HYPOGONADISM AND TESTOSTERONE REPLACEMENT/BENIGN PROSTATIC
HYPERPLASIA
| HYPOGONADISM AND TESTOSTERONE REPLACEMEMNT IN OLDER MEN —Thomas M. Mulligan, MD, Ruth
S. Jewett Professor of Medicine, and Chief, Division of Geriatrics, University of Florida, College of Medicine, Gainesville
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| Serum testosterone and aging: study—homogeneous population of men (healthy monks; all vegetarian; same sleep
schedules), 26 to 82 yr of age; blood sampled 5 times during 24-hr period; mean level of serum testosterone, 659 ng/dL in
younger group, 490 ng/dL in older group (450 ng/dL considered lower limit of normal); Massachusetts Male Aging
Study—population-based study of almost 1200 men, 40 to 70 yr of age; subjects followed for 7 to 10 yr; 2 blood samples
taken (in morning, 30 min apart); mean level of serum testosterone in older men (≥63 yr of age) ≈450 ng/dL at baseline;
level decreased below lower limit of normal by end of study (≈385 ng/dL); total testosterone levels peak at ≈30 yr of age,
then decline 2% to 3% per year; prevalence of low serum testosterone—47% of veterans ≥65 yr of age presenting to primary
care clinic had serum testosterone levels <300 ng/dL; 82% had levels <450 ng/dL; another study found 38% of men
\>45 yr of age (in primary care setting) had low levels of total serum testosterone
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| Circadian rhythm: in healthy young men, total serum testosterone peaks at ≈8:00 AM , lowest at ≈8:00 PM ; circadian
rhythm in older men generally much flatter (except “master athletes”); ultradian rhythm—blood samples taken every 2.5
min in healthy young men reveal sawtooth pattern of total serum testosterone; pulse of testosterone released approximately
every 90 min; flatter pattern in older men indicates fewer and smaller secretory events, with less testosterone released;
hourly secretion decreases by ≈50% in older men (≈60 yr of age); sleep quality—testosterone production directly
related to rapid eye movement (REM) sleep; disrupting REM disrupts secretion of testosterone; improving sleep in older
men may improve testosterone levels (unstudied); luteinizing hormone (LH)—sawtooth pattern in young men (pulse every
90 min); older men have frequent low-amplitude release of LH into blood (chronic stimulation of receptors down-
regulates production of testosterone, similar to effect of leuprolide [eg, Lupron]); conclusion—age-associated hypogonadism
likely due to acceleration of gonadotropin-releasing hormone (GnRH) and LH secretory pulse rates and deceleration
of testosterone secretory pulse rate
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| Bone mineral density (BMD): blood samples taken and dual energy x-ray absorptiometry (DEXA) performed in 49
healthy, community-dwelling men; multivariate analysis showed ≈15% of variation in BMD explained by variation in serum
total testosterone; hip fracture—study found men sustaining hip fractures (subjects not taking medication that affects
BMD) had lower levels of free testosterone, compared to controls; another study showed men with low serum testosterone
have 9-fold increased risk for minimal-trauma hip fracture
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| Libido: treatment with oral testosterone for 1 mo increased frequency of sexual thoughts and arousal in hypogonadal men;
effect dose dependent
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| Spatial cognition: randomized controlled study of 56 healthy older men given 3 times normal replacement dose of testosterone,
found small but statistically significant increase in spatial cognition; findings confirmed by additional study
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| Coronary artery disease (CAD): faulty notion that testosterone negatively impacts CAD based on sudden death in
athletes who had taken 15 times usual replacement dose; angina study—62 older men with confirmed CAD (medications
discontinued, except sublingual nitroglycerin); ≈90% of men receiving placebo described no effect; almost 80% of
men receiving testosterone noted efficacy of treatment; however, perceived efficacy possibly due to increase in pain
threshold; exercise study—randomized controlled study using standard replacement doses of transdermal testosterone (5
mg, q24h for 12 wk) looked at time to ST segment depression during exercise challenge (treadmill); small training effect
seen in placebo group; statistically significant increase in time to ST depression seen in men receiving testosterone;
conclusion—significant, objective improvement in coronary performance with testosterone replacement therapy
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| Muscle strength: 32 older hypogonadal men given placebo or standard replacement dose of testosterone (200 mg, intramuscularly
every 2 wk for 12 mo); no improvement in grip strength in placebo group; grip strength in treatment group increased
by 4 kg within 3 mo (sustained throughout study); rehabilitation outcomes—small study of men undergoing
inpatient rehabilitation found improved physical performance (assessed by functional independence measure [FIM]) in
men receiving testosterone replacement therapy
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| Testosterone supplementation: not recommended for all men with low serum testosterone; risks—acceleration of occult
prostate cancer; worsening of benign prostatic hyperplasia (BPH); questionable effect in men with congestive heart
failure; ≈10% incidence of gynecomastia and ≈3% incidence of sleep apnea; 10% incidence of acute hepatitis with oral
therapy; contraindications—prostate cancer; breast cancer; polycythemia (hematocrit \>55%); BPH with incipient retention;
treatment options—weekly injections (eg, 75 mg Delatestryl); transdermal patch (eg, Androderm); transdermal gel
(eg, AndroGel, Testim); buccal system (Striant)
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 | Future medical treatments: dihydrotestosterone (DHT)—not metabolized to estradiol, so no risk for gynecomastia or
stimulation of prostate; selective androgen-receptor modulators (SARMs)—do not stimulate prostate
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| Practice guidelines: before treating—perform digital rectal examination (DRE); check levels of prostate-specific antigen
(PSA), hemoglobin, and testosterone; follow-up—check PSA, hemoglobin, and testosterone every 6 mo; decrease dose if
hematocrit \>55% (increased risk for stroke); discontinue if PSA \>4 ng/dL, PSA doubles, or cancer suspected
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| BENIGN PROSTATIC HYPERPLASIA: EFFECTIVE AND APPROPRIATE EVALUATION —Christopher J. Kane,
MD, Associate Professor of Urology, University of California, San Francisco, School of Medicine
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| Benign prostatic hyperplasia: histologic diagnosis; stromal and epithelial cell hyperplasia begins in periurethral
zone; 50% of men 60 yr of age and 90% of men 80 yr of age have microscopic BPH; BPH often results in lower urinary
tract symptoms (LUTS); moderate or severe LUTS occur in ≈50% of patients with microscopic disease, but LUTS not
specific to BPH
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| Evaluation: history—focus on urinary tract, surgical history, and conditions that contribute to polyuria and bladder dysfunction;
recommend voiding diary; physical examination—DRE; focused neurologic examination; mental status; ambulatory
status; neuromuscular function of lower extremities (largely observational); sphincter tone
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| Urinalysis: required to rule out bladder cancer, carcinoma in situ (CIS), urinary tract infection (UTI), strictures, and ureteral
and bladder stones
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| PSA assay: offered to men with life expectancy ≥10 yr, when results would affect management decisions; not screening
test in this population; useful when making decisions about medical therapy (PSA level roughly correlates with prostate
volume)
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| Cytology: appropriate for men with predominantly irritative symptoms and history of smoking, but urinalysis picks up
most cases of CIS and bladder cancer
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| Serum creatinine: routine testing no longer recommended by American Urological Association (AUA); renal insufficiency
reported in <1% of patients with LUTS due to BPH (and 1.8% of men with moderate-to-severe BPH); measurement
appropriate in men with history or findings suggestive of renal disease or urinary retention
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| Symptom index: AUA recommends International Prostate Symptom Score (IPSS) with quality-of-life questionnaires included
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| Flow rate: testing not strongly recommended (may help in patients with complex medical histories); LUTS in patients
with normal flow rates usually not caused by BPH; Qmax <10 mL/sec likely caused by urodynamic obstruction (indication
for surgery); flow rate does not predict response to medical therapy or watchful waiting
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| Urine retention: large postvoid residual (PVR) may indicate bladder dysfunction; patients with large PVRs may respond
poorly to therapy; presence of residual urine may predict failure of watchful waiting; high test/retest variability; PVR
≤300 mL not correlated with response to medical therapy; many patients with residual urine do not have renal insufficiency,
infection, or severe symptoms; no level of residual urine mandates invasive therapy
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| Cystoscopy: useful when considering invasive therapy; mandatory in patients with hematuria or abnormal cytology
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| Urodynamics: expensive; generally reserved as diagnostic tool for complex cases; useful for patients who fail surgical intervention
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| AUA practice guidelines: initial evaluation—history and physical examination; urinalysis; PSA measurement in selected
patients; serum creatinine not recommended for most patients; severe symptoms or complications—surgery considered;
minor symptoms—watchful waiting appropriate in men with AUA symptom score <7; intermediate
symptoms—additional tests (eg, PVR) may help; medical therapy generally preferred; ultrasonography of prostate appropriate
for patients who opt for invasive therapy (if prostate enlarged); flow studies and cystoscopy sometimes appropriate
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| Saw palmetto: most common agent prescribed in Europe for LUTS due to BPH; most common herbal supplement in
men \>50 yr of age in United States; review of 14 placebo-controlled trials—2 of 4 trials report improvement in symptom
score; 6 of 10 trials report improvement in flow rates; problems include small sample sizes, short duration, lack of
standardized scoring for symptoms, and no assessment of blinding (critical in BPH studies)
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| Study: 225 men randomized to placebo or saw palmetto; 97% of subjects completed study, medication adherence rate of
92%; symptoms—saw palmetto and placebo both associated with significant improvement in symptoms (≈3 points; 2-
point improvement considered clinically significant); peak flow rate—improved to similar degree in patients from
both groups; conclusion—no evidence of benefit or harm; results need further exploration
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| alpha1 blockade: nonselective—phenoxybenzamine (rarely used); short-acting selective—prazosin (more adverse effects
than long-acting formulations); long-acting selective—terazosin (Hytrin), doxazosin (Cardura), and alfuszosin;
similarly safe and effective; terazosin and doxazosin inexpensive and preferred in managed care, require titration (3-7
days at each dose); higher doses improve efficacy but increase adverse effects; maximum dose of terazosin, 10 mg; maximum
dose of doxazosin, 16 mg; adverse effects include first-dose syncope (caution in older patients); alfuzosin does not
require titration; long-acting selective alpha1a -blocker—tamsulosin (Flomax); once-daily dosing; nighttime dosing reduces
risk for postural hypotension, as does taking medication 30 min after meal
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| 5alpha-reductase inhibition: finasteride (Proscar)—inhibits type II 5α-reductase; reduces serum and intraprostatic
DHT; increases serum testosterone by 10% to 20% (remains in physiologic range); does not stimulate androgen receptors;
dosed once daily (5 mg); shown to reduce risk for prostate cancer by 24% over 4 yr (Prostate Cancer Prevention
Trial); dutasteride—competitive nonselective inhibitor of types I and II 5α-reductase; once-daily dosing (0.5 mg); efficacy
similar to finasteride
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| Medical Therapy of Prostatic Symptoms (MTOPS) Trial: multicenter clinical trial sponsored by National Institutes
of Health (NIH); \>3000 men randomized to α-blocker (doxazosin), 5α-reductase inhibitor (finasteride), combination
therapy, or placebo; average follow-up 4.5 yr; multiple primary outcomes identified patients who improved with
treatment but failed due to symptom exacerbation or progression of BPH (complications)
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| Results: treatment failure rates—20% of patients receiving placebo progressed to primary endpoints; fewer patients in
treatment arms failed therapy; best outcomes with combination therapy; symptom scores—finasteride associated with
some improvement; more improvement seen with doxazosin; combination yielded best results (α-blocker primarily responsible
for benefit); incidence of invasive therapy—risk decreased with finasteride and combination therapy but not
with doxazosin; urinary retention—α-blocker associated with 30% reduction in risk; finasteride alone and in combination
further reduced risk (ie, majority of risk reduction credited to 5α-reductase inhibition); adverse events—risk increases
with combination therapy; asthenia, headache, and postural hypotension associated with doxazosin; abnormal
ejaculation and impotence associated with finasteride
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| Conclusion: although risk for adverse events increases, combination therapy appears beneficial in men with enlarged
prostates
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| Indications for surgery: acute urinary retention; recurrent UTIs; recurrent gross hematuria; recurrent bladder calculi;
obstructive uropathy; \>80% of men who undergo surgery choose intervention because of urinary symptoms, not complications;
options—open prostatectomy (men with large prostates); transurethral resection of prostate (TURP); transurethral
incision of prostate (TUIP); transurethral electrovaporization (TEVP); laser treatment (holmium: yttrium aluminum
garnet [Ho:YAG] and potassium titanyl phosphate [KTP]); microwave therapies; radiofrequency transurethral needle ablation
(RFA); chemical ablation
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Educational Objectives
| The goal of this program is to educate the listener about testosterone replacement therapy and the evaluation and treatment
of men with benign prostatic hyperplasia (BPH). After hearing and assimilating this program, the clinician will be better
able to:
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| 1. Explain the pathophysiology of hypogonadism in the aging man.
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| 2. List the risks and benefits of testosterone replacement therapy in older men.
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| 3. Assess the severity of lower urinary tract symptoms (LUTS) in men with BPH.
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| 4. Discuss the use of saw palmetto in the treatment of men with LUTS suggestive of BPH.
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| 5. Compare the pharmacologic options for treating men with BPH.
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Suggested Reading
Beckman TJ, Mynderse LA: Evaluation and medical management of benign prostatic hyperplasia. Mayo Clin Proc
80:1356, 2005; Bhasin S, et al: Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies
for chronic illness an aging. Nat Clin Pract Endocrinol Metab 2:146, 2006; Frye SV: Discovery and clinical development
of dutasteride, a potent dual 5alpha-reductase inhibitor. Curr Top Med Chem 6:405, 2006; Gould DC, et al:
Prostate-specific antigen testing in hypogonadism: implications for the safety of testosterone-replacement therapy. BJU Int
98:1, 2006; Gupta N, et al: Comparison of standard transurethral resection, transurethral vapour resection and holmium
laser enucleation of the prostate for managing benign prostatic hyperplasia of \>40 g. BJU Int 97:85, 2006; Kaplan SA:
Medical therapy for benign prostatic hyperplasia: new terminology, new concepts, better choices. Rev Urol 8:14, 2006; Liu
PY, et al: Does individual response to androgen replacement therapy affect bone density? Nat Clin Pract Endocrinol
Metab 2:76, 2006; MacDonald R, Wilt TJ: Alfuszosin for treatment of lower urinary tract symptoms compatible with
benign prostatic hyperplasia: a systematic review of efficacy and adverse effects. Urology 66:780, 2005; Nair KS, et al:
DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 355:1647, 2006; Sandhu JS,
Vaughan ED Jr: Combination therapy for the pharmacological management of benign prostatic hyperplasia: rationale
and treatment options. Drugs Aging 22:901, 2005; Schopp LH, et al: Testosterone levels among men with spinal cord
injury admitted to inpatient rehabilitation. Am J Phys Med Rehabil 85:678, 2006; Suzuki H, et al: Clinical impact of
tamsulosin on generic and symptom-specific quality of life for benign prostatic hyperplasia patients: using international
prostate symptom score and Rand Medical Outcomes Study 36-item health survey. Int J Urol 13:1202, 2006; The Practice
Committee of the American Society for Reproductive Medicine: Treatment of androgen deficiency in the aging male. Fertil
Steril 86:S236, 2006; Vesely S, et al: TURP and low-energy TUMT treatment in men with LUTS suggestive of bladder
outlet obstruction selected by means of pressure-flow studies: 8-year follow-up. Neurourol Urodyn 25:770, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Mulligan is an investigator for Solvay Pharmaceuticals; Dr. Kane is on the Speakers’ Bureau for Merck and
Boehringer-Ingleheim.
Dr. Mulligan was recorded in Orlando, FL at the 9th Annual Geriatric Medicine for the Primary Care Physician Summer
Conference, held August 3-5, 2006, and sponsored by Orlando Regional Healthcare System; Dr. Kane was recorded
in San Francisco, CA, at An Evidence-Based Approach to Common Problems in Urology, held February 3-4, 2006, and
sponsored by the Department of Urology, University of California, San Francisco, School of Medicine. The Audio-
Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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