SIDE EFFECTS OF ANDROGEN DEPRIVATION THERAPY:

MONITORING AND MINIMIZING TOXICITY

CELESTIA S. HIGANO

ABSTRACT
The current trends in favor of androgen deprivation therapy (ADT) for nonmetastatic prostate cancer at the
stage of biochemical recurrence or increasing prostate-specific antigen (PSA) raises the issue of exposing
otherwise asymptomatic patients to potential side effects over the longer term. Some of these side effects
can have deleterious effects on quality of life, and others may contribute to increased risks for serious health
concerns associated with aging. Sexual side effects are the most well-recognized adverse effects from ADT
and include loss of libido, erectile dysfunction (ED), and hot flashes. Loss of libido is distressing to many men,
and they may not pursue treatments for ED. However, for those who do maintain sexual interest, various
remedies are available. The incidence of hot flashes, which may not abate over the course of ADT, is close
to 80%. Estrogens, progestin megestrol acetate, medroxyprogesterone acetate, venlafaxine, and cyprot-
erone acetate have been shown to alleviate hot flashes and associated symptoms. Physiologic effects,
including gynecomastia, changes in body composition (weight gain, reduced muscle mass, increase in body
fat), and changes in lipids, are less commonly recognized as side effects of ADT. These may lead to an
exacerbation of potentially more serious conditions, such as hypertension, diabetes, and coronary artery
disease. Loss of bone mineral density, anemia, and hair changes also may occur. Additionally, both the
diagnosis of prostate cancer and the hormonal therapy can cause psychological distress. These side
effects need more systematic study in clinical trials. Physicians should be aware of far-reaching conse-
quences of ADT and should incorporate strategies for preventing and managing toxicities into routine
practice. UROLOGY 61 (Suppl 2A): 32–38, 2003. © 2003, Elsevier Science Inc.

U ntil recently, androgen deprivation therapy

(ADT) was reserved for patients with meta-
static prostate cancer. Now, however, asymptom-
atic patients without evidence of metastatic dis-
ease, but with evidence of biochemical recurrence
or an increase in prostate-specific antigen (PSA)
levels only (stage D0), are considered candidates
for ADT. Although a potential survival benefit for
ADT at this stage is still unclear, some studies have
suggested that certain patients treated with neoad-
juvant or adjuvant ADT may benefit in terms of
progression-free survival. However, there are sig-
From the Department of Urology, University of Washington
School of Medicine, University of Washington, Seattle, Washing-
ton, USA.
This supplement is funded by Sanofi-Synthelabo. Dr. Higano is
a study investigator funded by TAP Pharmaceuticals; is a study
investigator funded by, and a board participant for, Novartis
Pharmaceuticals; and was a paid consultant for Atrix Pharma-
ceuticals.
Reprint requests: Celestia S. Higano, MD, University of
Washington, Seattle Cancer Care Alliance, Mail Stop G3-200,
825 Eastlake Avenue, East, Seattle, WA 98109. E-mail: thigano@
uwashington.edu
nificant drawbacks to starting ADT earlier in the
course of the disease in a patient population with a
longer life expectancy. In this group, early initia-
tion of ADT prolongs the period during which the
patient is exposed to long-term androgen suppres-
sion and during which there may be consequences
that affect his quality of life and increase detrimen-
tal effects on health. ADT can be achieved primar-
ily by orchiectomy, or by the administration of lu-
teinizing hormone–releasing hormone (LHRH)
analogs in a variety of delivery vehicles. This article
reviews the side effects of ADT, their impact on
quality of life, and their influence on risks for seri-
ous health concerns. In this context, approaches to
preventing and managing potential long-term con-
sequences of ADT are proposed.
WELL-RECOGNIZED SIDE EFFECTS OF
ANDROGEN DEPRIVATION THERAPY
The most frequently recognized side effects,
common to all methods of ADT, are loss of libido,
erectile dysfunction (ED; formerly referred to as

© 2003, ELSEVIER SCIENCE INC. 0090-4295/03/$30.00

32 ALL RIGHTS RESERVED PII S0090-4295(02)02397-X
impotence), and hot flashes. Specific toxicities can
also result from the antiandrogen component of
combined androgen blockade. These include liver
function abnormalities, diarrhea and other gastro-
intestinal symptoms, pulmonary toxicities, de-
creased light accommodation, alcohol intolerance,
and rash. These toxicities will not be discussed in
this review, but are important to consider because
they are additive with the side effects illustrated in
the following sections.1
SEXUAL SIDE EFFECTS
Although a small fraction of men who have un-
dergone either orchiectomy or LHRH analog ther-
apy preserve their interest in sexual relations,
many complain of loss of libido. Individual differ-
ences that may account for this variation are nu-
merous and are not well understood. They may
include age, physical well-being, pretreatment tes-
tosterone levels, and probably many others. The
maintenance of sexual activity in some patients on
ADT is an indication that libido is not influenced
by testosterone alone.2 Loss of libido causes certain
types of ED, defined as the consistent or recurrent
inability, regardless of cause, to attain or maintain
a penile erection sufficient for sexual intercourse.
Formerly called impotence, this term was replaced
by the 1st International Consultation on Erectile
Dysfunction because of its lack of specificity and
pejorative connotations.3
For those patients who maintain libido, many
treatment options are available for ED. It must be
stressed, however, that these therapies may be of
little benefit for a patient who lacks libido. This
point highlights the lack of understanding of fac-
tors responsible for ED in men receiving ADT and
complicates its management. The most familiar
medical treatment for ED is the oral phosphodies-
terase type 5 inhibitor sildenafil. Local treatments
include intracavernosal injection of alprostadil and
alprostadil intraurethral therapy, use of a vacuum
constriction device, and use of a penile prosthesis.3
Various treatments for ED should be discussed
with the patient.
Loss of penile length or volume, as well as testic-
ular mass, also occurs often during treatment with
ADT (author’s anecdotal clinical experience). Pa-
tients are rarely warned of this possibility. This loss
of mass may be somewhat reversible after with-
drawal of ADT. In severe cases of loss of penile
length, surgical options may be indicated. Penile
fibrosis can also be a long-term consequence of
ADT and lack of sexual activity. It is important to
note that ED is also a frequent, and usually irre-
versible, consequence of prostatectomy or radio-
therapy. However, it has been hypothesized that
maintaining erections during a period of ADT,
even when sexual desire is reduced, may offer fur-
UROLOGY 61 (Supplement 2A), February 2003
ther benefit to patients by increasing oxygenation
of penile tissues and preventing fibrosis.4 When
LHRH agonists or other agents are withdrawn as
part of an intermittent regimen, libido is expected
to return as testosterone levels increase. Thus, us-
ing medical therapy to maintain erections in these
patients may be an important approach to under-
standing quality-of-life implications and should be
evaluated in clinical trials of intermittent ADT.
HOT FLASHES
A hot flash is a sudden rush of warmth in the
face, neck, upper chest, and back, which is some-
times associated with facial flushing and/or nausea,
and which lasts for a few seconds to an hour.
Brought on by stress, heat, or occurring spontane-
ously, hot flashes can be accompanied by profuse
sweating and can interrupt sleep. The true inci-
dence of hot flashes that occur because of ADT is
not well documented or measured. However, a few
studies have attempted to characterize the severity,
duration, and frequency of hot flashes (Table I). 5– 8
However, no validated hot flash severity scale ex-
ists. Nonetheless, when hot flashes are mild, pa-
tients may be aware of the symptoms but can easily
tolerate them. Moderate hot flashes produce dis-
comfort sufficient to interfere with usual activity.
Severe hot flashes are incapacitating, resulting in
the inability to do work or usual activity.9 The in-
cidence of hot flashes in men undergoing ADT has
been estimated at about 55% to 80%. Contrary to
popular belief, hot flashes do not necessarily abate
over the course of therapy.5– 8,10,11
Numerous treatments for hot flashes are avail-
able. Diethylstilbestrol (DES)12 and other estro-
gens11,13 effectively relieve symptoms. However,
DES is no longer manufactured in the United
States, although it is available through compound-
ing pharmacies. The progestin megestrol acetate
also is an effective therapy, decreasing hot flashes
by 85% in a placebo-controlled crossover trial,14 as
is medroxyprogesterone acetate.15 However, even
low-dose megestrol acetate has been associated
with increased PSA levels, a situation that can be
reversed after withdrawal.16 The antidepressant
venlafaxine has been shown to alleviate hot flashes
in men undergoing ADT, simultaneously treating
symptoms of depression.17 Cyproterone acetate
tablets or depot have also been shown to reduce
subjective difficulties related to hot flashes by
⬎80%,18 but this agent is not available in the
United States.
Acupuncture decreased the frequency of hot
flashes by 70% in a small study of 7 patients.19 Soy
and vitamin E therapies are currently being evalu-
ated for their potential to reduce hot flash symp-
toms.20 Although clonidine was initially reported
33
 to be useful for men with hot flashes, a careful

Loosening or changing

wet towels, taking a

clothing or bedding

clothing or bedding
clothing, removing
Actions Required

changing bedding,
toweling off, using
clinical study failed to demonstrate efficacy.21

Fanning, loosening

Changing clothing,

bath or shower,
LESS COMMONLY RECOGNIZED

resting
SIDE EFFECTS OF ANDROGEN
DEPRIVATION THERAPY
None

ADT can impose additional and often unex-

pected physiologic and metabolic side effects in
patients with prostate cancer. Among these are
changes that affect the physique, initiative, or en-
None to very light perspiration

Light to moderate perspiration

nausea, shortness of breath,

ergy level, as well as the emotions and even cogni-

dizziness, nausea, shortness

Heavy perspiration, dizziness,

of breath, weakness, chest

tion in some patients. Physical changes that may be
Physical Symptoms

experienced by the patient include gynecomastia,

Drenching perspiration,

discomfort, extreme
weight gain, loss of muscle mass and strength, and
weakness, extreme

hair changes. Metabolic and physiologic changes

that are associated with ADT include loss of bone
discomfort

discomfort
mineral density,22,23 anemia,24 changes in the lipid
TABLE I. Hot flash severity: description of symptoms

profile,25,26 and some exacerbation of underlying

conditions including hypertension, diabetes, and
perhaps coronary artery disease.22,26

GYNECOMASTIA
As with many other side effects of ADT, gyneco-
Moderate anxiety or

mastia has not been systematically studied in pa-

irritability; loss of

lessness, “totally
irritability, rest-

tients receiving therapy, and the frequency with

out of control”
concentration
Mild anxiety or
Emotion

which this side effect occurs is unclear. In general,

irritability

it appears that combined androgen blockade re-

Anxiety or

sults in a higher incidence of gynecomastia (50%)

than occurs with LHRH analog therapy alone
Rare

(25%) or with orchiectomy (10%).2,27 Because gy-

necomastia occurs more frequently in patients who
are treated with DES or high-dose bicalutamide, it
has been assumed that increases in estradiol levels
unbalanced by testosterone may be responsible, al-
Duration (min)

though other factors that predispose patients to

ⱕ3

ⱕ5

ⱕ10

ⱕ30

this state are not well understood. Gynecomastia

can be associated with breast tenderness or masto-
dynia. Prophylactic radiation therapy has been re-
ported to prevent or minimize gynecomastia28 and
is commonly used before treatment with DES or
high-dose bicalutamide, but is rarely used before
therapy with LHRH inhibitors. However, once gy-
Generalized warmth

necomastia has occurred, radiation is of no benefit.

More warmth and/

“Hotter” or “very

Again, because of a lack of understanding about

Sensation

or a flushed

the mechanisms that result in gynecomastia, it is

or flushing
sensation

“Very hot”

difficult to predict which patients may benefit from

Reprinted with permission from Urol Nurs.5

radiation prophylaxis. Some patients undergo sub-

hot”

cutaneous mastectomy or liposuction to ease the

symptoms of gynecomastia. Tamoxifen, although
not effective in treating prostate cancer, has been
shown in a few cases to alleviate the mastodynia.29
However, there is concern that tamoxifen, an an-
Very severe

tiestrogen, could interfere with the anticancer ef-

Moderate
Severity

fect of the DES or other estrogens. Finally, aro-

Severe

matase inhibitors have recently been used in the

Mild

treatment of prostate cancer and may have utility

34 UROLOGY 61 (Supplement 2A), February 2003

in reducing breast disorders in patients treated
with antiandrogens.30
BODY COMPOSITION AND LIPID CHANGES
Most patients, who are treated with ADT develop
weight gain, or at minimum, increases in body
fat.31 The median increase was 6 kg (range, 3 to 15
kg) in a study using combined androgen blockade1
and 2.3 kg in another study in patients treated with
LHRH agonist alone.32 Increases in body fat stud-
ied in healthy subjects were associated with aug-
mented appetite, increased insulin levels, and ex-
panded abdominal girth.33 In a study among
patients receiving LHRH agonist therapy, weight
remained constant, although fat mass increased
and lean body mass decreased.34 The weight gained
from ADT is not readily lost, even after discontinu-
ing therapy as part of an intermittent regimen.1
A recent report measured body mass, fat distri-
bution, and muscle size in 40 men with locally
advanced, node-positive, or biochemically recur-
rent prostate cancer after 48 weeks on ADT. In 32
evaluable subjects, weight increased by 2.4% ⫾
0.8%, fat body mass increased by 9.4% ⫾ 1.7%, and
lean body mass decreased by 2.7% ⫾ 0.05%.32 In
addition, total cholesterol, high-density lipopro-
tein cholesterol, and low-density lipoprotein cho-
lesterol concentrations increased by 9.0% ⫾ 2.1%,
11.3% ⫾ 2.6%, and 7.3% ⫾ 3.5%, respectively,
with serum triglycerides increasing by 26.5% ⫾
10%. These changes were associated with increases
in insulin levels and an increase in central arterial
pressure, suggesting large artery stiffening and in-
creased risk of developing cardiovascular disease,
as well as potential exacerbation of concomitant
diabetes.22
LOSS OF BONE MINERAL DENSITY
Although patients receiving ADT may not neces-
sarily become osteopenic or osteoporotic, losses in
bone mineral density in these men are comparable
to those in postmenopausal women. The risk of
long-term complications, particularly vertebral
fractures, from bone loss in these patients has not
been adequately addressed and deserves further
scrutiny. Underscoring this point, among men
treated with a combination of leuprolide plus flut-
amide, evaluation of bone mineral density in the
lumbar spine and hip showed losses of 4.7% and
2.7%, respectively, over a 9-month period, com-
pared with the normal losses of between 0.5% and
1% per year in men who did not undergo ADT.22
Bone mineral density should thus be monitored
in patients on ADT with baseline dual-energy
x-ray absorptiometry or quantitative computed
tomography. In addition, patients must be coun-
seled about calcium and vitamin D supplementa-
tion. It is also well known that weight-bearing
UROLOGY 61 (Supplement 2A), February 2003
exercise minimizes bone loss. If patients develop
overt symptoms of osteopenia or osteoporosis, bis-
phosphonate therapy may be beneficial.23 Al-
though bisphosphonate therapy may also prevent
bone loss, prophylactic administration is not rec-
ommended at this time because it is not yet possi-
ble to determine which patients might obtain sig-
nificant benefit from this treatment. In contrast,
patients with bone metastases who have failed
first-line ADT may benefit from administration of
zoledronic acid.35
ANEMIA
Some degree of normochromic, normocytic ane-
mia, temporally related to initiation of therapy, oc-
curs in many patients receiving combined hor-
mone blockade, and severe anemia occurs in 13%
of these patients.24 Anemia can be easily corrected
with recombinant human erythropoietin and is re-
versible after discontinuation of hormonal ther-
apy. Hematocrit usually returns to pretreatment
levels within 3 to 6 months after cessation of ther-
apy. Awareness that ADT can cause anemia is im-
portant, may be anticipated by physicians, and
should minimize undue investigation into other
causes for the anemia.
HAIR
Another physical change that physicians should
discuss with patients is the change in hair that may
be triggered in patients on ADT. The loss of body
hair is surprising and distressing to many patients.
Some patients report increases in scalp hair, as well
as softening of the beard and significant loss of
body hair. Patients may report that they shave less
frequently. As with many other side effects, after
discontinuation of ADT on an intermittent regi-
men, facial and body hair may return to normal
within 3 to 6 months.
MENTAL AND EMOTIONAL HEALTH IN
MEN RECEIVING ANDROGEN
DEPRIVATION THERAPY
The emotional consequences of prostate cancer
and ADT are substantial. Patients may experience
moodiness (shorter fuse), feeling emotional (cry-
ing easily), or depressive symptoms or anxiety.
These adverse effects can affect the patient’s social
interactions and are commonly reported by the pa-
tient’s spouse.1 Antidepressant treatment and
counseling may be appropriate.
Alterations in cognitive function in androgen-
deprived men are currently being studied. Prelim-
inary results of a prospective study in men with
stage D0 prostate cancer treated with intermittent
therapy have revealed a decrease in 1 measure of
spatial ability, but no evidence of significant de-
35
crease in other domains of cognitive function mea-
sured in the study after 9 months of ADT.36 In
another trial, men receiving ADT were evaluated
for attention and memory. Decreases in ⱖ1 cogni-
tive tests after 6 months of therapy were observed
in 24 of 50 men receiving treatment, in comparison
with no decreases in performance tests for those
under observation.37 In geriatric patients, hypo-
gonadal men who are given testosterone demon-
strate improved spatial ability, verbal memory, and
fluency.38
The prevalence of fatigue in men receiving ADT
is also common, but as with other side effects that
are not easily quantified, it has been understudied.
In the past, fatigue and lack of energy in these
patients was attributed to the presence of meta-
static disease and its physiologic consequences.
However, 8 of 58 (14%) patients in a study group
experienced severe fatigue after 3 months of treat-
ment.39 Multivariate analysis revealed that psycho-
logical distress explained only part of the fatigue
experienced by patients. Voluntary muscle func-
tion was decreased, in addition to loss of muscle
mass and sexual potency. In another study, men
who received ADT had a lower overall quality of
life that was associated with more fatigue, loss of
energy, and emotional distress than men who de-
ferred ADT.40
MINIMIZING SIDE EFFECTS
AND PRESERVING QUALITY OF LIFE
IN MEN RECEIVING ANDROGEN
DEPRIVATION THERAPY
The numerous side effects enumerated in this
review should caution physicians that patients
with elevated PSA values as the only indication for
treatment may be exposed to unnecessary and of-
ten serious consequences from this treatment.
Along with the well-recognized aspects of reduced
sexual function and hot flashes, these conse-
quences include more serious metabolic changes
that can lead to bone loss and increases in cardio-
vascular risk, as well as depression/anxiety, fa-
tigue, and cognitive difficulties that seriously affect
quality of life.
Nutritional counseling, with or without pharma-
cologic therapy, as in the general population, may
be considered to minimize the changes in body
composition and lipids that occur as a result of
ADT.26 Statin drugs may also be useful in the treat-
ment of patients who develop dyslipidemias while
undergoing ADT. Nonetheless, it is clear that
changes in body composition may be expected for
most patients. Exercise is an important and inte-
gral component in the prevention of bone loss in
postmenopausal women, and may offer this benefit
to patients treated with ADT as well. The fatigue or
36
lack of energy or initiative that patients often de-
scribe may also be improved with an appropriate
exercise program. Certainly exercise is thought to
alleviate anxiety and depression as well. Extrapo-
lating from evidence gained by studies of women
with breast cancer,41 a home-based walking exer-
cise program is a potentially effective and safe in-
tervention to manage fatigue and to improve qual-
ity of life. The evidence that exercise can improve
many aspects of the lives of patients in general, but
especially in those that are affected by ADT, sug-
gests that all patients treated with ADT should in-
clude an appropriate exercise program, however
limited, in an effort to preempt or curtail many of
the potentially serious consequences of therapy. It
is prudent therefore, before the initiation of ADT,
to offer counseling on diet and exercise to patients
as part of a treatment program and to initiate a
supervised plan as is done for other individuals at
risk for heart disease.
INTERMITTENT THERAPY
Intermittent ADT with an LHRH agonist plus or
minus antiandrogen is an alternative investiga-
tional approach that has been proposed to prevent
progression of prostate cancer and delay develop-
ment of the androgen-independent state. Initial re-
ports support the feasibility of this approach and
the sparing effects on loss of bone and muscle mass
and on a relative improvement in most toxicities
when patients are off therapy.42,43 Large prospec-
tive trials are under way to evaluate the potential of
intermittent ADT to offer a more favorable
adverse-event profile without compromising effi-
cacy.1
CONCLUSION
At present, controversy exists about whether
asymptomatic patients with biochemical recur-
rence of prostate cancer, but without evidence of
metastatic disease, may obtain a survival benefit by
early initiation of ADT. Although no studies have
demonstrated an increase in overall survival, some
have indicated that progression-free survival, as
well as some of the complications of metastatic
disease, may be improved by early treatment. How-
ever, initiation of ADT in men with longer life ex-
pectancy than those with symptomatic metastases
will also place these patients at increased risk of the
long-term effects of hypogonadism. Side effects of
ADT include not only the well-recognized adverse
events, such as diminished libido, ED, and hot
flashes, but also the physiologic and metabolic
consequences (gynecomastia, bone loss, anemia,
and changes in body composition) that may previ-
ously have been attributed to metastatic disease.
Furthermore, ADT is associated with depression,
UROLOGY 61 (Supplement 2A), February 2003
anxiety, fatigue, and even, perhaps, cognitive func-
tion, all of which unquestionably affect the pa-
tient’s quality of life. The true incidence of these
adverse events is not generally understood or ap-
preciated by physicians or patients and requires
more systematic study in clinical trials. Many of
the side effects of ADT are reversible and may dis-
sipate on withdrawal of ADT administered in an
intermittent regimen. However, investigations of
other strategies to manage the toxicities of hor-
mone suppression are warranted. Finally, because
many of the metabolic and physiologic changes
may predispose patients to a higher risk of cardio-
vascular disease and osteopenia, physicians should
proactively recommend a program of diet and ex-
ercise that is intended to minimize or prevent the
development of serious consequences from long-
term ADT. Such a program is expected to have an
added global benefit in reducing fatigue and de-
pression and improving quality of life.
REFERENCES
1. Higano CS, Ellis W, Russell K, et al: Intermittent andro-
gen suppression with leuprolide and flutamide for prostate
cancer: a pilot study. Urology 48: 800 –804, 1996.
2. Potosky AL, Knopf K, Clegg LX, et al: Quality-of-life
outcomes after primary androgen deprivation therapy: results
from the Prostate Cancer Outcomes Study. J Clin Oncol 19:
3750 –3757, 2001.
3. Recommendations of the 1st International Consulta-
tion on Erectile Dysfunction, in Jardin A (Ed), Erectile Dys-
function. Plymouth, UK, Health Publications, Ltd, 2000, pp
711–726.
4. Zippe CD, Raina R, Thukral M, et al: Management of
erectile dysfunction following radical prostatectomy. Curr
Urol Rep 2: 495–503, 2001.
5. Quella S, Loprinzi CL, and Dose AM: A qualitative ap-
proach to defining “hot flashes” in men. Urol Nurs 14: 155–
158, 1994.
6. Smith JA Jr: A prospective comparison of treatments for
symptomatic hot flushes following endocrine therapy for car-
cinoma of the prostate. J Urol 152: 132–134, 1994.
7. Karling P, Hammar M, and Varenhorst E: Prevalence
and duration of hot flushes after surgical or medical castration
in men with prostatic carcinoma. J Urol 152: 1170 –1173,
1994.
8. McCallum KA, and Reading C: Hot flushes are induced
by thermogenic stimuli. Br J Urol 64: 507–510, 1989.
9. Walsh PC, and Farrar J: The Prostate: A Guide for Men
and Women Who Love Them. New York, Warner Books, 1997.
10. Schow DA, Renfer LG, Rozanski TA, et al: Prevalence of
hot flushes during and after neoadjuvant hormonal therapy
for localized prostate cancer. South Med J 91: 855–857, 1998.
11. Spetz A-C, Hammar M, Lindberg B, et al, the Scandina-
vian Prostatic Cancer Group-5 Trial: Prospective evaluation of
hot flashes during treatment with parenteral estrogen or com-
plete androgen ablation for metastatic carcinoma of the pros-
tate. J Urol 166: 517–520, 2001.
12. Atala A, Amin M, and Harty JI: Diethylstilbestrol in
treatment of postorchiectomy vasomotor symptoms and its
relationship with serum follicle-stimulating hormone, lutein-
izing hormone, and testosterone. Urology 39: 108 –110, 1992.
13. Gerber GS, Zagaja GP, Ray PS, et al: Transdermal estro-
gen in the treatment of hot flushes in men with prostate can-
cer. Urology 55: 97–101, 2000.
UROLOGY 61 (Supplement 2A), February 2003
14. Loprinzi CL, Michalak JC, Quella SK, et al: Megestrol
acetate for the prevention of hot flashes. N Engl J Med 331:
347–352, 1994.
15. Charig CR, and Rundle JS: Flushing. Long-term side
effect of orchiectomy in treatment of prostatic carcinoma.
Urology 33: 175–178, 1989.
16. Sartor O, and Eastham JA: Progressive prostate cancer
associated with use of megestrol acetate administered for con-
trol of hot flashes. South Med J 92: 415–416, 1999.
17. Quella SK, Loprinzi CL, Sloan J, et al: Pilot evaluation of
venlafaxine for the treatment of hot flashes in men undergoing
androgen ablation therapy for prostate cancer. J Urol 162:
98 –102, 1999.
18. Cervenákov I, Kopecný M, Jancár M, et al: “Hot flush,”
an unpleasant symptom accompanying antiandrogen therapy
of prostatic cancer and its treatment by cyproterone acetate.
Int Urol Nephrol 32: 77–79, 2000.
19. Hammar M, Frisk J, Grimås Ö, et al: Acupuncture treat-
ment of vasomotor symptoms in men with prostatic carci-
noma: a pilot study. J Urol 161: 853–856, 1999.
20. Moyad MA: Complementary/alternative therapies for
reducing hot flashes in prostate cancer patients: reevaluating
the existing indirect data from studies of breast cancer and
postmenopausal women. Urology 59(4 suppl 1): 20 –33, 2002.
21. Loprinzi CL, Goldberg RM, O’Fallon JR, et al: Trans-
dermal clonidine for ameliorating post-orchiectomy hot
flashes. J Urol 151: 634 –636, 1994.
22. Higano CS, Stephens CNP, Fearne V, et al: Prospective
serial measurements of bone mineral density (BMD) in pros-
tate cancer patients without bone metastases treated with in-
termittent androgen suppression (IAS). Presented at the 35th
Annual Meeting of the American Society of Clinical Oncology
(ASCO); Atlanta, GA; May 15–18, 1999. Abstract 1207.
23. Smith MR, McGovern FJ, Zietman AL, et al: Pami-
dronate to prevent bone loss during androgen-deprivation
therapy for prostate cancer. N Engl J Med 345: 948 –955,
2001.
24. Strum SB, McDermed JE, Scholz MC, et al: Anaemia
associated with androgen deprivation in patients with prostate
cancer receiving combined hormone blockade. Br J Urol 79:
933–941, 1997.
25. Cutter CB: Compounded percutaneous testosterone
gel: use and effects in hypogonadal men. J Am Board Fam Pract
14: 22–32, 2001.
26. Whitsel EA, Boyko EJ, Matsumoto AM, et al: Intramus-
cular testosterone esters and plasma lipids in hypogonadal
men: a meta-analysis. Am J Med 111: 261–269, 2001.
27. Kolvenbag GJ, Iversen P, and Newling DW: Antiandro-
gen monotherapy: a new form of treatment for patients with
prostate cancer. Urology 58(suppl 2A): 16 –23, 2001.
28. Payne H, Tyrrell C, Tammela T, et al: Prophylactic
breast irradiation significantly reduces the incidence of bica-
lutamide (‘Casodex’)-induced gynecomastia. Int J Radiat On-
col Biol Phys 54(suppl): 135–136, 2002.
29. Serels S, and Melman A: Tamoxifen as treatment for
gynecomastia and mastodynia resulting from hormonal depri-
vation. J Urol 159: 1309, 1998.
30. Auclerc G, Antoine EC, Cajfinger F, et al: Management
of advanced prostate cancer. Oncologist 5: 36 –44, 2000.
31. Tayek JA, Heber D, Byerley LO, et al: Nutritional and
metabolic effects of gonadotropin-releasing hormone agonist
treatment for prostate cancer. Metabolism 39: 1314 –1319,
1990.
32. Smith MR, Finkelstein JS, McGovern FJ, et al: Changes
in body composition during androgen deprivation therapy for
prostate cancer. J Clin Endocrinol Metab 87: 599 –603, 2002.
33. Seidell JC, Bjorntorp P, Sjostrom L, et al: Visceral fat
accumulation in men is positively associated with insulin, glu-
37
cose, and C-peptide levels, but negatively with testosterone
levels. Metabolism 39: 897–901, 1990.
34. Smith JC, Bennett S, Evans LM, et al: The effects of
induced hypogonadism on arterial stiffness, body composi-
tion, and metabolic parameters in males with prostate cancer.
J Clin Endocrinol Metab 86: 4261–4267, 2001.
35. Saad F, Gleason DM, Murray R, et al: A randomized,
placebo-controlled trial of zoledronic acid in patients with
hormone-refractory metastatic prostate carcinoma. J Natl
Cancer Inst 94: 1458 –1468, 2002.
36. Rose A, Cherrier M, Ahlgren A, et al: The effects of
intermittent androgen suppression (IAS) on cognitive func-
tion (CF) in patients with biochemical relapse of prostate can-
cer. Proc Am Soc Clin Oncol 21: 163b, 2002. Abstract 2470.
37. Green HJ, Pakenham KI, Headley BC, et al: Altered cog-
nitive function in men treated for prostate cancer with lutein-
izing hormone-releasing hormone analogues and cyproterone
acetate: a randomized controlled trial. BJU Int 90: 427–432,
2002.
38
38. Tan RS: Andropause and testosterone supplementation
for cognitive loss. J Androl 23: 45–46, 2002.
39. Stone P, Hardy J, Huddart R, et al: Fatigue in patients
with prostate cancer receiving hormone therapy. Eur J Cancer
36: 1134 –1141, 2000.
40. Herr HW, and O’Sullivan M: Quality of life of asymp-
tomatic men with nonmetastatic prostate cancer on androgen
deprivation therapy. J Urol 163: 1743–1746, 2000.
41. Mock V, Pickett M, Ropka ME, et al: Fatigue and quality
of life outcomes of exercise during cancer treatment. Cancer
Pract 9: 119 –127, 2001.
42. Bruchovsky N, Klotz LH, Sadar M, et al: Intermittent
androgen suppression for prostate cancer: Canadian Prospec-
tive Trial and related observations. Mol Urol 4: 191–199,
2000.
43. Goldenberg SL, Bruchovsky N, Gleave ME, et al: Inter-
mittent androgen suppression in the treatment of prostate
cancer: a preliminary report. Urology 45: 839 –844, 1995.
UROLOGY 61 (Supplement 2A), February 2003