and Doppler imaging of arterial flow to the corpora cavernosa is performed.

Allows assessment of the flow through the main dorsal artery and the cavernous artery

Source: Adapted with permission from Burnett AL, Nehra A, Breau RH, et al. American Urological Association Erectile dysfunction: AUA Guideline (2018). https://www.auanet.org/gidelines/erectile-dysfunction-(ed)-guideline#x8057.

International Index of Erectile Function, Sexual Health Inventory for Men, and Brief Male Sexual Function Inventory

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 overall satisfaction with his sexual performance for the past month.33 The questionnaire takes approximately 10 to 15 minutes to complete. Total scores for each domain can be calculated, and each of these scores is associated with a severity level. 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. The IIEF is summarized in Table 25-10.28

TABLE 25-10.

Domains and Maximum Score for Each Domain of the IIEF

NUMBER OF QUESTIONS RELATED TO THE DOMAIN

RANGE OF SCORES FOR QUESTION

MAXIMUM TOTAL SCORE FOR THE DOMAIN

Erectile functiona

6

0–5

30

Orgasmic function

2

0–5

10

Sexual desire

2

0–5

10

Intercourse satisfaction

3

0–5

15

Overall satisfaction

2

0–5

10

aThis focus area allows for quantitation of ED severity. Score range for erectile function ranges from 0 to 30. A score <10 implies severe dysfunction; 11 to 17 implies moderate dysfunction; 18 to 25 implies mild dysfunction; 26 to 30 implies no dysfunction.

Source: Adapted with permission from Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49(6):822–830.

A shorter self-assessment questionnaire is an abridged IIEF, which includes five of the 15 questions from the original survey that focus on erectile dysfunction; the last question concerns the patient’s overall satisfaction with his sexual performance. This is known as the Sexual Heath Inventory for Men.36 Some clinicians consider this shorter questionnaire to be more practical than the original IIEF. Other commonly used tools are the Brief Male Sexual Function Inventory37 or the Erection Hardness Scale.38 Table 25-11 summarizes the differences among these three self-assessment questionnaires.

TABLE 25-11.

Summary of Self-Assessment Tools for Patients with Erectile Dysfunction

SEXUAL HEALTH INVENTORY FOR MEN (SHIM)36

BRIEF MALE SEXUAL FUNCTION INVENTORY37

ERECTION HARDNESS SCALE38

Number of questions in the tool

5

11

1

Focus of questions

Erectile dysfunction

Sexual drive, erection, ejaculation, perception of problems with sexual function, overall satisfaction

Erection hardness

Assessment scale

Each item is rated on a 5-point scale; the score for each item ranges from 1–5; total score for the survey characterizes the severity of erectile dysfunction, such that 5–7 equals severe dysfunction; 8–11 equals moderate dysfunction; 12–16 equals mild-to-moderate dysfunction; 17–21 equals mild dysfunction; 22–25 equals no dysfunction

Each item is rated on a 5-point scale; the point scale; the score for each item ranges from 0–4 and each score has an individualized anchor descriptor; total score for the survey ranges from 0–44 and correlates with the patient’s overall perception of sexual function and sexual satisfaction. A total score of 0 implies that sexual dysfunction is a big problem, a total score of 22 implies that sexual dysfunction is somewhat of a problem, and a total score of 44 implies that sexual dysfunction is no problem

Scale ranges from 0–4. 0 = penis does not enlarge; 1 = penis enlarges when patient is aroused but is not hard; 2 = penis is enlarged and hard but not hard enough for vaginal penetration; 3 = penis is hard enough for penetration but not completely hard; 4 = penis hard and fully rigid

Prolactin

Normal range, adult men: 0 to 15 ng/mL or 0 to 15 mcg/L (0 to 652 pmol/L)

The precise role of prolactin in men is unclear; however, it has been hypothesized that high circulating prolactin levels suppress LH and FSH, thereby decreasing testosterone production, decreasing semen volume and spermatogenesis.39 It also is known that hyperprolactinemia decreases libido, which may lead to erectile dysfunction.

Prolactin is secreted by the lactotroph cells of the anterior pituitary gland in multiple pulses during the day. The normal daily production rate is 200 to 536 mcg/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 IgG immunoglobulin (also known as big, big prolactin or macroprolactin), 85% to 95% exists as monomeric prolactin, which is physiologically active hormone.40 Its pulsatile secretion is predominately controlled by prolactin inhibitory factor, which is thought 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 also may regulate prolactin secretion; however, its chemical structure still needs to be identified. It may be similar to vasoactive intestinal polypeptide or thyrotropin-releasing hormone, which both simulate prolactin secretion.40 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. Prolactin is excreted renally.

True hyperprolactinemia occurs in 1% to 2% of men who present with decreased libido, erectile dysfunction, and gynecomastia and is characterized by the presence of high levels of monomeric prolactin. Medical conditions and medications that can produce hyperprolactinemia are included in Table 25-12. They can be broadly classified as disorders of the hypothalamus or pituitary gland, neoplastic conditions, metabolic disorders, or medication-related causes. Whereas hypothalamic (eg, craniopharyngioma), pituitary (eg, large prolactinoma), and paraneoplastic syndromes can cause significant increases in serum prolactin levels exceeding 250 ng/mL,42 systemic diseases, medications, sleep, pain, or meals cause smaller increases in serum prolactin level that rarely exceed 200 ng/mL.4244

TABLE 25-12.

Medical Conditions and Medications Associated with Increased or Decreased Prolactin Levels

INCREASED PROLACTIN LEVELS

DECREASED PROLACTIN LEVELS

Pituitary adenoma (nonprolactinoma)

Pituitary prolactinoma

Acromegaly

Severe head trauma

Craniopharyngioma

Paraneoplastic syndrome with ectopic production of prolactin

Primary hypothyroidism

Renal failure, chronic

Liver cirrhosis

Addison disease

Idiopathic pituitary hyperprolactinemia

Stress provoked by surgery, hypoglycemia, myocardial infarction

Sarcoidosis

Chest wall trauma

Seizures

Epilepsy

Anorexia nervosa

Sexual intercourse

Medications: phenothiazines, butyrophenones, thioxanthenes, buspirone, olanzapine, risperidone, haloperidol, loxapine, pimozide, tricyclic antidepressants, selective serotonin reuptake inhibitors, molindone, quetiapine, monoamine oxidase inhibitors, oral contraceptives, estrogens, megestrol, opiates, methadone, cocaine, tetrahydrocannabinol, antihistamines, ranitidine, cimetidine, metoclopramide, pimozide, reserpine, methyldopa, verapamil, labetalol, phenytoin

Panhypopituitarism

Pituitary infarction

Extended critical illness

Medications: carbamazepine, phenytoin, valproic acid, bromocriptine, clonidine, ergot alkaloids, levodopa, pergolide, nifedipine, rifampin, tamoxifen

Source: Adapted from references 4146.

Hypoprolactinemia in a man is a rare condition. The clinical significance of this finding is unknown as it is not associated with symptoms or disease.

Indications for assessing serum prolactin levels include (1) a patient who is <50 years and reports decreased libido, erectile dysfunction, infertility, and gynecomastia or has low serum testosterone levels; (2) a patient who is >50 years and reports gynecomastia; (3) a patient with late-onset hypogonadism and erectile dysfunction whose symptoms are not corrected with a testosterone replacement regimen; and (4) a patient with symptoms consistent with prolactinoma (ie, persistent headache, cranial nerve palsies, and visual field defects). Of note, prolactin levels should not be routinely obtained in patients who present with erectile dysfunction.

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 to 30 minutes.40 A diagnosis of hyperprolactinemia generally requires documentation of two elevated prolactin levels.39

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 increase prolactin levels, and to distinguish macroprolactin from prolactin, polyethylene glycol extraction and centrifugal ultrafiltration assay methods can be used.41,42 Although simple to perform, the assay methods are sensitive but not specific.

Big prolactin and big, big prolactin (macroprolactin), which are the less active or inactive forms of prolactin, cross-react with prolactin in immunoassays.45 Macroprolactinemia is diagnosed when the majority of the circulating prolactin is of the macroprolactin form. Separating patients with macroprolactinemia from those with true hyperprolactinemia is important to avoid expensive diagnostic testing and unnecessary or invasive treatment of the former, which is a benign disease. Gel filtration chromatography is considered the gold standard assay.41,45

Extremely high serum levels of prolactin may saturate the ability of immunoassays to measure correct levels. This is known as the hook effect. Because larger size prolactinomas are associated with higher amounts of prolactin secretion, it may be necessary to dilute the blood specimens of these patients to 1:100 before assaying for prolactin.41,42,46

BENIGN PROSTATIC HYPERPLASIA

Benign prostatic hyperplasia (BPH) is an enlargement of the prostate gland that occurs in all men as they age. The histologic disease prevalence is 80% in men 70 to 79 years.47 Furthermore, 50% of men with a histologic diagnosis of BPH develop clinical symptoms of at least moderate severity.48 Beginning at approximately age 40 years in men, the prostate gland undergoes a second growth spurt, which is stimulated by DHT, and the prostate grows from a normal adult size of 15 to 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, they are not specific for BPH and may be due to other genitourinary tract disorders (eg, neurogenic bladder, prostate cancer, urethral stricture, prostatitis, and urinary tract infection).49 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 anatomic block of the bladder neck. In time, this causes hypertrophy of the bladder muscle and increased intravesical pressure, which translates to urgency, frequency, nocturia, and urge incontinence. These symptoms are referred to as irritative voiding symptoms. 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, recurrent or intermittent gross hematuria, urolithiasis (primarily bladder stones), and chronic renal failure.

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 Index (AUA-SI) score or the International Prostate Symptom Score (IPSS).48,49

Signs of disease are evaluated by the physician using clinical procedures that can be performed easily in an outpatient setting. A careful medical history is taken to identify any concurrent medical illnesses or medications (eg, α-adrenergic agonists, anticholinergic agents, or androgens, etc., that may cause or worsen 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 as well as anal sphincter tone. 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 (WBCs) 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 cytologic assessment. Bladder neoplasms typically shed cancer cells into the urine. For patients in whom the urinalysis is suspicious for renal impairment (eg, protein or casts are detected) or cancer or in whom surgical treatment of BPH is being considered, specialized testing is performed. Serum creatinine level 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 imaging to assess renal function and anatomy.48 In such high-risk patients, a renal ultrasound would be a better test for evaluation of renal anatomy.

Routine objective testing includes uroflowmetry and postvoid residual urine volume; both are discussed later. In addition, cystoscopy may be performed. Cystoscopy requires that an endoscope be passed transurethrally so that the urologist can visualize the urethra, bladder neck, and bladder. In patients with BPH, the classic findings are muscular changes in the bladder wall (specifically, smooth muscle hypertrophy) secondary to prolonged bladder neck obstruction. BPH gives the appearance that the three sidewalls of the prostatic urethra bulge out and appear to “kiss” each other.

American Urological Association Symptom Index, International Prostate Symptom Score, and Benign Prostatic Hyperplasia Impact Index

The AUA-SI is a validated survey instrument administered to the patient. It includes seven questions about the severity of obstructive and irritative voiding symptoms.4850 For each question, the patient rates symptom severity on a scale of 1 to 5, where 0 is not at all bothersome and 5 is almost always bothersome. Thus, the lowest total score is 0 and the maximum total score is 35. Scores are interpreted according to the following ranges:

  • No or mild symptoms, score of 0 to 7

  • Moderate symptoms, score of 8 to 19

  • Severe symptoms, score of 20 to 35

The AUA-SI 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.48 Similarly, once specific treatment for moderate or severe symptoms of bladder outlet obstruction is initiated, the AUA-SI 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-SI score by 30% to 50% or decrease the score by at least three points51 (Minicase 2).

The IPSS is a survey tool that includes all seven questions in the AUA-SI 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 indicating that the patient has no symptoms and 35 indicating that the patient has severe symptoms.

Both the AUA-SI score and the IPSS 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-SI score and the IPSS do not always correlate with prostate gland size, urinary flow rate, or postvoid residual urine volume. However, patients with a high AUA-SI score and a high IPSS generally show significant improvement with surgical treatment for BPH.49

The BPH Impact Index is a four-question tool. For the first three questions, the patient rates voiding symptoms on a scale of 0 (not bothersome) to 3 (causes a lot of bother). The fourth question focuses on the impact of the patient’s voiding symptoms on daily activities, which is rated on a scale of 0 (no impact) to 4 (impacts my activities all of the time). The BPH Impact Index may be used in conjunction with the AUA-SI to correlate symptoms with quality of life.52

Lower Urinary Tract Symptoms and an Enlarged Prostate

Sam B. is a 70-year-old white man who reports poor-quality sleep. He feels tired all the time when he is awake. He falls asleep when he is driving. He says that he “can’t live like this.”

Cc: Sam B. has to urinate three times a night, sometimes four, and he cannot get a good night’s sleep. His nocturia began about 4 months ago. He has reduced caffeine intake and stopped drinking fluids in the evening to control his symptoms, but he has noticed minimal improvement.

HPI: Sam B. reports that over the last 4 years, his symptoms gradually worsened. He used to get up only once a night to urinate, but over time, the number of nighttime voidings has increased. Now he hardly falls asleep before he has the urge to urinate. He reports no urinary incontinence or blood in his urine. He also states that he has not been treated for urinary tract infections. The last visit to his urologist was 1 year ago, and he was told to reduce caffeine intake and withhold fluids 3 hours before bedtime. No medications were prescribed. At that time, the urologist told him that his problem was a natural part of getting old, that his prostate was big, and that he should not worry.

Sam B. remembers that the urologist ran some tests, but he does not remember the results.

PMH: Diabetes mellitus, type II

Medications: metformin

Allergies: ampicillin (skin rash, all over his trunk)

Physical exam:

  • ROS: Well-developed, well-nourished male with nocturia × 3

  • Vital signs: BP 138/85 mm Hg; HR 70 beats/min; RR 15 breaths/min; temperature 98.6°F; weight 80 kg; height 5′10″

  • Genitourinary tract: Normal penis, no curvature; testes, mildly atrophic; anal sphincter tone intact and within normal limits; digital rectal exam reveals enlarged, symmetric, soft prostate, approximately 40 g, no nodules or induration; pedal pulses +3, bilaterally

  • Laboratory results: SMA-6 all results are within normal limits; HbA1c 5.5%; PSA (from 2 weeks ago) 2.5 ng/mL

  • Urinalysis: No bacteria, WBCs, RBCs, or crystals on microscopic examination

Assessment: Nocturia and urinary urgency most likely due to an enlarged prostate; patient is not taking any medications that would exacerbate LUTS; diabetes mellitus is well controlled and is probably not contributing to LUTS

Plan: Conduct assessments to determine the severity of the patient’s lower urinary tract symptoms.

QUESTION: From the test results below, how would you assess the severity of this patient’s disease?

  • AUA-SI score: 30

  • Peak urinary flow rate: 7 mL/sec

  • Postvoid residual urine volume: 300 mL

DISCUSSION: The AUA-SI score indicates that the patient perceives his voiding symptoms as severe. The peak urinary flow rate is below the normal range, which indicates that he has significant obstruction to urinary outflow from the bladder. He retains a significant amount of urine in his bladder after voiding, as the postvoid residual urine volume is high. This is consistent with bladder outlet obstruction. The patient also reports that he has not been treated for urinary tract infections. In addition, the digital rectal exam reveals a large prostate with no signs consistent with prostate cancer. His PSA is below the age-related normal range, which is consistent with the digital rectal exam findings of an enlarged but noncancerous prostate gland. Thus, this patient has severe lower urinary tract symptoms, most likely due to benign prostatic hypertrophy. He requires symptomatic treatment.

Digital Rectal Exam of the prostate

Normal size in adult men, 15 to 20 g or 15 to 20 cm3

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 that 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 to 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 can 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 clinician who is conducting the exam. Because of skill variability among clinicians for this physical assessment technique, a transrectal ultrasound (TRUS) is often performed to better assess the volume of an enlarged gland and to check for nodules or induration. TRUS may reveal hyperechoic, hypoechoic, or isoechoic areas of the prostate. By so doing, targets for needle biopsy can be better identified.48,53

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 5α-reductase inhibitors. These agents are most effective in patients with prostates that are least 40 g in size. Treatment can reduce the risk for acute urinary retention, slow BPH progression, and delay the need for surgery.54,55 In addition, the size of the prostate helps determine the best surgical approach (ie, transurethral versus open) for large prostate glands.

Estimated prostate size does not correlate with the severity of voiding symptoms or degree of bladder neck obstruction.49 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 caused by the anatomic blockade of the urethra caused by the enlarged prostate gland. In other patients, obstructive voiding symptoms may be due to excessive α-adrenergic stimulation of receptors in the smooth muscle fibers of the prostate and bladder neck, which decreases the caliber of the urethral lumen. 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 TRUS.

Finally, during a digital rectal exam, anal sphincter tone is also assessed. The anus is innervated by branches of the pudendal nerve, which emanates from the sacral plexus at S2-S4 and is responsible for bladder contraction and emptying.

Peak Urinary Flow Rate

Peak urinary flow rate, normal range: ≥25 mL/sec in young men; ≥10 to 15 mL/sec, minimum, in older men

The peak urinary flow rate refers to the speed with which urine is emptied out of a full bladder. It is assessed as a simple outpatient procedure. The patient is instructed to drink water until his bladder is full and is then 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.48 The average urinary flow rate is calculated from the total volume (milliliters) of urine collected divided by the total time (seconds) that it took to empty his bladder.

Although there is no absolute cutoff for urinary flow rate that identifies a patient with clinically significant urinary obstruction, a low peak urinary flow rate is suggestive of bladder outlet obstruction, particularly when the peak urinary flow rate is <10 to 12 mL/sec.48 In addition, a patient with a peak urinary flow rate of <10 mL/sec is more likely to benefit from surgical correction of BPH than a patient with a higher flow rate.48 However, there is no direct correlation between voiding symptom severity and urinary flow rate, which is likely due to a patient’s attribution of voiding difficulty to advancing age (and not due to a prostate disorder) or denial of the presence of symptoms.48

In patients with BPH, the urinary flow rate is typically used along with the AUA-SI score and the absence or presence of complications secondary to bladder neck obstruction to assess the severity of the patient’s disease.48 The choice of therapy is influenced by patient perception of symptom severity in addition to objective measures of disease.

A limitation of uroflowmetry testing 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.48 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.48 The latter occurs in patients with diabetes mellitus, peripheral neuropathy, or spinal cord injury.48

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 to 150 mL. In a normal person, the postvoid residual urine volume should be 0, usual range 0.09 to 2.24 mL, but may be as high as 12 mL.56 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 urinary retention.

A noninvasive determination of the postvoid residual urine volume with abdominal ultrasonography is inexpensive, readily available, and commonly used.48 Less frequently, postvoid residual urine volume is measured manually. That is, 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 associated with some risk of urethral injury and pain secondary to catheter insertion.

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 is cause for concern.48 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 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 or bladder outlet obstruction.48,57 It is also found in patients with peripheral neuropathies secondary to severe diabetes mellitus, spinal cord injury, or chronic alcoholism.

PROSTATE CANCER

Prostate cancer is the most common cancer of American men and the second leading cause of cancer-related death among American men.58 The prevalence is highest in men ≥50 years, and the median age at diagnosis is 66 years.58 The clinical presentation of prostate cancer is variable. 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 of 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 of complications of prostate cancer and its treatment. Today, because of increased screening for prostate cancer, most patients with this disease are diagnosed when their cancer is localized and at an early stage, and the 5-year survival is 100% with surgery or radiation therapy.59

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 glandular enlargement, which can lead to obstructive voiding symptoms (eg, decreased force of urinary stream, inability to completely empty the bladder, and overflow urinary incontinence, similar to BPH). Tumor spread to bone can cause bone pain and anemia; spread to the vertebral bodies can lead to spinal cord compression resulting in peripheral neuropathies, urinary or fecal incontinence, or difficulty walking; spread to the lymph nodes can cause lymphadenopathy, lower extremity peripheral edema, or ureteral obstruction; and spread to the rectum can cause rectal bleeding.60

When a patient has an elevated PSA and a suspicious finding on a digital rectal exam, an ultrasound-guided (or an ultrasound-guided biopsy combined with magnetic resonance imaging) prostate needle biopsy is performed. A tissue diagnosis of prostate cancer confirms the presence of the tumor. Based on the Gleason score of the tumor specimen, PSA, digital rectal exam, transrectal ultrasound of the prostate, and a variety of other tests to check for extraprostatic spread (Table 25-13), the clinical stage of disease can be determined and a risk assessment for tumor recurrence can be performed. If a patient has low volume disease on biopsy confined to the prostate, a PSA <10 ng/mL, and a Gleason score ≤6, he is considered to be at low risk of tumor recurrence and is a candidate for active surveillance, which includes PSA testing every 6 months, a digital rectal exam annually, and a prostate needle biopsy every 1 to 3 years.60 On the other hand, if the patient has localized disease but is at high risk for tumor recurrence, aggressive treatment that includes surgery and/or radiation therapy with androgen deprivation therapy is indicated for clinically significant disease.

TABLE 25-13.

Clinical Tests Used to Stage Prostate Cancer

AREA TO CHECK FOR METASTASES

INITIAL CLINICAL TEST

ADDITIONAL CLINICAL TESTS IF INITIAL CLINICAL TEST IS POSITIVE

Bone

Bone scan

Bone survey (radiograph of entire bony skeleton)

MRI of bone

Lung

Chest radiograph

CT of the chest

Liver

Liver function tests

CT of the abdomen

Lymph nodes

PSA >20 ng/mL or Gleason score of 8–10; or peripheral edema on physical exam; or high-volume disease on prostate needle biopsy

CT of the pelvis

MRI of the pelvis

Lymph node biopsy

Periprostatic tissue (eg, seminal vesicles, fat tissue)

Digital rectal exam of the prostate, TRUS of the prostate, or MRI with ultrasound fusion biopsy

CT = computed tomography; MRI = magnetic resonance imaging; TRUS = transrectal ultrasound.

Screening for prostate cancer is recommended for men with at least a 10-year life expectancy. In the past, such screening was performed annually, but it resulted in overdiagnosis of prostate cancer such that patients were subjected to unnecessary and repeated prostate needle biopsies and overaggressive surgical or radiation treatment of a slow-growing, noninvasive, or indolent tumor. Not only are these measures associated with adverse effects but they are also costly to the healthcare system.61 Finally, screening is associated with improved life expectancy in only about 20% to 32% of patients.61

As a result, many professional organizations took a conservative position on who should be screened, when screening should begin, and how often screening procedures should be repeated. Despite differing recommendations for prostate cancer screening among various professional organizations (a sampling of which is shown in Table 25-14), the following statements are commonly held:

  • Although PSA has been used alone as a prostate cancer screening tool, its specificity is improved when it is combined with a digital rectal examination, performed by an experienced examiner.70

  • Lengthening the interval between repeat PSA tests from 1 to 2 or more years increases the specificity of PSA when used for prostate cancer screening and reduces the potential harms of screening. This is particularly applicable to patients with very low PSA levels (<1 ng/mL).

  • PSA screening should be offered only to men with a life expectancy of at least 10 to 15 years.

  • The decision to start prostate cancer screening should be a joint decision of the patient and his physician.64,67

  • Patients at high risk of prostate cancer include black or African American men and those with a first-degree relative (father or brother) with prostate cancer. These patients should be screened starting at age 40 to 45 years, depending on the national guideline.

  • Patients with low-stage, low-grade prostate cancer do not require immediate treatment for prostate cancer. However, they should be managed by active surveillance with repeat PSA testing, digital rectal exams, and prostate biopsies at regular intervals to check for upstaging or upgrading of the disease.60,62,64,67

  • Patients vary in terms of the value they place on diagnosing and treating prostate cancer early, which should impact joint decision-making by the patient and physician as to the timing and frequency of prostate cancer screening for an individual patient.60,62

TABLE 25-14.

Comparison of Prostate Cancer Screening Recommendations by Selected Professional Organizations

ORGANIZATION

AGE (YEAR) AT WHICH SCREENING SHOULD START FOR HIGH-RISK PATIENTS

AGE (YEAR) AT WHICH SCREENING SHOULD START FOR AVERAGE RISK PATIENTS

AGE (YEAR) AT WHICH SCREENING IS NO LONGER RECOMMENDED

RECOMMENDED FREQUENCY OF PSA SCREENING

National Comprehensive Cancer Network60

40, if African American or with BRCA-1 or BRCA-2 mutations

45

If life expectancy is <10 yr

If PSA >1 ng/mL, repeat every 1–2 yr

If PSA <1 ng/mL, repeat every 2-4 yr

American Cancer Society64

40, if male with one first-degree relative with prostate cancer at an early age

45, if black or African American male with first-degree relative diagnosed with prostate cancer at age <65 yr

50

If life expectancy is <10 yr

If PSA is 2.5 ng/mL or higher, repeat annually

If PSA is <2.5 ng/mL, repeat every 2 yr

U.S. Preventive Services Task Force65

The U.S. Preventive Services Task Force recommends discussing with men age 55–69 yr the potential benefits and harms of PSA-based screening for prostate cancer. Screening offers a small potential benefit of reducing the chance of dying of prostate cancer. However, many men experience potential harms: false-positive results that require additional testing and possible prostate biopsy, overdiagnosis, and overtreatment and treatment complications such as incontinence and impotence. Individualized decision-making about screening is recommended.

Patients who are unwilling to be screened or are older than 70 years of age should not be screened.

55

70

No specific recommendation, periodic screening per patient preference

National Cancer Institute66

Insufficient evidence to recommend PSA or digital rectal exam

No specific recommendation, periodic screening per patient preference

No specific recommendation, periodic screening per patient preference

No specific recommendation, periodic screening per patient preference

American Urological Association67

40, if African American male with family history of metastatic or lethal adenocarcinomas affecting multiple generations and multiple first-degree relatives developed cancers at a younger age

55; shared decision-making recommended

70 or if life expectancy is <10–15 yr

Every 2 yr for average-risk patients

American College of Physicians68

American College of Physicians: 40–45, if African American race and a first degree relative with prostate cancer, or a man with multiple first-degree family members with prostate cancer before age 65 years

50; shared decision-making recommended

70 or if life is <10–15 yr

If PSA is ≥ 2.5 ng/dL, repeat annually

Canadian Urological Association69

Canadian Urological Association: 45–49, with a family history of prostate cancer in a first or second-degree relative.

50

If age 60 and PSA is <1 ng/mL, or if age 70 and life expectancy is <10 yr

If PSA is 1–3 ng/mL, repeat every 2 yr

If PSA is >3 ng/mL, repeat more frequently

BRCA-1 or BRCA-2 = two different mutations of the breast cancer gene.

Currently, there is a focus on the development of new laboratory tests to identify additional tools that can distinguish patients with clinically significant prostate cancer who are at high risk for tumor invasiveness and deserve early aggressive treatment from patients who do not need additional prostate biopsies, frequent PSA testing, or treatment. Table 25-15 includes some biomarker tests using tissue or urine specimen.7174 Some of these tests have not been validated in large-scale clinical trials with long-term follow up of patients, are much more expensive than PSA, may not be covered by insurance plans, and may not be available from all clinical laboratories.73

TABLE 25-15.

Prostate Tissue and Urine-Based Laboratory Tests for Prostate Cancer Management

PROSTATE TISSUE TESTS

BRAND NAME OF TEST

HOW TEST IS ASSESSED

IS TEST COMBINED WITH OTHER PARAMETERS?

PURPOSE OF TEST

Prolaris®

46 different genes

Yes. Combined with PSA and Gleason score to produce Prolaris score.

This test helps to predict disease progression in patients with localized disease, which can be used to help decide on the most appropriate treatment or active surveillance.

Prolaris score ranges from 0–10. The higher the score, the more aggressive the tumor, and the patient is at high risk of metastases and cancer-specific mortality.

ProstaVysion™

ERG gene fusion (found in aggressive prostate tumors) and PTEN suppressor gene (found in 60% of prostate cancer metastases)

No

If test is positive, it is associated with an aggressive tumor and an unfavorable prognosis.

Oncotype DX®

17 genes necessary for growth and survival of prostate tumor

Yes. Genomic prostate score (GPS) is based on results of this assay, PSA, Gleason score, and NCCN clinical stage of prostate cancer.

If positive, it predicts a patient’s risk of cancer-related death and metastases within 10 yr.

Decipher®

22 selected messenger RNA markers

No

Test results are converted to genomic classifier (GC) scores, which predict the rate of metastases within 5 yr. A GC score <0.4 is associated with a 2.4% probability of metastases in 5 yr; whereas a GC score of 0.6 has a 22.5% probability of metastases in 5 yr. This can be used to help with treatment decisions for a patient.

ProMark®

8 protein biomarkers

No

Test generates a personalized score that relates to the aggressiveness of the tumor. Score ranges from 1–100 with higher scores associated with more aggressive tumors. This can be used to help with treatment decisions for a patient.

ConfirmMDx®

3 genes for DNA methylation

No

Used to predict future biopsy results after an initial negative biopsy.

If positive, it indicates that the prostate tumor is aggressive.

If the patient has an elevated PSA, but has a negative prostate biopsy, this test can detect occult cancer.

Mitomic Prostate Core Test™ (MPCT)

Mitochondrial DNA deletion

Yes. Combined with PSA >4 ng/mL, PSADT <3 mo, life expectancy >10 yr, family history, and black race

Used for men with at least one negative biopsy. Results classify patients into two groups. If MPCT negative, patient is at low risk of undiagnosed prostate cancer. If MPCT positive, patient is at high risk of undiagnosed prostate cancer.

Urine Tests

SelectMDx®

2 genes: DLX1 (associated with tumor progression) and HOXC6 (associated with cell proliferation)

Yes. Combined with patient age, PSA, prostate volume, and digital rectal exam

Used in patients prior to first biopsy or after a negative biopsy. Test results stratify patients into two groups: those at increased risk of a Gleason score 7 (aggressive tumor) or higher prostate tumor and those at low risk for an aggressive tumor.

ExoDx™ Prostate Test (EPI)

Exosomes and RNA from tumor cells that are shed in urine

No

Used for patient with a negative biopsy.

Measurement results in EPI score, range 0–100. Cut off score is 15.6. If score is >15.6, the patient is at higher risk for having a clinically significant prostate tumor. If the score is <15.6, the patient is at low risk of having a clinically significant tumor and this reduces unnecessary additional biopsies.

EPI = ExoDx Prostate Test; ERG gene = erythroblast transformation specific-related gene; PTEN gene = phosphatase and tensin gene; MPCT = Mitomic Prostate Core Test; NCCN = National Comprehensive Cancer Network.

Source: Adapted with permission from references 7174.

Clinical tests to stage prostate cancer (Table 25-13) fail to identify approximately one-third of patients with low-volume prostate cancer that has spread outside of the prostate gland. Thus, the search continues for improved diagnostic tools. For example, ProstaScint is a type of scan that uses 111In capromab pendetide, a monoclonal antibody against prostate specific membrane antigen, to detect prostate cancer cells that may have spread to soft tissue outside of the prostate gland.75 Initial evaluation shows that ProstaScint may be useful for detecting tumor recurrence or identifying patients with disease that has spread locally outside the prostate.

Prostate-Specific Antigen

Non–age-related normal range: <4 ng/mL or <4 mcg/L

Age-related normal ranges:

  • 40 to 49 years, 0 to 2.5 ng/mL (0 to 2.5 mcg/L)

  • 50 to 59 years, 0 to 3.5 ng/mL (0 to 3.5 mcg/L)

  • 60 to 69 years, 0 to 4.5 ng/mL (0 to 4.5 mcg/L)

  • ≥70 years, 0 to 6.5 ng/mL (0 to 6.5 mcg/L)

Prostate-specific antigen (PSA) is a glycoprotein produced by the androgen-dependent glandular epithelial cells that line the acini and ducts in the transition zone of the prostate gland.76 PSA is produced by both normal cells and prostate cancer cells. Small amounts also are produced by breast tissue, parotid glands, and periurethral glands. In normal, healthy men, 20 to 45 years of age, mean plasma PSA levels are undetectable or at the low end of the normal range, usually <1.14 ng/mL in white men and <1.37 ng/mL in African American men. PSA is undetectable in younger men because it is carried out of the prostate through ducts to the urethra, where it is passed out of the body in the ejaculate during coitus. PSA liquefies semen after ejaculation. However, once the prostate gland becomes cancerous, the duct system in neoplastic tissue is disrupted. As the gland grows, PSA production increases and it leaks into the circulation, which 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 level measured in plasma, 30% is fPSA, and 70% is complexed to α1-antichymotrypsin (ACT) and α2-macroglobulin (A2M).76 Free PSA is renally excreted, while cPSA is hepatically catabolized. The plasma half-life of PSA is 2 to 3 days.

In the bloodstream, fPSA exists in several forms. ProPSA is the inactive precursor of PSA and is associated with prostate cancer.77 It may be modified or clipped to produce two different inactive forms; however, most of it is converted to active (also known as intact) PSA. Active PSA can be converted to inactive PSA or benign PSA (BPSA), which is produced by BPH tissue, as opposed to normal prostate tissue.76 High levels of BPSA are associated with high-volume BPH and obstructive voiding symptoms.77 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.

For the current cutoff value of 4 ng/mL, the specificity of PSA decreases as men age8 because PSA normally increases as men age and develop BPH. Thus, to minimize the risk of interpreting an increased PSA as due only to prostate cancer, age-related normal value ranges (which have been further delineated for Asian and African American men), as shown in Table 25-16, are often provided by clinical laboratories.76,79 An advantage of age-related normal value ranges is that they increase the likelihood of prostate cancer detection in young men. However, a disadvantage is that they delay biopsies in older men, which can delay the diagnosis of prostate cancer.76,79

TABLE 25-16.

Age-Specific Median and Normal Value Ranges for PSA in Adult Men of Various Races

PATIENT AGE (yr)

OVERALL MEDIAN (ng/mL)

WHITE (ng/mL)

ASIAN (ng/mL)

AFRICAN AMERICAN (ng/mL)

40–49

0.7

0–2.5

0–2.0

0–2.0

50–59

0.9

0–3.5

0–3.0

0–4.0

60–69

1.3

0–4.5

0–4.0

0–4.5

>70

1.7

0–6.5

0–5.0

0–5.5

Source: Adapted with permission from references 76,79.

In some published literature, the normal value of total PSA is considered to be <2.5 ng/dL, particularly in men <60 years. Thus, patients with a total PSA of ≥2.5 ng/dL 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 to 4 ng/dL.80 However, lowering the normal value of PSA also is likely to increase the number of biopsies that are negative.

False-negative PSA test results can lead to misdiagnosis and undertreatment. The Prostate Cancer Prevention Trial showed no threshold PSA below which the absence of prostate cancer is guaranteed. Men with PSAs ≤0.5 ng/mL, 0.6 to 1 ng/mL, 1.1 to 2 ng/mL, 2.1 to 3 ng/mL, and 3.1 to 4 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 carried a worse prognosis than low-grade tumors.73,76,81

A 20% biological variation in measured PSA levels has been documented when the PSA ranges from 0.1 to 20 ng/mL. For this reason, it is common practice to repeat a single elevated PSA and not take action based on a single elevated value.76,82

A radioimmunoassay is commonly used to measure total and fPSA levels. Assays are quick to perform and commonly available. Newer commercially available assay kits allow for measurement of PSA concentrations that are <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 in an individual patient.83

Four Uses of PSA

As a tumor marker, PSA has several uses: (1) as a diagnostic screening test for prostate cancer, (2) in combination with other clinical tests to determine the clinical stage of disease, (3) to assess a patient’s prognosis or likelihood of disease recurrence, and (4) to assess a 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 to 4 ng/mL, PSA has a positive predictive value of 18%. In the range of 4 to 10 ng/mL, PSA has a positive predictive value of 20% to 25%. Above 10 ng/mL, PSA has a positive predictive value of 42% to 64%.84 PSA is commonly used in combination with a digital rectal examination of the prostate for prostate cancer screening because the combination has better sensitivity and specificity than either test alone. When used in combination with a digital rectal exam, the sensitivity of PSA increases to 85% to 90% and the positive predictive value for a PSA cutoff of 4 ng/mL increases from 32% to 49%.85

Although the PSA level 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 <10 ng/mL suggests that the tumor is confined to the prostate, a PSA level of >20 ng/mL suggests extracapsular spread, and a PSA level of ≥ 80 ng/mL suggests advanced disease86 (Minicase 3).

Pretreatment PSA is used along with the Gleason score of prostate tissue and the clinical stage of disease to predict the patient’s posttreatment risk of disease recurrence.8789 This information is then used to guide treatment selection for individual patients. Although multiple risk-stratification schemes have been devised,87,88 the National Comprehensive Cancer Network stratification guideline is commonly used (Table 25-17).60

TABLE 25-17.
Example of National Comprehensive Cancer Center Stratification of Risk for Disease Progression Based on Disease Stage, PSA, and Gleason Score

RISK CATEGORY FOR DISEASE PROGRESSION

STAGE OF PROSTATE CANCERa

PSA (NG/ML)

GLEASON SCORE

TREATMENT OPTIONS

Very Low

T1C

<10

≤6

Active surveillance if life expectancy <10 yr; surgery or radiation therapy if life expectancy ≥10 yr

Low

T1 to T2A

<10

≤6

Active surveillance if life expectancy <10 yr; surgery or radiation therapy if life expectancy ≥10 yr

Intermediate, favorable

T2B to T2C

10–20

7

Active surveillance if life expectancy <10 yr; radiation therapy with or without androgen deprivation therapy, or surgery with or without androgen deprivation therapy if life expectancy ≥10 yr.

High

T3A

>20

8–10

Radiation therapy with or without androgen deprivation therapy, or surgery with or without androgen deprivation therapy if life expectancy ≥10 yr.

aStages T1 and T2 refer to localized to the prostate. Stage T3 refers to cancer that has directly extended to periprostatic tissue or seminal vesicles. 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 = one focus; B = two foci; and C = multiple foci of tumor.

Source: Adapted with permission from National Comprehensive Cancer Network (NCCN) guideline version 2. Prostate cancer early detection; 2019. www2.tri-kobe.org/nccn/guideline/urological/English/prostate_detection.pdf.

When used to assess a 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 2-fold reduction in PSA level, with effective treatment. For patients with localized prostate cancer, the PSA should be undetectable after a successful radical prostatectomy.

Interpreting Prostate-Specific Antigen in a Patient with Prostate Cancer

Robert R. is a 70-year-old black man with cancer of the prostate diagnosed 2 years ago. At that time, his disease was localized to the prostate, and he was offered active surveillance with PSA testing every 6 months and an annual digital rectal exam. However, his most recent three PSAs show an upward trend.

HPI: On a routine annual physical exam, Robert R. has an abnormal digital rectal exam. The prostate is enlarged and asymmetric. A 1-cm indurated area is palpated and subsequently biopsied; it shows adenocarcinoma, Gleason grade 8 in 60% of the biopsy specimens. Three PSA tests, conducted 1 month apart prior to the prostate needle biopsy, showed the following results:

  • January: 10 ng/mL

  • February: 20 ng/mL

  • March: 25 ng/mL

The patient’s liver function tests, blood urea nitrogen, and serum creatinine are 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 135/80 mg Hg; HR 80 beats/min; RR 15 breaths/min; weight 190 lb

QUESTION: What does the patient’s PSA suggest about his disease? What additional tests should be performed to confirm the stage of prostate cancer?

DISCUSSION: This patient’s PSADT is less than 3 months and is associated with prostate cancer recurrence. This is not unexpected based on his most recent prostate biopsy result, which showed Gleason grade 8 prostate cancer in most of the specimen. That finding suggests that the patient is at high risk of tumor metastasis. To determine if tumor has spread outside the prostate, additional testing should include liver enzymes, bone scan, magnetic resonance imaging of the prostate, computed tomography of the pelvis, and chest radiograph.

Factors That Alter Prostate-Specific Antigen Levels

Prostate-specific antigen serum levels are affected by several patient factors (Table 25-18).90,91 Decreased PSA levels are associated with obesity. It has been postulated that obese patients have larger circulating plasma volumes, which dilute PSA concentrations in the bloodstream.94 Decreased PSA also is seen in hypogonadism, which results in shrinkage of the prostate gland—the major site of PSA production. Increased PSA levels are observed in some elderly patients because BPH occurs with a high prevalence, and the increased prostate volume results in an increased volume of glandular epithelial tissue. Also, increased PSA normal range levels are reported in African American men <60 years.95 The reason for this is unknown. Inflammatory disorders of the prostate, including prostatitis, or manipulation of the prostate during a digital rectal exam or massage may increase PSA.

TABLE 25-18.
Diseases, Procedures, and Medications That Increase or Decrease (Total) PSA

INCREASE PSA

DECREASE PSA

BPH

Obesity

Prostatitis, infectious or inflammatory

Hypogonadism

Prostate trauma (eg, massage, biopsy, digital rectal exam)

Medications: 5α-inhibitors (eg, finasteride, dutasteride), HMG-CoA reductase inhibitors (eg, statins), aspirin, thiazide diuretics

Herbals: saw palmetto

Prostate surgery or proceduresa

Urethral catheterization

Acute urinary retention

Urinary tract infection

Ejaculation

Exercising on a bicycle for 30 min

Medications: parenteral testosterone supplements

PSA bounce after radiation treatment for prostate cancer

HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A.

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

Source: Adapted with permission from references 76,92,93.

Medications That May Alter Prostate-Specific Antigen Levels

Of importance, the 5α-reductase inhibitors (eg, 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 finasteride and dutasteride daily for treatment of BPH and also with the lower daily dose of finasteride used for androgenetic alopecia.9698 To preserve the usefulness of PSA as a tumor marker in patients who are taking 5α-reductase inhibitors, it is essential to obtain a pretreatment PSA as a baseline. When PSA levels are repeated after at least 6 months of treatment, 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.

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.97 It is likely that because finasteride shrinks the prostate, it is easier to locate a suspicious nodule or area of induration when performing a digital rectal exam or prostate biopsy.

An increase in PSA can occur for up to 14 weeks after docetaxel treatment of castration-resistant prostate cancer or 17 to 18 months after radiation therapy for prostate cancer.99,100 This phenomenon is known as PSA bounce or PSA flare. Such increases in PSA should not be interpreted as biochemical evidence of disease relapse or should not be used to decide additional treatment for the patient. Instead, in the face of metastatic prostate cancer, other objective signs of disease progression should be used to make treatment-related decisions.

To minimize the impact of noncancerous conditions on PSA, it is recommended to allow an adequate interval after the condition has resolved before measuring PSA. Consideration of PSA’s plasma half-life of 2 to 3 days along with the time it takes the condition to resolve affects the time interval. 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. Prostatitis produces sustained elevations in PSA until the infection or inflammation is resolved; therefore, it is recommended that PSA testing be held for up to 8 weeks after symptom resolution. Also, in a patient with PSA levels in the gray zone of 4 to 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 biopsies; however, it is considered a controversial measure at this time.101

PSA Gray Zone

The total PSA range of 4 to 10 ng/mL is 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 as a screening test when the digital rectal exam is normal, to reduce the number of unnecessary prostate biopsies, or to better assess prognosis of patients, the following strategies have been recommended by some investigators72,102:

  • PSA density (PSAD). The PSAD is increased in patients with prostate cancer as compared with patients with BPH. The PSAD is calculated by dividing the total PSA by the prostate volume as determined by TRUS. A normal PSAD is <0.15 ng/mL/cm3. If the PSAD is ≥0.15 ng/mL/cm3, 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.103 In addition, to derive PSAD, a TRUS must be performed. This adds an extra cost and is usually uncomfortable for the patient. Finally, a TRUS measurement of prostate volume is difficult to reproduce in the same patient.76

  • 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 at least three PSA tests performed, one at least 3 to 6 months apart; alternatively, the patient must have three PSA tests performed over a 1.5-year period.72,103,104 A PSA velocity of >0.75 ng/mL/yr suggests that the patient has prostate cancer and should undergo additional diagnostic testing. A PSA velocity that is >0.75 ng/mL/yr has a sensitivity of 90% to 100% and a specificity of 95% as a screening test for prostate cancer. In men <60 years whose lifespans are potentially more severely impacted by aggressive prostate cancer, it is suggested that a PSA velocity >0.4 ng/mL/yr be used as a threshold value.104 PSA 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 be considered as suggestive of prostate cancer in place of the 0.75-ng/mL/yr cutoff.76 However, the long period of time needed to collect enough PSA measurements to determine PSA velocity is a significant disadvantage of using this strategy. It also should be noted that a recent analysis of more than 5,500 men in the Prostate Cancer Prevention Trial showed no advantage of PSA velocity over PSA in clinical practice.105,106

  • PSA doubling time (PSADT). The PSADT is the length of time it takes for the PSA level to double. The preoperative PSADT has been used to indicate the presence of a more aggressive tumor and predict cancer recurrence after radical prostatectomy. A preliminary study suggests that a PSADT of <3 months indicates that the patient probably has tumor recurrence, has metastatic disease, and is at high risk of prostate cancer–related death; a PSADT <12 months suggests that the patient is at risk for tumor recurrence.72,107 In the past, a disadvantage to using PSADT was the absence of a standardized number and timing of specimen collections for PSA. However, more recently, the Prostate Specific Antigen Working Group has standardized the determination of PSADT by establishing the following criteria: (1) PSA levels should be at least 0.2 ng/L (0.2 mcg/L); (2) PSA levels should be obtained every 4 weeks for 3 consecutive months; (3) the same clinical laboratory should run all the PSA assays using the same method; and (4) the serum testosterone level should be stable during the PSA measurement period.107

  • Percentage of fPSA (%fPSA). Prostate cancer is associated with a decreased %fPSA and an increased %cPSA because cPSA produced by prostate cancer cells resists normal intracellular proteolytic processing.72,74

    If the %fPSA is <25%, the patient has up to a 56% probability of having prostate cancer (Table 25-19).108,109 One study showed that in the PSA range of 2.5 to 10 ng/mL, the %fPSA cutoff of 25% had more than a 90% sensitivity for screening for organ-confined prostate cancer and reduced unnecessary biopsies by 20%.109 These findings have been confirmed by other clinical studies.110,111 Thus, prostate needle biopsy is performed on patients with a %fPSA of <10%; patients with a fPSA of 10% to 25% would be advised to have a prostate needle biopsy. %fPSA levels also identify patients with aggressive prostate cancer. In one study, men 50 to 58 years old had a 2.4-fold increased risk of aggressive prostate cancer when the %fPSA was <20% when compared with men in the same age group with %fPSA percentages >20%.112

    Free PSA is renally excreted; therefore, in patients with renal failure, the fPSA level increases.113 Free PSA increases after digital rectal exam of the prostate, prostate needle biopsy, and ejaculation. 5α-reductase inhibitors decrease fPSA and cPSA 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°C or assayed within 3 hours of specimen collection.

  • cPSA. As previously mentioned, prostate cancer is associated with an increased fraction of cPSA. With this assay, the concentration of PSA complexed to ACT and A2M 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 to but have higher specificity than total PSA assays, cPSA assays have not replaced PSA assays.114

  • Prostate Health Index (PHI). The PHI is mathematically calculated from three laboratory test values for total PSA, fPSA, and proPSA. The PHI is used to distinguish patients with prostate cancer from those with benign prostate disorders, identify patients who likely have clinically significant high-grade prostate cancer and should undergo prostate biopsy, and identify patients who were undergoing active surveillance but should be offered treatment.73,74,115,116 A PHI of ≥30 to 35 is associated with a clinically significant prostate tumor as defined by a Gleason score of ≥7. A meta-analysis of eight studies showed that PHI has a sensitivity for detecting prostate cancer of 90% and a specificity of 31.6%.117 When the PHI is <25.0 to 28.6, it implies that the increased PSA is probably not due to prostate cancer; therefore, prostate biopsy is not necessary. Using this PHI cut off score reduces 40% of unnecessary prostate biopsies but misses a prostate cancer diagnosis in approximately 5% to 10% of patients.73,75,117120

  • 4K Score. The 4K score is based on measurement of four blood tests: total PSA, fPSA, intact PSA, and hK2, an enzyme known as human kallikrein that is thought to promote cancer growth. These lab values are combined with patient age, digital rectal exam findings, and previous prostate biopsy findings to produce a 4K score that estimates a patient’s risk of having high grade prostate cancer (ie, with a Gleason score of ≥7) and the need for aggressive treatment.119,121 A score of ≥7.5% is associated with a sensitivity of 94% in identifying patients at high risk of a clinically significant tumor and high risk of prostate cancer-related death. A score <7.5% is associated with a low likelihood of prostate cancer metastases and low risk of prostate cancer–related death.72,74,121,122

TABLE 25-19.
Estimated Probability of Prostate Cancer Depending on the Percentage of Free PSA

FREE PSA RANGE (%)

PROBABILITY OF PROSTATE CANCER (%)

0–10

56

10–15

28

15–20

20

20–25

16

>25

8

Source: Adapted with permission from references 108,109.

Gleason Scoring of a Prostate Biopsy Specimen

A needle biopsy of the prostate is used to establish a tissue diagnosis of prostate cancer. It may be performed transrectally in one of three ways: digitally guided, guided by TRUS, or guided by real-time ultrasound fused to magnetic resonance imaging.123,124

The false-negative rate is 20% to 25% when four to six biopsy specimens are obtained from the base lateral midportion and apex of the prostate gland.125 To reduce the false-negative rate, the number of random biopsy specimens is increased from six to 8 to 20.126,127 With the increase in tissue sampling, the false-negative rate is only 4%.128 Table 25-20 shows the probability of detecting prostate cancer from a prostate needle biopsy based on the patient’s prebiopsy PSA.

TABLE 25-20.

Common Interpretation of Increased PSA Laboratory Values as They Relate to Prostate Needle Biopsy for Prostate Cancer

0–3.9 ng/mL

Normal range

4–9 ng/mL

Biopsy is recommended (the probability of detecting prostate cancer is 25% to 30%)

≥10 ng/mL

Biopsy is recommended (the probability of prostate cancer is at least 50%)

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 one for the less prevalent pattern. Uniform, round, well-formed cells 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. 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 6 to 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 suggests that the patient is at intermediate or high risk of developing metastatic disease (Table 25-17).

Prostate needle biopsy is an invasive procedure. It can be painful and result in minor bleeding and infection. Severe adverse effects requiring hospitalization can occur in 1% of patients.

PCA3 Score (Progensa)

Unlike PSA, which is secreted by both normal prostate and prostate cancer cells, PCA3 (also known as DD3 prostate-specific gene or differential display code 3) is a long noncoding RNA marker that is expressed 10- to 100-fold higher in prostate cancer cells when compared with noncancerous prostate tissues.73 PCA3 regulates the survival of prostate cancer cells by directing protein transcription and chromosomal remodeling.73 PCA3 is measured from prostate cancer cells shed in a 20- to 30-mL sample of urine collected approximately 1 hour after a prostate massage, in which each lobe of the prostate is stroked three times.74 PCA3 does not increase with patient age or prostate volume.129

A PCA3 score is mathematically calculated from the ratio of PCA3 RNA copies to PSA RNA copies. A PCA3 score is used in a patient >50 years with one or more negative prostate biopsies for prostate cancer and a PSA of 2.5 to 4 ng/mL. The score is used to guide decision-making regarding the need for a repeat prostate biopsy (because it would likely be negative) in a patient. The cutoff PCA3 score is 25. If the PCA3 score is <25, it is considered a negative test, which is interpreted that it is unlikely for the patient to have a positive biopsy if a biopsy were to be repeated. If the PCA3 score is ≥25, it is considered a positive test, which is interpreted that it is likely that the patient will have a positive biopsy if a biopsy is performed. Using this cutoff score in patient sample, the PCA3 score exhibits a sensitivity of 77.5% and specificity of 57.1%.74,129

The PCA3 assay should not be used in patients when the most recent prostate biopsy shows atypical small acinar proliferation or when a patient’s current biopsy is <3 months old or >7 years after the last biopsy or to interpret the first prostate needle biopsy of a patient.130 PCA3 assay results may be altered by radiation therapy to the prostate, prostatectomy, or 5α-reductase inhibitor use.

The PCA3 assay appears to be comparable to PHI but better than PSA or %fPSA as a tool to assist the physician in reducing the number of repeat biopsies that would most likely show low-grade prostate cancer.72,118 However, collecting the urine specimen after prostate massage for PCA3 is more time-consuming and inconvenient than the blood testing needed for PHI. Additional studies to enhance the sensitivity and specificity of PCA3 scores to detect high grade prostate cancer by combining PCA3 score with a patient’s age, race, and PSA, and digital rectal exam findings appear promising.129,130

PROSTATITIS

Prostatitis is the most common genitourinary tract disorder among men <50 years. The lifetime prevalence is 15% to 16%.131133 Prostatitis is an inflammatory condition of the prostate gland due to an infection or a noninfectious cause. Risk factors for prostatitis include BPH, lower urinary tract infection, sexually transmitted diseases, and stress.132 The National Institutes of Health (NIH) has stratified patients with prostatitis into four unique categories (Table 25-21).134 Of these, only the first two categories—acute and chronic prostatitis—have infection as the etiology and are generally responsive to antibiotic treatment. For the other two categories—chronic pelvic pain syndrome and asymptomatic inflammatory prostatitis—the etiology is unclear, which accounts for the low response rates to existing treatments. Chronic pelvic pain syndrome can be inflammatory or noninflammatory (ie, inflammation is evidenced by the presence of WBCs in the expressed prostate secretion [EPS], semen, or tissue removed from the prostate during prostatectomy or biopsy).133

TABLE 25-21.

National Institutes of Health Categories of Types of Prostatitis

CATEGORY

SYMPTOMS/SIGNS

PROSTATITIS CASES (%)

INFECTIOUS ETIOLOGY

RESULTS OF FOUR-GLASS SPECIMEN COLLECTION METHOD

Acute bacterial prostatitis

Acute onset of urinary frequency, urgency, dysuria; perineal or suprapubic pain; and urinary retention; may be associated with fever, chills, rigors nausea, vomiting, malaise, myalgia, lower abdominal or suprapubic discomfort perineal or rectal pain; swollen, warm, tense, boggy, tender prostate on palpation; urinalysis shows significant WBCs and bacteria; blood cultures are often positive, urine culture is positive

2–5

Yes

VB1 and VB2 are positive for infection

Chronic bacterial prostatitis

History of recurrent urinary tract infection; episodes of perineal, penile, suprapubic pain; frequency, urgency, and dysuria, which are separated by asymptomatic periods; symptoms are present for a minimum of 3 mo duration; prostate may be normal on digital rectal exam, may be mildly tender and boggy, or focally indurated with crepitation; urinalysis shows significant WBCs; prostatic fluid is purulent

2–5, up to 15% in some studies

Yes

EPS and VB3 are positive for infection

There is a 10-fold or more increase in bacteria in VB3 when compared with VB1 or VB2

WBCs are present in EPS and VB3

Chronic pelvic pain syndrome that can be classified as inflammatory or noninflammatory

Waxing and waning dull aching perineal, suprapubic, scrotal or penile pain; pain on ejaculation, may be associated with frequency, urgency, and dysuria; minimum of 3 mo duration; digital rectal exam is unremarkable; this is stratified into inflammatory and noninflammatory disease

90–95

No

All specimens are negative for infection; patients with inflammatory disease have WBCs in EPS, VB3, and semen; patients with noninflammatory disease have no WBCs or bacteria in EPS, VB3, or semen

Asymptomatic inflammatory prostatitis

No symptoms; this is incidentally diagnosed on histologic review of a prostate tissue biopsy specimen; digital rectal exam is unremarkable

Unknown

No

WBCs in EPS, VB3, or semen

VB1 = first 10 mL of urine voided; VB2 = midstream urine collection; VB3 = first 5–10 mL of urine after prostate massage.

Source: Adapted with permission from Nickel JC. Classification and diagnosis of prostatitis: a gold standard? Andrologia. 2003;35(3):160–167.

Differentiation among the types of prostatitis is largely determined by clinical presentation of the patient, digital rectal exam of the prostate, and the laboratory analysis of EPS (Table 23-22). Digital exam of the inflamed prostate is described as boggy or having a softer consistency than usual. Because of the concern that prostate massage could expel bacteria from the prostate into the bloodstream, prostate massage is not performed in patients with suspected acute prostatitis. Instead, symptoms and blood and urine cultures are used to diagnose the disease. EPS is key for diagnosing chronic bacterial prostatitis, chronic pelvic pain syndrome, and asymptomatic inflammatory prostatitis. It is collected after a prostate massage in which the prostate is stroked from side to side and then from top to bottom during a digital rectal exam for 2 to 3 minutes (the resulting fluid is collected as it drips out of the urethral meatus).134

To assess symptoms and their severity, the NIH has devised a Chronic Prostatitis Symptom Index, which is a self-assessment tool comprised of 13 questions: eight questions focus on the quality and intensity of the patient’s pain, two questions focus on urinary voiding symptoms, and three questions focus on the impact of the symptoms on the patient’s quality of life. The total score ranges from 0 to 43; the higher the score, the worse the symptoms. A subscore for pain and urinary symptoms also can be calculated. The subscore range is 0 to 31, with 0 to 9 indicating mild symptoms, 10 to 18 indicating moderate symptoms, and 19 to 31 indicating severe symptoms. This tool is used for a baseline assessment and then repeated at regular intervals during the course of the patient’s care. This symptom survey is considered a reliable and valid instrument and is commonly used in practice to assess a patient’s response to treatment or disease progression.133,135

Chronic pelvic pain syndrome is associated with a plethora of symptoms, and treatment is directed at specific symptoms.136 As a tool for selecting specific treatments for symptomatic relief, UPOINT is a clinical classification system for a patient’s symptoms. Six symptom domains are used: urinary, psychosocial, organ specific, infection, neurologic/systemic, and tenderness. Based on the symptom classification of a particular patient, specific treatments are indicated.137,138

Four-Glass Versus Two-Glass Method of Specimen Collection

The gold standard classic method for collecting a specimen to diagnose chronic prostatitis is the four-glass specimen collection method.131,132

  • Glass 1 or voided bladder (VB1) specimen (first 10 mL of urine): This represents the urethral specimen.

  • Glass 2 or VB2 specimen (a midstream urine collection): This represents the bladder specimen.

  • Glass 3 or EPS: After 1 to 3 minutes of prostate massage, EPS drips out of the urethra over the next few minutes. This represents the prostate specimen.

  • Glass 4 or VB3 (first 5 to 10 mL of urine after the prostate massage): This sample includes any residual EPS in the urethra. This represents the prostate specimen as well.

Although the four-glass specimen collection method has been considered the standard for diagnosis, it should be noted that the method has not been validated for accuracy.139 The diagnosis of chronic bacterial prostatitis is made when the bacterial culture in EPS or urine specimen after the prostate massage (VB3) has a 10-fold greater bacterial count as compared with the urethral (VB1) and bladder specimens (VB2).

In addition to sending all specimens for bacterial culture, EPS and VB3 are checked for the presence of WBCs. A drop of EPS is applied to a glass side, a cover slip is placed on top, and the specimen is examined under high power on the microscope. VB3 specimens are typically centrifuged for 5 minutes first, and the sediment is examined in a similar fashion. The presence of >5 to 10 WBCs per high power field is considered significant for inflammation. Twenty or more WBCs per high power field or a VB3 with a WBC count of ≥1,000/µL or more is diagnostic of chronic bacterial prostatitis.135,140 Finally, it should be noted that when chronic prostatitis is strongly suspected but EPS cultures are negative, semen specimens have been used as a substitute for EPS. However, semen cultures are only positive in approximately 50% of men with chronic bacterial prostatitis.141,142

Because of the complexity and time-consuming nature of the four-glass specimen collection method, many clinicians use only a two-glass method (which also is known as the Nickel premassage and postmassage test), collecting a VB2 and VB3 specimen premassage and postmassage, respectively. The two-glass method produces results that are comparable to the four-glass method and has a sensitivity and specificity of at least 90% and is 96% to 98% as accurate as the four-glass method.140 A positive test result is indicated by a 10-fold greater bacterial count in the VB3 specimen compared with the VB2 specimen.

SUMMARY

This chapter reviews common clinical tests and laboratory tests used for diagnosing and monitoring treatment for common urologic disorders in elderly men, including late-onset hypogonadism, erectile dysfunction, BPH, prostate cancer, and prostatitis. Many of these disorders are managed with tests other than laboratory tests.

LEARNING POINTS

1. How does a clinician differentiate between serum total testosterone levels and free testosterone levels?

ANSWER: Testosterone circulates in the bloodstream in several forms: free testosterone and testosterone bound to proteins. Most protein-bound testosterone is tightly bound to SHBG and only a small portion is loosely and reversibly bound to albumin, corticosteroid-binding globulin, and orosomucoid. The free testosterone fraction is physiologically active. When a clinician orders a testosterone serum level, the level reflects the total testosterone concentration in the bloodstream, which includes free and protein-bound testosterone. A free testosterone serum level reflects only the unbound portion of testosterone in the bloodstream. A free testosterone level may be measured or calculated. Free testosterone serum levels are indicated in patients in whom the concentration of SHBG is decreased or increased. In such patients, a free testosterone serum level is a better indicator of the concentration of physiologically active testosterone. Increased SHBG is associated with cirrhosis, hyperthyroidism, old age, and drug treatment with estrogens or anticonvulsants. Decreased SHBG is associated with hypothyroidism, obesity, or drug treatment with excessive doses of testosterone supplements.

2. A 60-year-old man reports urinary frequency and nocturia. He wakes up four times every night to urinate. The patient has a slow urinary stream and incomplete bladder emptying. A transrectal ultrasound of the prostate reveals a 30-g prostate with no nodules or induration. The patient’s AUA symptom score is 18. His peak urinary flow rate is 9 mL/sec. How would you assess the severity of this patient’s BPH?

ANSWER: Based on the patient’s AUA symptom score, his voiding symptoms are moderately severe. This is consistent with his reports of urinary frequency and nocturia, slow urinary stream, feeling of incomplete bladder emptying, and urinary flow rate <10 mL/sec.

3. A patient has symptomatic metastatic prostate cancer and is started on androgen-deprivation therapy with leuprolide and bicalutamide. One month after the start of treatment, the patient reports feeling so much better. His bone pain, tiredness, appetite, and urinary difficulty have all improved. He says that he has gained 5 lb since starting treatment. Before the start of treatment, the patient’s PSA was 50 ng/mL. What change in PSA is expected 1 month after the start of treatment?

ANSWER: Effective treatment should result in a return to the normal range (ie, PSA <4 ng/mL) or at least a 2-fold reduction in PSA level (ie, PSA 12.5 ng/mL).

4. A patient with a history of chronic prostatitis and dull rectal pain presents with new-onset dysuria. He has completed a 6-month course of daily therapeutic dosing regimen of trimethoprim-sulfamethoxazole. The results of a four-glass method of specimen collection are as follows:

  • VB1: mixed flora

  • VB2: Streptococcus faecalis 105 colony forming units/mL

  • VB3: no growth

  • VB4: no growth

5. When interpreting the results of the four-glass method of specimen collection, does this patient have recurrence of chronic prostatitis?

ANSWER: The VB2 is a midstream urine collection and shows significant bacterial growth, which suggests that the patient has cystitis. Because the VB3 and VB4, which represent EPS, are negative, chronic prostatitis is ruled out. The VB1 shows mixed flora or contamination of the specimen. No conclusion can be drawn as to whether the patient has urethritis.

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QUICKVIEW | Testosterone

PARAMETER

DESCRIPTION

COMMENTS

Reference range

Adult, men

280–1,100 ng/dL (9.7–38.17 nmol/L)

Normal range exhibits variability among laboratories

Largely due to the immunoassay method, which is commonly used

It is recommended that each laboratory establish its own normal range

Critical values

<200–230 ng/dL (<6.94–7.98 nmol/L) is generally associated with symptomatic hypogonadism

≤50 ng/dL (≤1.74 nmol/L) is associated with surgical or medical castration for prostate cancer

Residual serum testosterone levels reflect continuing adrenal androgen production

Extremely high or low values should be reported quickly

Inherent action?

Yes

Exerts different physiologic effects at different stages of life in men (Table 25-1)

Location

Production

Storage

Secretion/excretion

Testosterone is produced in the testes

It is not stored

Testosterone is activated to DHT intracellularly in some target tissues by 5α-reductase; in adipose tissue, excess testosterone is converted to estrogen

The testes produce 95% of circulating androgen; the rest is produced by the adrenal glands

In some target tissues (eg, brain) testosterone is active; in other target tissues (eg, prostate and scalp) testosterone must be activated to DHT to exert an effect; peripheral conversion of testosterone to estrogen results in gynecomastia

Causes of abnormal values

High

Hyperthyroidism, adrenal tumors, adrenal hyperplasia, testicular tumors, precocious puberty, anabolic steroids, excessive testosterone supplementation

Low

Primary or secondary hypogonadism, late-onset hypogonadism, primary or secondary hypopituitarism, Klinefelter syndrome, orchiectomy, traumatic injury to testicles, mumps, maldescent of testicles, hepatic cirrhosis, prolactinoma, high-dose corticosteroids, LHRH antagonists, LHRH agonists, estrogens, cytotoxins, high dose ketoconazole

Signs and symptoms

High level

Increased libido, mood swings

Low level

Absent or depressed libido, lack of energy, decreased sense of well-being, erectile dysfunction, gynecomastia, small testicles, decreased body hair, decreased muscle strength, visceral obesity, hot flashes

After event, time to…

Initial evaluation

Peak values

Normalization

After orchiectomy, serum testosterone levels decrease to ≤50 ng/dL (≤.74 nmol/L) in several hours

After depot LHRH agonist injection, serum testosterone levels decrease to ≤50 ng/dL (≤1.74 nmol/L) in 2–3 wk

With testosterone supplementation for late-onset hypogonadism, an adequate clinical trial is 3 mo in length

After supplementation is started, serum testosterone should be repeated every 3–4 mo during the first year

A low baseline serum testosterone level should return to the normal range with adequate supplementation

Orchiectomy is indicated for symptomatic management of metastatic prostate cancer

LHRH agonists are alternatives to orchiectomy for symptomatic management of metastatic prostate cancer

Depending on the dosage formulation of testosterone supplement, supraphysiologic serum testosterone concentrations may be produced after administration

This occurs with intramuscular depot injections

In contrast, with other dosage formulations (eg, testosterone transdermal patches or buccal patch systems), only physiologic serum testosterone concentrations are produced after drug administration

The clinical significance of this difference is not known

Causes of spurious results

Excessive testosterone supplementation

Additional information

Testosterone bound to SHBG is inactive; therefore, conditions which significantly alter the concentration of SHBG can increase or decrease the concentration of free testosterone, which is physiologically active (refer to Table 25-2 for a listing of such conditions)

In such patients, a calculated or measured free or bioavailable testosterone level would be preferred over a total serum testosterone level

QUICKVIEW | Prostate-Specific Antigena

PARAMETER

DESCRIPTION

COMMENTS

Reference range

Adult men

<4 ng/mL (<4 mcg/L)

This cutoff value misses 27% of patients with organ-confined prostate cancer; as a result, some experts recommend using age-related normal ranges (Table 25-16), %fPSA, PSA velocity, or PSA doubling time, instead

Critical values

≥10 ng/mL is highly suggestive of prostate cancer

Extremely high values should be reported to the physician quickly

Inherent action?

Yes

Responsible for liquefying semen after ejaculation

Location

Production

Storage

Secretion/excretion

PSA is produced by the prostate

It is not stored

PSA normally passes out of the body in the ejaculate; it liquefies semen

Blood levels of PSA are usually very low; however, in patients with prostate cancer or other diseases of the prostate, the normal prostatic architecture of ducts is not intact

Instead of passing out of the body, PSA enters the bloodstream, which results in elevated blood levels

Causes of abnormal values

High

Prostate cancer

Noncancerous causes of high results include BPH, prostatitis, prostate trauma, prostate surgery, acute urinary retention, ejaculation, exercise bicycling, exogenous testosterone supplements

Low

Low laboratory results are normal

Signs and symptoms

High level

This disease is commonly asymptomatic until the prostate cancer is large enough to cause voiding symptoms, or until the tumor has metastasized; in the latter case, the patient may complain of bone pain, shortness of breath, or leg weakness due to bone, lung, or spinal cord metastases, respectively

Low level

Not applicable

After insult, time to…

Initial evaluation

After prostate manipulation, the PSA levels increase within hours and remain elevated for the duration of the prostatic inflammation; for example, after prostate massage, PSA may return to the normal range within days, whereas after transurethral prostatectomy, it may take weeks

Peak values

No maximum value

Causes of spurious results

As patients age, PSA normally increases BPH and organ-confined prostate cancer show overlap in PSA levels

Refer to Table 25-18 for other conditions that increase or decrease PSA

aPercentage of fPSA, PSA velocity, PSA density, and PSA doubling time are additional types of PSA tests used to improve the usefulness of PSA as a tumor marker for prostate cancer screening and monitor treatment response.