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Complications of Androgen Deprivation Therapy: Prevention and Treatment

Complications of Androgen Deprivation Therapy: Prevention and Treatment

ABSTRACT: Androgen deprivation, as a form of treatment for prostate cancer, has been used for decades. Within the last decade, however, its use has increased significantly. Therefore, it is incumbent upon the physician to be familiar with the side effects associated with this treatment. Some of these side effects (eg, osteoporosis, changes in lipid profiles, and anemia) may be associated with significant morbidity, whereas others (eg, impotence, decreased libido, fatigue, and hot flashes) primarily affect the patient’s quality of life. Prevention strategies and treatments exist for many of these side effects. In addition, alternative forms of antiandrogen therapy such as intermittent hormone ablation and antiandrogen monotherapy may be effective, with the added benefit of minimizing side effects. This review focuses on the wide range of side effects associated with androgen ablation as well as preventive and treatment strategies.

Androgen deprivation as a form
of treatment for prostate cancer
was first discovered by
Huggins and Hodges in 1941; in 1966,
this important discovery earned
Huggins the Nobel Prize in medicine.[
1] Androgen deprivation was
initially achieved via orchiectomy,
then later by using estrogen. However,
patient acceptance of orchiectomy was
poor, and problems with thromboembolic
and cardiovascular events were
associated with the early use of estrogen.
Fortunately, in the mid-1980s the
approval of lutenizing hormone-releasing
hormone (LHRH) agonists by
the US Food and Drug Administration
(FDA) provided many prostate cancer
patients with an alternative method for
achieving androgen deprivation. In
addition, researchers developed antiandrogen
medications that block the
androgen receptor. These medications
have given rise to a multimillion dollar
industry for the pharmaceutical
companies; according to conservative
estimates, approximately $230 million
per year is spent on LHRH agonists.[2]

Initially, the role of androgen deprivation
was relegated to patients who
had disease that was not curable by local measures such as radical prostatectomy
or radiation, and to those
who were not candidates for definitive
local therapy due to other health
problems. More recently, however,
emerging data have suggested a progression
and survival benefit with early
hormone therapy in patients with
metastatic prostate cancer.[3] Other
data have shown an improvement in
outcome after radiotherapy for higherstage
tumors in patients who received
concomitant hormone therapy.[4]
Studies are now being conducted to
determine whether the early use of
hormone therapy for biochemical recurrence
alone is advantageous.

With these expanding indications,
androgen deprivation therapy (ADT)
is being used more commonly in men
with prostate cancer. Indeed, a recent
report by Cooperberg et al documented
the dramatic rise in the use of ADT
from 1989 to 2001.[5] Most dramatic
was its increased use in combination
with external-beam radiotherapy, with
rates rising from 9.8% to 74.6% of
such patients.[5]

One common misconception about
hormone therapy was that because it
was not "chemotherapy" in the traditional
sense, it did not produce as
many side effects as other chemotherapeutic
agents. Recent reports have begun to describe the comprehensive
list of side effects associated
with ADT. In this review, we describe
the various side effects of ADT as
well as some of the treatments for
those side effects.

Osteoporosis

Osteoporosis after menopause has
long been recognized as a serious
health problem in women, and the
controversy about hormone replacement
therapy after menopause continues
to be debated. However,
osteoporosis in men has not received
similar attention. At present, 33% of
all hip fractures occur in men, and
interestingly, men are more likely to
die from complications due to hip fracture
than women.[6] Recently, the
attention given to "andropause" (the decline in testosterone seen in many
aging males) has heightened the
awareness of many physicians to the
possibility of osteoporosis and its complications
in men. This has led to an
increased concern about the osteoporosis
seen in men on ADT among
physicians who treat men with prostate
cancer.

Despite the fact that androgen deprivation
has been used to treat prostate
cancer since the 1940s, it was not
until 1989 that Stepan et al first reported
the association between androgen
deprivation and osteoporosis.[7]
This study demonstrated that there
was progressive loss of bone mineral
content in the lumbar spine of men
who had undergone orchiectomy as
compared to eugonadal men. Osteoporosis
as a complication of androgen
deprivation is now well
recognized, and a recent report demonstrated
a 2.5 times increased risk
of bone fracture in men who had undergone
orchiectomy as compared to
community fracture rates.[8] Strikingly,
the cumulative incidence of
fractures in patients followed for up
to 10 years was 65%.

Bone Mineral Content/Density
Evidence shows that LHRH agonist
therapy results in significant
changes in both bone mineral density
and bone mineral content.[9] Stoch et
al evaluated 60 men with prostate cancer.
Of this group, 19 received LHRH
agonist therapy, and 41 did not. Bone
mineral density was measured by dualenergy
x-ray absorptiometry, and bone
mineral content, by markers of bone
turnover such as urinary N-telopeptide,
bone-specific alkaline phosphatase,
and osteocalcin. The results
revealed a statistically significant decrease
in bone mineral density among
patients on LHRH agonists compared
to those who did not receive hormonal
therapy. In addition, bone turnover
was significantly increased in the
LHRH agonist therapy group. These
results confirm that the osteoporosis
seen in these patients is due to the
androgen deprivation itself rather than
the prostate cancer, and that LHRH
agonist therapy results in changes in
bone similar to those associated with
orchiectomy.

Etiology Theories
The etiology of osteoporosis due
to ADT is currently not well understood.
It appears that the condition is
caused by the absence of circulating
testosterone. Support for this theory
comes from data showing that patients
on nonsteroidal antiandrogen monotherapy
had lower levels of urinary
N-telopeptide and serum osteocalcin
than men treated with LHRH agonists.[
10] Androgens have been shown
to mediate osteoblast proliferation and
differentiation and increase bone matrix
production and osteocalcin secretion.[
11] In addition, testosterone has
been shown to stimulate growth factors
such as transforming growth factor-
beta and insulin-like growth
factor-1, which may be important in
osteoblast proliferation.[11]

Data suggest, however, that what
is truly important is the peripheral
conversion of testosterone to estrogen
and the positive effects of estrogen
on bones. This theory is supported
by a case report from Smith et al, who
described a male patient with significant
osteoporosis despite normal testosterone
levels but a mutation in the
estrogen-receptor gene.[12]

Estradiol levels have been shown
to be significantly reduced in men
receiving LHRH agonist therapy,
lending further support to the importance
of estrogen in preventing osteoporosis.[
13] Scherr et al further
confirmed the significant role of estrogen
in preventing osteoporosis by
demonstrating that men on LHRH agonists
who also received 1 mg/d of
diethylstilbestrol (Stilphostrol) had
decreased bone turnover, as measured
by urinary N-telopeptide levels.[14]

Prevention of Osteoporosis
Intermittent androgen therapy has
been evaluated as a possible means of
preventing osteoporosis. In a study
by Higano et al, the effects of intermittent
androgen ablation on bone
mineral density, as measured by dualenergy
x-ray absorptiometry, were
examined.[15] Patients were treated
for 9 months with LHRH agonist therapy
and then followed off therapy.
Androgen deprivation was reinitiated
when prostate-specific antigen (PSA)
levels began to rise. Bone mineral density was measured at the end of each
treatment cycle and was found to be
significantly decreased, suggesting
that measurable changes in bone density
occur after as little as 9 months of
androgen deprivation. At 1 year, the
loss of bone mineral density is approximately
3% to 5%, with less bone
loss over subsequent years.[16]

Because osteoporosis is a well-recognized
adverse effect of ADT, measures
to prevent its development
should be discussed with the patient
at the initiation of ADT. Many of these
preventive measures are the same as
those recommended to postmenopausal
women, including smoking
cessation, moderation of alcohol and
caffeine consumption, vitamin D and
calcium supplementation, and regular
weight-bearing or resistance exercise.
Seeman et al demonstrated that
smoking and excessive alcohol consumption
were independent risk factors
for osteoporosis in men, thus
underscoring the need for these modifications
in lifestyle.[17] Interestingly,
obesity had a protective effect,
presumably due to the increased peripheral
conversion of testosterone to
estrogen. Some reports have shown a
significant deficiency in vitamin D
and calcium among men with prostate
cancer.[18,19] Therefore, current
recommendations are to maintain calcium
intake at 1,200 to 1,500 mg/d
and to supplement vitamin D with
400 IU/d.[18,19]

  • Bisphosphonates-More effective
    medical options for the prevention
    and treatment of osteoporosis are
    now available, and bisphosphonates
    constitute one such option. These
    agents inhibit osteoclasts, thereby
    decreasing the resorption of bone.
    Currently, alendronate (Fosamax), pamidronate
    (Aredia), and zoledronic
    acid (Zometa) are the three bisphosphonates
    used in clinical practice.
    Alendronate recently became the first
    agent to be approved by the FDA for
    the treatment of male osteoporosis
    and offers the advantage of oral
    administration.

    One of the first studies to address
    the use of bisphosphonates for the
    prevention of osteoporosis in prostate
    cancer patients was conducted by Orwoll et al.[20] In this study, a mean
    increase in the bone mineral density
    of the lumbar spine and femoral neck
    was observed among those receiving
    alendronate.[20] However, none of the
    study participants was receiving ADT,
    and thus the efficacy of this drug in
    preventing or improving osteoporosis
    in men on ADT is unknown. Patients
    who are to be started on alendronate
    should be informed that the medication
    must be taken on an empty stomach
    with the patient sitting in an
    upright position for at least 30 minutes.
    Moreover, there is a risk of gastrointestinal
    side effects such as
    epigastric pain, severe esophagitis, and
    gastroesophageal ulceration.[21]

    Pamidronate and zoledronic acid
    are currently only available in an intravenous
    formulation. In a study by
    Smith et al, 47 men with prostate cancer
    and no evidence of bone metastases
    were randomized to receive either
    LHRH agonist therapy alone or LHRH
    agonist therapy plus pamidronate.[18]
    Patients who received 60 mg of IV
    pamidronate every 12 weeks did not
    show a loss in bone mineral density,
    in contrast to those who did not receive
    pamidronate.

    Zoledronic acid is the most potent
    of the three bisphosphonates, demonstrating
    up to 850 times the potency
    of pamidronate in animal studies.
    At a dose of 4 mg IV every 3 weeks,
    it has been shown to decrease skeletal-
    related events (including fractures)
    in men with hormone-refractory prostate
    cancer and bone metastases.[22]
    It has also demonstrated efficacy in
    decreasing pain due to bone metastases
    and their complications.[22] A
    recently reported prospective randomized
    controlled trial of zoledronic acid
    at 4 mg IV was shown to prevent
    bone loss in men on LHRH agonists
    for nonmetastatic prostate cancer.[23]
    Therefore, in those men with evidence
    of osteoporosis on dual-energy x-ray
    absorptiometry scan, zoledronic acid
    may improve bone mineral density.

    Side effects of bisphosphonates include
    fever, anemia, constipation, hypophosphatemia,
    and reactions at the
    injection site.[24,25] Decreased renal
    function manifested by elevated creatinine
    levels was observed in initial
    trials of zoledronic acid.[25] This effect appears to be associated only with
    the 8-mg dose, shorter infusion times,
    and smaller infusion volumes, although
    most physicians continue to
    monitor creatinine levels in patients
    receiving zoledronic acid on any
    schedule.

Screening Considerations
No standardized recommendations
for osteoporosis screening in men exist.
In addition, no clear definition of
osteoporosis in men has been described,
as men have higher peak bone
mass and larger bones than women.[
26] Risk factors such as activity
level, patient age, tobacco use, alcohol
consumption, and the presence of
hypogonadism should be considered
when deciding when to screen men
for osteoporosis. Given the data from
Higano et al, which suggest that bone
mineral density can be decreased after
as few as 9 months of therapy, a
dual-energy x-ray absorptiometry scan
within the first year is probably
indicated.

Although no trials have addressed
the benefit of screening for osteoporosis
in men on ADT, Ross et al
recommended a dual-energy x-ray absorptiometry
scan at the initiation of
ADT and at 1 year posttherapy.[16]
Further screening is based on the results
of previous scans, with more frequent
evaluation recommended for
those nearing osteoporosis.

Hot Flashes

When counseling a man about
ADT, we may look to the patient's
female partner to confirm the side
effects of the therapy. In particular,
postmenopausal women can often accurately
portray one of the more common
side effects-hot flashes. Up to
80% of patients on LHRH agonists
will experience hot flashes.[27,28]
The degree to which these hot flashes
disrupt their lives varies, but up to
27% of those surveyed in one study
found this side effect to be the most
bothersome of all.[28-30]

Hot flashes are typically described
as an intense sensation of warmth in
the face and upper portion of the body.
They may be associated with nausea
and sweating and may even occur during
sleep. They vary in duration from
several seconds to up to 1 hour but
most commonly occur for less than
5 minutes. Triggers for hot flashes
include heat, stress, changes in body
position, or ingestion of hot liquids,
although many patients cannot identify
any inciting factors.[31] Hot
flashes may spontaneously resolve,
but many patients continue to experience
them as long as they are receiving
ADT.

Hot flashes are thought to result
from an alteration in the feedback
mechanism to the hypothalamus due
to the lack of testosterone. An increase
in catecholamine secretion in
response to decreased endogenous
peptide secretion stimulates the nearby
thermoregulatory center of the
hypothalamus, resulting in the perception
of increased heat.[31,32]

Treatment
Many of the treatments employed
for hot flashes in men on ADT are
similar to those used to treat postmenopausal
women. They include
progestins, estrogen, phenobarbital,
megestrol acetate, antidepressants,
clonidine, acupuncture, soy, and
vitamin E.[33-40]

  • Diethylstilbestrol-An estrogen,
    diethylstilbestrol has been used successfully
    to treat hot flashes in men
    on ADT.[31,33] Doses as low as
    0.3 mg have been shown to be effective
    and have not been associated with
    the cardiovascular complications seen
    with the higher doses of diethylstilbestrol
    used in the past.[33] The advantages
    of this therapy are its low
    cost and the prevention of osteoporosis;
    drawbacks are the potential side
    effect of tender gynecomastia and difficulty
    in obtaining the medication.
    Currently, only approximately 15
    pharmacies in the United States carry
    diethylstilbestrol. However, most
    pharmacies that do compounding can
    produce it at little cost.
  • Megestrol Acetate-This progestin
    is a commonly used medication
    that has been shown to reduce hot
    flashes by up to 85%.[41] The side
    effects of megestrol can include chills,
    weight gain, and carpal tunnel-type
    pain, although most patients tolerate
    the medication with few such problems.[
    41] One concern associated with
    its use for hot flashes in men on ADT
    came from a case report by Sartor et
    al, which showed an increase in PSA
    level among patients on megestrol.[
    40] However, to our knowledge,
    this is the only published report of
    such an occurrence.
  • Cyproterone Acetate-This synthetic
    derivative of hydroxyprogesterone
    is a steroidal antiandrogen that
    has been used in Europe (it is not an
    approved medication in the United
    States) as monotherapy for prostate
    cancer.[42] It has been shown to produce
    fewer side effects in terms of hot
    flashes, but its efficacy as monotherapy
    is dubious. Furthermore, it does
    not appear to decrease the incidence
    of osteoporosis and is associated with adverse effects on lipid profiles and
    increased cardiovascular risk.[42]

    Cervenakov et al reported the use
    of cyproterone to relieve hot flashes
    in men on complete androgen blockade.[
    43] In this study, 50 mg of cyproterone
    twice daily or a 300-mg
    intramuscular depot injection given
    every 2 weeks was effective in decreasing
    hot flashes in approximately
    80.6% of the patients studied.

  • Medroxyprogesterone Acetate-
    Another progestin, medroxyprogesterone
    acetate (Depo-Provera), has
    been reported to be effective in relieving
    the hot flashes associated with
    ADT. Ellsworth et al demonstrated
    an 82% complete response rate and a
    12% partial response rate, with only
    6% of patients reporting no response.[
    35] Patients were treated with
    a 400-mg intramuscular depot injection
    at the time ADT therapy was initiated.
    Interestingly, several patients
    who stopped therapy due to the resolution
    of hot flashes had no recurrence
    of symptoms. The medication
    was well tolerated, with side effects
    mainly limited to sexual dysfunction.
  • Other Agents-Clonidine was
    initially thought to have some efficacy
    in the treatment of hot flashes.
    However, more rigorous placebocontrolled
    studies have failed to
    demonstrate the efficacy of this
    medication.[44]

    Other centrally acting agents such
    as the antidepressants have been reported
    to decrease the incidence of
    hot flashes.[45,46] In particular, the
    serotonin-reuptake inhibitor venlafaxine
    hydrochloride (Effexor) has demonstrated
    efficacy in treating hot
    flashes associated with ADT. In placebo-
    controlled studies, this drug was
    shown to decrease the incidence of
    hot flashes by up to 50%. Breast cancer
    patients received doses of 75 mg;
    however, lower doses of 12.5 mg have
    been reported to be effective in
    men.[45-47] Side effects include dry
    mouth and constipation, but overall,
    the medication is well tolerated. In
    addition, venlafaxine offers the added
    benefit of treating depression,
    which is commonly present in cancer
    patients.

Complementary and
Alternative Treatments

The fastest growing segment of the
health-care market in recent years has
been complementary and alternative
medicine. Prostate cancer management
is certainly affected by such
treatments, and some of these methods
have been used to treat the side
effects associated with ADT. Acupuncture
is one such therapy, and its
efficacy was examined by Hammar et
al.[36] In this study of seven men,
acupuncture was performed twice
weekly for 2 weeks, then once a week
for 10 weeks. All patients reported a
decrease in hot flashes, with an average
decrease of 70% after 10 weeks.

  • Soy Products-The use of soy
    products for the treatment of hot flashes
    in both men and women has grown
    in popularity, even achieving commercial
    success among postmenopausal
    women. The basis for this
    success is hypothesized to be soy's
    phytoestrogenic properties. Two components
    of soy-genistein and diadzein-
    are believed to be particularly
    responsible for decreasing hot flashes,[
    38] but the substance may also
    provide benefits such as reducing cholesterol
    and modestly reducing PSA
    levels. The source from which soy is
    obtained is important when recommending
    this form of treatment to patients.
    Foodstuffs such as soy milk,
    and some soy powders do not result
    in large amounts of bioavailable soy,
    and soy sauce has essentially no bioavailable
    soy. Soybeans are typically
    the best source of soy and can often
    be found in the frozen food section of
    most grocery stores.
  • Vitamin E-Vitamin E has also
    been shown to be effective in reducing
    hot flashes. Barton et al conducted
    a placebo-controlled study of
    vitamin E in women with breast cancer
    who were suffering from hot flashes
    and found that their symptoms
    decreased by 30%.[39] However, up
    to 22% of patients in the placebo group
    also experienced a decrease in
    symptoms.

    Given recent attention to the beneficial
    effects of vitamin E and soy in
    prostate cancer patients, there is probably little downside to using these
    therapies with or without other treatments
    for hot flashes. Many of these
    therapies tend to be initiated by the
    patient, but when initiated by the physician,
    patient acceptance is typically
    very good.

Anemia

Fatigue is a common complaint of
patients on ADT. Often, no objective
cause for the fatigue can be determined,
but anemia is one side effect
that may contribute to the problem.
The anemia seen in patients on ADT
is usually normocytic and normochromic.
The condition is thought to be
due to the lack of testosterone and
5-beta-dihydrotestosterone stimulation
of erythroid precursors as
well as a decrease in erythropoietin
production.[48]

Strum et al examined the incidence
and severity of anemia in patients on
complete androgen blockade.[48] In
this study, the investigators found that
up to 90% of patients experienced at
least a 10% decline in hemoglobin
levels, and in 13%, hemoglobin declined
by 25% or more. Importantly,
a decrease in hemoglobin was noted
as quickly as 1 month after the initiation
of ADT, but the nadir hemoglobin
level was not reached until after
5.6 months of therapy.

Symptoms directly related to anemia
occurred in 13% of patients. Anemia
was worse in patients on complete
androgen blockade than in those on
LHRH agonist therapy alone, and
when an antiandrogen was added to
the regimen of a patient on LHRH
agonist therapy, a further drop in hemoglobin
was seen. No statistically
significant difference was seen in
terms of percent decrease based on
patient age; however, because older
patients tended to have lower baseline
hemoglobin levels, the change in
hemoglobin may be more significant
in these patients.

The authors found that typically
the anemia was easily corrected with
the subcutaneous administration of
recombinant human erythropoietin.
Previous reports suggested that the
anemia seen with ADT reversed fairly
rapidly with the discontinuation of therapy. In this study, however, resolution
of anemia in patients receiving
long-term ADT often took more than
1 year. Antiandrogen monotherapy
also appears to be associated with anemia,
although the mechanism of this
effect is not clear. Strum et al recommended
following hemoglobin levels
every 2 to 3 months in patients on
ADT, and more closely in those who
complain of anemia-related symptoms
such as chest pain, shortness of breath
with exertion, or syncope.[48]

Changes in Body Mass
and Lipid Profiles

Patients often complain of weight
gain during ADT. The etiology of this
effect may be related to several factors,
such as an increase in sedentary
activity secondary to fatigue, a change
in appetite, or the decrease in serum
testosterone levels. Serum testosterone
concentrations have been shown
to correlate positively with increased
muscle mass and negatively with increased
body fat.[49]

Higano et al examined the effect
of combined androgen blockade on
weight, and found a median increase
of 6 kg (~13 lb).[50] In a study by
Smith et al, weight and body mass
index were increased by 2.4% after
only 48 weeks of therapy.[51] Strikingly,
this increase in weight appeared
to be due to an 11% increase in fat
body mass, whereas lean body mass
decreased by 2.4%. Because this study
was performed in patients with no
evidence of metastatic prostate
cancer, the changes in body composition
are attributed to the effects
of ADT. Also documented in this
study was a 9% increase in total cholesterol
and a 26.5 % increase in serum
triglycerides. Although no link
has been documented between an increase
in cardiovascular complications
and ADT (other than with high
doses of diethylstilbestrol), the change
in body composition and lipid profiles
is worrisome and deserves further
study.

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