ISSUES OF CONCERN IN MEN
| UROLOGIC DISEASE IN MEN —Jeffrey Waxman, MD, Assistant Professor, Department of Surgery, Division
of Urology, Texas A & M University Health Science Center College of Medicine, Temple, Texas
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| Prostate-specific antigen (PSA): biomarker; good cancer biomarker should have ability to detect disease early,
be inexpensive and noninvasive, and have low false-positive rate (high specificity)
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 | Phases of biomarker development: phase 1—preclinical studies (observe differences between benign and malignant
tissue); phase 2—develop assay for marker (distinguishes between people with and without disease),
then see how early it detects cancer; phase 3—retrospective longitudinal studies; phase 4—measure sensitivity,
specificity, and cost; phase 5—cancer control studies (ability of test to save lives)
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| Problems with current reliance on PSA: has not gone through all 5 developmental phases, and establishment
of “normal” range as 0-4 ng/mL based on clinical finding that very few men with PSA <4 ng/mL have
prostate tumors; may not be appropriate in every case, especially considering patient age; also, now
known that traditional 4 to 6 core biopsies obtained on transrectal ultrasonography often too few to find
cancer; in study of men with normal PSA levels and digital rectal examinations, 7-yr follow-up showed
correlation between high PSA levels (even within normal range) and digital rectal examination and risk
for cancer; suggests need for re-evaluation of PSA test; current cutoff of 4 ng/mL specific but not sensitive
(eliminates many unnecessary biopsies but misses many cancers); lowering cutoff to 2.5 ng/mL detects
more cancers but also means more unnecessary biopsies
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| Need for lowering cutoff level: data from National Prostate Cancer Prevention Trial show that men who started
study with higher (though normal) levels of PSA had 39% risk for cancer 7 yr later; conclusions—risk of
having prostate cancer increases as PSA levels rise; argues for obtaining many core biopsies in patients with
high PSA; no PSA level below which prostate cancer risk disappears; high-grade cancer may occur at any
PSA level; consider using PSA cutoff <4 ng/mL in patients with family history of prostate cancer; when
PSA reaches 3 ng/mL, suggest biopsy or follow patient closely
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| Other conclusions: prostate cancer more prevalent than previously thought; in United States, 92% of men
have PSA <4 ng/mL (suggests many men have undiagnosed prostate cancer, of which 50% high grade);
lifetime risk for prostate cancer diagnosis 17%, but likelihood of dying 3% (suggests overdiagnosis common);
keep medicolegal implications in mind (tell patient no PSA cutoff can rule out cancer absolutely)
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| Complementary medicine for urologic disease: in 1994, sales of dietary supplements reached $9 billion; by
2000, approaching $16 billion
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| Dietary Supplement Health and Education Act: established in 1994; permits general claims about supplements,
eg, “promotes sexual health”; approval of Food and Drug Administration (FDA) not required for supplements;
act places burden on government to prove that product claim false, misleading, or irresponsible; no
quality-control standards established (in one study of ginseng preparations, listed concentration of active ingredient
varied from 15 to 200 times actual concentration in product; in another study, products with 16-dehydroepiandrosterone
actually had 0% to 150% of what label listed; in third study, 9 of 10 products touted to
enhance sexual function had active ingredients in minimal or undetectable concentrations; one product in
which active ingredient measurable had <50% of level advertised); actual effect of supplements impossible
to measure due to lack of standardization
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| Interaction with other medications: Hippocrates software program lists interactions; interaction with surgical
anesthetics of particular concern
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| Placebo effect: contribution impossible to determine
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| Complementary remedies for male health concerns
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| Erectile dysfunction (ED): acupuncture—only data from unpublished pilot study of 10 patients who underwent
acupuncture (5 received ED-specific treatment; other 5 received nonspecific therapy; treatment
lasted 10 wk); patients who did not respond to placebo shifted to other group; 7 patients self-reported
good results (6 declared themselves “cured”); 3 derived no benefit from acupuncture but improved with
sildenafil; results require validation, but acupuncture may prove helpful adjunctive therapy; anabolic
steroids—technically outlawed but still readily available on Internet; in 1998 study involving 30 men
with normal testosterone levels, androstenedione did not increase testosterone or muscle mass, estradiol
and estrone increased, and high-density lipoproteins (HDL) decreased; in another study, 100 mg androstenedione
associated with lower HDL and increased estradiol, compared to placebo, with no change in
sexual function; several randomized trials show direct correlation between steroid dose and blood estradiol
levels, and inverse correlation with HDL, but no improvement in sexual function; exceptions men
with normal levels of testosterone but low levels of dihydroepiandrosterone (DHEA); small trial suggests
DHEA supplementation for 6 mo may improve erectile function, despite no change in other hormone levels;
however, effect on HDL still concern
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| Prostate cancer: green tea—contains polyphenol (30% of leaves’ dry weight) that belongs to class of compounds
called flavonols (catechins; several found in green tea); at least 2 epidemiologic surveys show
lower risk for prostate cancer in regular drinkers of green tea; incidence of prostate cancer very low
among Chinese and Japanese men (risk rises when they adopt Western diet); laboratory studies show
green tea inhibits growth of prostate cancer cells, lowers PSA production, promotes apoptosis, and arrests
cell division cycle; selenium—intake decreased among United Kingdom residents due to less importation
of fortified flour from North America; incidence of prostate cancer rising; in United States, selenium
intake higher, and mortality from some cancers lower; Health Professionals Follow-Up Study (HPFS) associated
high toenail selenium levels (surrogate for long-term selenium consumption) with >60% reduction
in incidence of prostate cancer; supports possible role for selenium, although exact implications unknown
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| Bladder cancer: in United States, almost always linked to smoking; occupational link to certain organic chemicals
also exists; in study of 65 patients with bladder cancer treated with Bacillus Calmette- Guérin (BCG), one
group took recommended daily allowances of vitamins, while second group took those plus megadoses of
vitamins thought to have antioncogenic properties (40,000 U vitamin A; 2000 mg vitamin C; 400 U vitamin
E, and 90 mg zinc); >10- mo use of megavitamins associated with significantly lower rate of bladder cancer
recurrence, compared to patients taking ordinary vitamins (5-yr risk for recurrence 91% among men taking
ordinary vitamins, while those who took megavitamins had <50% of that risk); side effects included mild
nausea (reduced by taking with food); should be recommended routinely to people with bladder cancer
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| Bladder outlet obstruction associated with benign prostatic hyperplasia (BPH): saw palmetto—actual
mechanism of action unknown; most widely quoted study uses European prescription product; compared
to finasteride in 6-mo randomized double-blind study; saw palmetto as effective as finasteride (both associated
with significant improvements over baseline); however, no placebo group included, so unable to
determine role of placebo effect; no double-blind randomized placebo-controlled trial conclusively demonstrates
value of saw palmetto
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| TESTOSTERONE REPLACEMENT THERAPY: ASSESSMENT OF PROSTATE CANCER RISK —
Abraham Morgentaler, MD, Associate Clinical Professor of Urology, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston
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| Issues of concern: many men harbor small cancers in prostate; if testosterone promotes cancer growth, testosterone
replacement therapy (TRT) may hasten tumor growth (castration associated with shrinkage of prostate cancer)
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| Misperceptions: testosterone growth factor for prostate and prostate cancer cells (high doses of testosterone
administered to men with normal levels do not affect prostate volume or PSA level); hypogonadal men experience
only limited increase in PSA levels and prostate volume with TRT); castrated men do not develop
prostate cancer (no data to support this statement); prostate cancer more prevalent among black than white
men because black men have higher serum testosterone levels (serum testosterone higher only up to age 40
yr, and then only because of higher levels of carrier protein [bioavailability same for black and white men])
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| Case reports: one recent study reported on 20 men diagnosed with prostate cancer after TRT (cases found
only after searching 6 urology practices; 6 patients had no baseline PSA or digital rectal examination [may
have had cancer before going on TRT]; number of all men receiving TRT unknown; some diagnoses made
8 yr after patient started TRT); actual connection questionable (TRT risk factor only if cancer rate rises
among men who receive it, compared to those who do not); in review of 7 trials involving testosterone administration
for 6 mo to 3 yr to 400 men, 5 cancers occurred (1% risk), similar to that of general population;
in comparison of hypogonadal symptomatic men with and without prostatic intraepithelial neoplasia (PIN)
treated with testosterone for 1 yr, change in PSA similar in both groups; of 20 men with PIN, one developed
cancer (“certainly not an explosion of cancer due to testosterone therapy”)
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| Association between high testosterone and prostate cancer risk: of 12 prospective longitudinal studies involving
thousands of men, 11 showed no relationship
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| Physician’s Health Study: first obtained blood in 1982; by 1992, 222 participants diagnosed with prostate
cancer, and their testosterone levels compared to those of age-matched controls without cancer; of men
with cancer, mean testosterone 481 ng/dL; mean level in controls 468 ng/dL; relationship between testosterone
level and cancer risk seen only after data adjusted for multiple other variables, including 4 other
hormones; clinical significance, if any, difficult to determine
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| Relationship between low testosterone and prostate cancer risk: speaker and colleagues obtained biopsies from
men with low testosterone and PSA <4 ng/mL; prostate cancer risk 14%; prostate cancer usually develops as
testosterone levels decline with age; no support for belief that TRT or high testosterone level increases prostate
cancer risk
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| Conclusions: beliefs about relationship between prostate cancer risk and TRT historical and based on overly
simplistic model; no evidence of direct dose-response relationship; burden of proof on those who would withhold
useful therapy due to belief it is not safe; “study after study after study has come up with negative results”
on link between elevated testosterone and prostate cancer; perhaps time to rethink bias against TRT
because of supposed risk for prostate cancer; TRT effective treatment for many men
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Educational Objectives
| The goal of this program is to review evidence about the diagnosis and development of prostate cancer and the
role of complementary and alternative medicine in men’s health. After hearing and assimilating this program,
the listener will be able to:
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| 1. Explain why 4 ng/mL is currently considered the upper limit of a normal PSA level.
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| 2. Discuss the argument for lowering the PSA level at which a biopsy is indicated.
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| 3. Name the dietary supplements that may have a demonstrable impact on men’s health.
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| 4. Describe the common misperceptions about testosterone replacement therapy and risk for prostate cancer.
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| 5. Present reasons for reconsidering the practice of withholding testosterone because of fear of increasing prostate
cancer risk.
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Discussed on this Program
Alprostadil (prostaglandin E1 ; PGE1 ) [Caverject, Caverject Impulse, Edex, other trade names]
| BCG, intravesical (Bacillus of Calmette and Guérin) [Pacis, TheraCys, TICE BCG]
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| Dehydroepiandrosterone (DHEA) [Fidelin]
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Finasteride [Propecia, Proscar]
Saw palmetto (Serenoa repens)
Sildenafil citrate [Viagra]
Testosterone (several preparations and trade names)
Suggested Reading
Barqawi A, Crawford ED: Testosterone replacement therapy and the risk of prostate cancer. Is there a link?
Int J Impot Res Nov 10 2005 [Epub ahead of print]; Bhasin S et al: Managing the risks of prostate disease during
testosterone replacement therapy in older men: recommendations for a standardized monitoring plan. J Androl
24: 299, 2003; Bozeman CB et al: Prostate cancer in patients with an abnormal digital rectal examination
and serum prostate-specific antigen less than 4.0 ng/ml. Urology 66: 803, 2005; Chan JM et al: Total and specific
complementary and alternative medicine use in a large cohort of men with prostate cancer. Urology 66:
1223, 2005; Etminan M et al: Intake of selenium in the prevention of prostate cancer: a systematic review and
meta-analysis. Cancer Causes Control 16: 1125, 2005; Gould DC, Kirby RS: Testoterone replacement therapy
for late onset hypogonadism: what is the risk of inducing prostate cancer? Prostate Cancer Prostatic Dis Nov 1,
2005 [Epub ahead of print; Lamm DL et al: Megadose vitamins in bladder cancer: a double-blind clinical trial.
J Urol 151: 21, 1994; Ochiai A et al: Influence of anthropometric measurements, age, and prostate volume on
prostate-specific antigen levels in men with a low risk of prostate cancer. Urology 66: 819, 2005; Rayman MP:
Selenium in cancer prevention: a review of the evidence and mechanism of action. Proc Nutr Soc 64: 527, 2005;
Rhoden EL, Morgentaler A: Risks of testosterone-replacement therapy and recommendations for monitoring.
N Engl J Med 350:482, 2004; Rhoden EL, Morgentaler A: Testosterone replacement therapy in hypogonadal
men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia.
J Urol 170:2348, 2003; Ricke WA et al: Steroid hormones stimulate human prostate cancer progression and
metastasis. Int J Cancer Dec 5, 2005 [Epub ahead of print; Savage P, Waxman J: PSA and prostate cancer diagnosis.
Eur J Cancer 32A:1097, 1996; Welch HG et al: Prostate-specific antigen levels in the United States:
implications of various definitions for abnormal. J Natl Cancer Inst 97: 1132, 2005; Zhu H et al: Biopsy of men
with PSA level of 2.6 to 4.0 ng/mL associated with favorable pathologic features and PSA progression rate: a
preliminary analysis. Urology 66: 547, 2005.
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. Morgentaler is a member of the Speakers’ Bureaus of Solvay and Auxilium
Pharmaceuticals and receives grant support from Auxilium.
Dr. Waxman was recorded at The Adult Patient: Male and Female Issues, held June 20-24, 2005, on South Padre
Island, Texas, and sponsored by the Scott & White Clinic, Temple, Texas. Dr. Morgentaler spoke at Urology
Update 2005, held October 21-22, 2005, in Toronto, Canada, and sponsored by the University of Toronto. The
Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this
program.
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