Review Article

Psychological Effects of Androgen-Deprivation Therapy on Men

With Prostate Cancer and Their Partners
Kristine A. Donovan, PhD1; Lauren M. Walker, PhD2,3; Richard J. Wassersug, PhD4,5; Lora M. A. Thompson, PhD1;
and John W. Robinson, PhD2,3,6

The clinical benefits of androgen-deprivation therapy (ADT) for men with prostate cancer (PC) have been well documented and
include living free from the symptoms of metastases for longer periods and improved quality of life. However, ADT comes with a host
of its own serious side effects. There is considerable evidence of the adverse cardiovascular, metabolic, and musculoskeletal effects
of ADT. Far less has been written about the psychological effects of ADT. This review highlights several adverse psychological effects
of ADT. The authors provide evidence for the effect of ADT on men’s sexual function, their partner, and their sexual relationship. Evi-
dence of increased emotional lability and depressed mood in men who receive ADT is also presented, and the risk of depression in
the patient’s partner is discussed. The evidence for adverse cognitive effects with ADT is still emerging but suggests that ADT is asso-
ciated with impairment in multiple cognitive domains. Finally, the available literature is reviewed on interventions to mitigate the psy-
chological effects of ADT. Across the array of adverse effects, physical exercise appears to have the greatest potential to address the
psychological effects of ADT both in men who are receiving ADT and in their partners. Cancer 2015;121:4286-99. V C 2015 American

Cancer Society.

KEYWORDS: androgen-deprivation therapy, cognition, depression, prostate cancer, sexual function.

INTRODUCTION
Androgen-deprivation therapy (ADT) in the form of surgical castration or, more commonly, medical castration is the
most common form of treatment for metastatic prostate cancer (PC).1-3 The clinical benefits of ADT for men who have
metastatic disease have been well documented and include living free from the symptoms of metastases for longer periods
and improved quality of life.3,4 The use of ADT has increased over time based on clinical trial evidence of improved out-
comes. This is especially true for men with high-risk, localized PC who receive radiotherapy and for those with lymph
node-positive PC who undergo radical prostatectomy.1,5,6 In industrialized nations, 50% of men with PC can anticipate
being prescribed ADT at some point during the course of their disease.2 In North America, ADT is currently prescribed
for more than 600,000 men with PC.7 Furthermore, men are being exposed to ADT for periods as long as 5 to 10 years
compared with a median duration of 2 to 5 years for patients with metastatic disease.8
The objective of ADT for men with PC is to reduce levels of androgens—the hormones responsible for stimulating
PC cell growth. The principal androgen, testosterone, plays a significant role in male morphology and is the primary de-
terminant of men’s sexual behavior, most notably their instinctual sex drive. Testosterone also has been described as a
social hormone.9 Thus, testosterone regulates not only men’s desire for sex but also their tendency toward competiveness,
dominance, reactive aggression, and stoic emotional presentation.10-12 Descriptive studies of men with PC report that
many men feel less energetic and less decisive and are also more emotionally responsive during ADT.13-15
Although ADT is not considered curative, it effectively enables many men with PC to live for years without the
symptoms of metastatic disease. The relative 10-year survival rate for patients with PC at any stage is 99%.16 However,
castrate levels of testosterone and the secondary loss of estrogen (which is normally derived from testosterone in men) are
associated with several significant physical and psychological adverse effects. These include an increased risk of cardiovas-
cular disease as well as increased insulin resistance and incident diabetes, osteoporosis and fractures, anemia, fatigue,

Corresponding author: Kristine A. Donovan, PhD, MBA, H. Lee Moffitt Cancer Center and Research Institute, MRC-SCM, 12902 Magnolia Drive, Tampa, FL 33612;
Fax: (813) 745-3906; kristine.donovan@moffitt.org
1
Supportive Care Medicine Department, Moffitt Cancer Center and Research Institute, Tampa, Florida; 2Department of Psychosocial Resources and Rehabilitation
Oncology, Tom Baker Cancer Center, Calgary, Alberta, Canada; 3Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta,
Canada; 4Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; 5Australian Research Center in Sex, Health, and
Society, La Trobe University, Melbourne, Victoria, Australia; 6Department of Psychology, University of Calgary, Calgary, Alberta, Canada

DOI: 10.1002/cncr.29672, Received: April 20, 2015; Revised: July 24, 2015; Accepted: July 29, 2015, Published online September 15, 2015 in Wiley Online
Library (wileyonlinelibrary.com)

4286 Cancer December 15, 2015


sarcopenic obesity, kidney disease, sexual dysfunction,
breast growth, hot flashes, and affective and cognitive
symptoms.6,17-20 The incidence and severity of these
effects depend largely on the duration of therapy, yet each
is known to adversely affect men’s health and quality of
life.6,21 To date, abundant literature has been published
regarding management of the adverse cardiovascular, met-
abolic, and musculoskeletal effects of ADT in men with
PC (eg, see Isbarn et al,6 Smith,7 Grossman and Zajac21).
However, far less has been published regarding the psy-
chological effects of ADT. The objective of the current
review is to present evidence of the psychological effects of
ADT on men with PC and their partners and to make rec-
ommendations for the management of these effects.
Sexual Function
It has been demonstrated that ADT adversely affects
men’s self-image, sexual desire, erectile function, ability to
become aroused, and ability to achieve orgasm, all of
which may hinder a man’s sexual function and disrupt
sexual relations. Some contexts for the use and administra-
tion of ADT are likely to affect sexual function more than
others. For example, short-term administration of ADT,
in the context of adjuvant external-beam radiation ther-
apy, may only temporarily affect a man’s sexual function.
Men may receive adjuvant ADT in the form of
luteinizing-hormone–releasing hormone (LHRH) ago-
nists for as little as 6 months, although those at high risk
may be placed on an adjuvant LHRH agonist for up to 3
years. Typically, the longer the duration of ADT, the
more adverse may be its effects.21 However, patients who
receive short-term ADT are not spared sexual dysfunc-
tion; sexual function reportedly can be adversely affected
as early as 2 months after initiating ADT.22 Although
sexual function is similar between men who receive com-
bined ADT and external-beam radiation therapy versus
those who receive ADT alone, worse sexual bother has
been reported in the combined treatment group. Fortu-
nately, the shorter the duration of ADT, the more likely it
is that testosterone levels will recover with time.23
There is some evidence to support the intermittent
administration of ADT over continuous administration
when possible, because it may help to alleviate adverse
effects, particularly those regarding libido.24 In this con-
text, patients receive an LHRH agonist for a specific pe-
riod (the duration of this on-treatment period varies25,26)
and then are given a drug holiday (the off-treatment
period). During the off-treatment period, androgen titers
in the body start to recover. For about 70% of men,
recovery of testosterone to 10 ng/mL occurs by 24 months
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Psychological Effects of ADT/Donovan et al
off ADT (median, 10.4 months).13 When prostate-specific
antigen reaches a threshold level (the testosterone level also
may be monitored), the LHRH agonist is reinstated. It is
worth noting that the longer the on-treatment period,
the longer the off-treatment period required for sexual
recovery.13,24,27 For example, Ng et al13 reported that 46%
of men who were receiving ADT for PC were sexually
active at the time ADT was initiated. In that study, the
proportion of sexually active men declined to 24% after 9
months of ADT. After 9 months, ADT was halted, and
half of the men who were sexually active at the time ADT
was initiated resumed sexual activity by 12 months off-
treatment.
In addition, some patients may receive antiandrogen
monotherapy (through the administration of a nonsteroidal
antiandrogen without LHRH agonists). In these patients,
smaller declines in sexual desire and function are
observed.28 ADT is commonly used in the context of bio-
chemical failure (ie, a rising prostate-specific antigen level
after primary curative treatment) or locally advanced
disease.29 Men who have already undergone radical prosta-
tectomy or received radiation therapy probably are experi-
encing some degree of erectile dysfunction (ED) before
they start ADT. Androgen suppression with ADT further
impairs erectile function.30 Thus, the effect of ADT on
men’s sexual function may be additive, based on the
patient’s treatment history.
The proportion of men receiving ADT who remain
sexually active is relatively small. Between 73%31 and
95%32 of men receiving ADT report ED, and the rates of
sexual activity cessation are higher, ranging from 80%31
to 93%.13 It is a challenge to capture accurate rates of sex-
ual activity cessation: the standard measures used to assess
this factor are actually measures that assess erectile func-
tion and frequency of penetrative intercourse rather than
the broader context of sexual activity. Consequently, these
measures miss nonpenetrative sexual activity and may
underestimate the number of men who are sexually active
in ways other than penetrative sex. Between 58%31 and
94%13 of men receiving ADT report a loss of sexual
desire. Some men report reduced sensitivity of the skin to
physical touch or changes in the kinds of touch that
induce arousal.33,34 Although prevalence rates are unavail-
able, many men experience difficulty in becoming suffi-
ciently aroused during sexual activity, such that
anorgasmia, or difficulty achieving orgasm, is also com-
mon. For patients who have not already experienced a loss
of ejaculate because of radical prostatectomy, ejaculatory
volume diminishes with time until orgasms become dry
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Review Article
entirely,33 the impact of which is particularly profound in
the gay community.33,35-37
In the literature, what is becoming increasingly clear
is that a loss of sexual desire does not equate to a loss of in-
terest in maintaining a sexual relationship. There have
been many documented motivators beyond spontaneous
sexual desire for engaging in sexual activity.38 For many
couples adapting to ADT, maintaining a sexual relation-
ship is an important conduit of closeness and connec-
tion39 and helps the couple stave off a shift to a platonic
relationship in which the partners feel more like room-
mates,40 a feeling that may accompany a loss of intimacy
in the relationship overall. Still, the loss of sexual desire is
perhaps the biggest barrier to maintaining sexual activity.
Men with the best of intentions to remain sexually active
for the benefit of their partner struggle to remember to
initiate sexual activity when they are no longer cued by
spontaneous sexual urges.
For the clinician, there is a delicate balance between
offering hope to couples that sex is still possible during
ADT and helping them anticipate the challenges they will
face should they choose to remain sexually active. In con-
trast, well meaning health care professionals, wishing to
prepare a couple, may tell their patients that their sex lives
are over. This view is consistent with the relatively nihilis-
tic representation of androgen-deprived men’s sexual
capacity presented in a recent article by Mazolla and Mul-
hall.41 In the traditional sense, it may be particularly chal-
lenging to maintain penetrative intercourse; however,
consistent with the growing opinion on sexual recovery af-
ter PC, health care professionals should encourage
patients who receive ADT to think more flexibly about
the kinds of activities they include in their sexual reper-
toire.42 Unfortunately, many patients who are told that
maintaining sexual activity during ADT is impossible go
on to fulfill this prophecy and stop being sexual. These
patients (and their partners) may have benefited from
modifying and/or redefining their sexual practices to
maintain satisfying sexual activity.39
Sexuality is greatly influenced by contextual factors,
including how individuals feel about themselves and what
is occurring in the context of their relationships. For
many men, the male body is a strong source of their per-
ceived masculinity, and bodily changes may adversely
affect men’s sexuality.15 Indeed, in a recent study, 60% of
men who received ADT had negative changes in body
image.32 Given the bodily feminization that can occur,
including hot flashes, breast growth, loss of lean muscles
mass, genital shrinkage, and weight gain around the
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hips,43 men receiving ADT commonly report experienc-
ing a loss of masculinity.15
Because those studies have documented changes in
perceived masculinity but have rarely defined or objectively
measured masculinity, it is challenging to draw conclu-
sions about the nature of these changes. Still, men con-
tinue to report a change in the way they perceive
themselves as having experienced a loss of masculinity in
their own right. In 1 study, after only 3 months of ADT,
50% of men reported feeling less masculine compared
with 26% at baseline.13 Furthermore, it has been demon-
strated that the sense of loss in some aspects of masculinity
intensifies as time on ADT increases. In a longitudinal
study, this perceived emasculation increased continuously
over the course of 36 months (most drastically increasing
between 24 and 36 months) and did not exhibit signs of
leveling off.44
A patient’s sense of his masculinity may be impacted
in different ways by ADT. Some patients may conceptual-
ize their masculinity in a more physical sense and, thus,
may be affected more by changes like bodily feminization,
infertility, or loss of muscle mass. For other men, mascu-
linity may be impacted more by social factors, including
changes in relationships and roles, or by psychological fac-
tors, including changes in body image, loss of sexual func-
tion, and emotional lability.
It is important to note that there may be other
potential explanations for changes in a man’s sense of his
own masculinity during ADT. The same study that docu-
mented an increase in loss of masculinity over time44 also
demonstrated that depressive and anxious symptomatol-
ogy was predictive of lower perceived masculinity. In
addition, lowered sexual desire may be symptomatic of
depression,45 which is also strongly associated with ED.46
Pharmacologic therapies for depression, such as the use of
selective serotonin reuptake inhibitors (SSRIs) and
serotonin-norepinephrine reuptake inhibitors (SNRIs),
may also negatively affect sexual function. To the extent
that the erosion of a man’s sense of his manhood may
strain his intimate relationship, this can affect a couple’s
ability and motivation to engage in sexual activity.
Effect on partners
Many couples adjusting to ADT have already had to deal
with the effects of the cancer diagnosis and primary treat-
ments administered with curative intent. For example, in
many relationships, there is a shift in roles at diagnosis
away from husband and wife toward patient and caregiver
roles47 during treatment. However, given the wide rang-
ing effects of ADT, it is not surprising that ADT can
Cancer December 15, 2015

transform intimate relationships in some unique ways.48
Navon and Morag40 were the first to draw attention to the
finding that ADT, because it reduces sexual desire and
erectile function, may erode the spousal relationship and
make the relationship more platonic in nature.40 Indeed,
maintaining intimacy has been documented as the most
difficult challenge of ADT.39
It has been well documented that women who are
partners of men with PC may be more distressed (eg, wor-
ried, depressed, anxious, experiencing cancer-related intru-
sive thoughts) than the men with PC.49-52 Predictors of
greater distress in women who are partners of men with PC
include: 1) greater patient distress; 2) less support from their
partner who is the patient; 3) lower marital quality; 4) low
levels of positive reappraisal coping; 5) searching for, but
not finding, meaning in the illness experience; and 6) uncer-
tainty about the patient’s health.53 Some have suggested
that greater distress may have more to do with the partners
being women than their being partners. This is because
research on couples coping with cancer has indicated that
women are more distressed than men regardless of whether
they are the patient or the partner.54,55 Kornblith et al50
have suggested that female partners are more distressed than
male patients because of a discordance in communication
between the partners. Specifically, the woman may sense a
need to discuss disease-related feelings and concerns,
whereas the patient may want to minimize the effects of his
disease and has minimal desire to openly discuss the changes
he is experiencing. Other research about couples coping
with illness indicates that both partners may suppress emo-
tions, worries, and concerns to protect the other.56,57 Given
the difficulties couples have in effectively communicating
about cancer, there is little wonder that open communica-
tion is associated with better partner adjustment.34 In fact, it
has been demonstrated that improving communication
between patients and their partners is an effective interven-
tion for improving the mental health of women who are
partners of men with PC.58
Finally, findings are mixed with regard to how signifi-
cantly partners of men who receive ADT are affected by the
loss of their sexual relationship. Some reports indicate that
men believe their partners are unaffected by the loss of sex-
uality.56 In support of this are partners who explain that
they can forego sexual activity because they feel it is a small
price to pay for the patient’s potentially life-extending treat-
ment. That said, some partners attempt to accept the loss of
their sexual relationship, only to discover over time that the
loss is more significant than they had anticipated.39 In fact,
1 of the most significant predictors of quality of life for part-
ners after PC treatment is the quality of their sexual relation-
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Psychological Effects of ADT/Donovan et al
ship.59 Little has been written about the partners of gay men
with PC, and even less has been reported about gay men
receiving ADT. One qualitative study of gay patients who
did not receive ADT demonstrated strains and changes in
the romantic relationship for gay men when dealing with
the side effects of the disease.60 Although findings are mixed
about the degree to which partners are affected by the loss of
the sexual relationship, partners suffer most when this loss
leads to emotional withdrawal and loss of affection. In short,
partners appear to adjust more easily to the loss of the sexual
relationship than to feeling abandoned.40
Interventions
Recent studies of sexual bother in men who received ADT
for advanced PC indicated that, contrary to expectations,
greater sexual bother was associated significantly with
greater marital satisfaction (as well as with younger age
and shorter duration of ADT).61,62 Those results suggest
that couples who are bothered by ADT-related changes in
sexual function and are in accord about the problem can
work together to address these changes; and this, in turn,
may increase marital satisfaction. This was borne out in a
recent intervention trial in which couples who partici-
pated in an educational intervention to help them adjust
to changes associated with ADT exhibited less declines in
intimacy and dyadic adjustment than couples in the con-
trol group.63 A similar intervention, founded on the book
Androgen Deprivation Therapy: An Essential Guide for Men
With Prostate Cancer and Their Loved Ones,64 contains a
self-directed program to help patients manage all side
effects associated with ADT, not just sexual changes. This
unique psychoeducational program is currently being dis-
seminated nationally in Canada. To date, it is the only
PC-related intervention targeted specifically at couples
who are dealing with ADT.58 Even if couples elect not to
maintain a sexual relationship, they should be counseled
about ways to maintain good relational intimacy. Efforts
to prevent emotional withdrawal and cessation of general
affection are likely to help couples remain intimately con-
nected, even if sexual activity ceases. Strategies that incor-
porate couple-based coping in PC are promising and
indicate that a similar approach would be valuable in the
ADT population.58,65,66
For men receiving ADT who are interested in treat-
ments that may restore erectile function, typical first-line
treatments like phosphodiesterase inhibitors are probably
insufficient. These medications are often ineffective, espe-
cially if there is nerve damage from primary treatments
like radical prostatectomy or radiation therapy. Therefore,
men receiving ADT may have better success starting with
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Review Article
intracavernous injections rather than phosphodiesterase
inhibitors.42 Patients also must understand that erectile
aids, such as phosphodiesterase inhibitors, intracavernous
injections, and vacuum erection devices, have no direct
effect on libido. Patients should be coached not to wait for
spontaneous sexual desire to initiate sexual activity and
taught that sexual stimulation is needed to facilitate arousal.
Those couples that persist in sexual activity will likely have
to make a conscious choice to engage in sex, because men
can no longer rely on a physiologic urge to motivate them to
be sexual. Although there is some evidence for the use of
parenteral estrogen as a treatment for libido preserva-
tion,43,67 further studies are needed. If erectile aids are not
pursued, then men should be encouraged to maintain a vari-
ety of sexual activities that do not depend on erections.42
Couples who are motivated to maintain a sexual relation-
ship may benefit from learning what other couples have
done to promote recovery; to this end, more details about
couples’ struggles and recovery strategies are provided in the
report by Walker and Robinson.34
There is increasing support for the role of exercise in
promoting sexual activity maintenance. A recent study of
men who were receiving ADT indicated that those who
engaged in a group-based exercise protocol had higher
rates of sexual activity.68 Another study by Ng et al69 dem-
onstrated that men receiving ADT who had greater quad-
ricep strength also were more likely to maintain sexual
activity. Thus, the same efforts to preserve lean muscle
mass may also promote sexuality. Hamilton et al68 have
published qualitative data suggesting that exercise also
may help to mitigate men’s perceived loss of masculinity
associated with ADT.
Emotional Lability
Exaggerated changes in mood, or emotional lability, have
been reported by men who receive ADT for PC.18 This
lability may be manifested differently; some men report
becoming more sensitive or sentimental, whereas others
may become more irritable and angry.14,33,70,71 The most
marked change for some men is the experience of becoming
more spontaneously tearful,14 particularly in situations that
previously would not produce such a response. Some men
find this confusing and difficult to understand, whereas
others may be embarrassed by their increased tearfulness.
This conspicuous increase in emotional expression may
affect patients’ interpersonal interactions, depending on
whether they perceive this as unmanly or shameful, in con-
trast to being indicative of heightened empathy and reflect-
ing improved sensitivity to others. Ultimately, how men
perceive this increase in emotionality and whether or not
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they accept it may influence how well they adapt to ADT
specifically and to PC in general.14,15,72,73
Depression
Testosterone levels decline naturally with age, and low
testosterone has been associated with depression in middle-
aged and older men who do not have cancer.74,75 The
finding that this depression seems to remit when these
patients without cancer are initiated on testosterone-
replacement therapy76,77 suggests that depression in men
who are receiving ADT may be the direct result of androgen
deprivation.78 Similarly, among men who have received
ADT, depression may persist because of persistently low tes-
tosterone levels, even after ADT treatment ends. Indeed, in
many men, post-ADT levels of testosterone do not return to
pre-ADT levels for a very long time, if at all.70,79-81
Rates of depressive symptoms and/or diagnosable
depression in men with PC have been described as rela-
tively high, with estimates ranging from 8% to 25%, and
the rates of depression among men who receive ADT are
even higher.82-85 Despite the well known association
between depression and diminished quality of life in
patients with cancer, including PC,86 there is a paucity of
research examining the relation between ADT and depres-
sion in patients with PC. This is particularly troubling,
because studies have demonstrated the significance of
depression and the risk of suicide in men with PC.87 Rele-
vant to this, in 1 of the larger studies published to date,
DiBlasio and colleagues88 conducted a retrospective
review of nearly 400 patients with PC who received ADT
over several years. Included in that review were men who
had pre-ADT psychiatric illnesses, including depression;
de novo psychiatric illness; and no psychiatric illness. At a
mean follow-up of 87 months, 28% of those men were
diagnosed with de novo psychiatric illness, most com-
monly depression. This was a 3-fold increase from a pre-
ADT rate of 8.6%. The results also suggested that receipt
of primary ADT and the duration of ADT may contribute
to the development of de novo psychiatric illness.
Although limited by its retrospective design, the findings
from the study by DiBlasio et al are intriguing and
strongly support the need for well designed, large-scale,
prospective studies of depressive symptomatology in men
who receive ADT.
Although relatively few in number, there are as many
studies with findings that do not support a link between
ADT and depression as there are studies that do support
such a link.89 This ambiguity may stem in part from meth-
odological shortcomings that limit the interpretation of
findings and the generalizability of results.89,90 The majority
Cancer December 15, 2015

of studies, for example, have been cross-sectional or retro-
spective, not prospective, in design. Most studies have used
self-report measures of depressive symptoms rather than
the gold-standard diagnostic interview for depression.
Furthermore, few have assessed for a history of depression,
which is a known risk factor for subsequent depression,
both in the general population and among patients with
PC, including those who receive ADT.82,84,85 Most studies
have not included a control group. Among those that have,
the choice of an appropriate control group may be debated.
Finally, studies have been characterized by small sample
sizes with limited statistical power to detect between-group
differences.
Most recently, in an effort to address many of these
methodological limitations, Lee et al78 used a longitudinal
design in a sample of men with PC who were receiving
ADT to assess the effects of ADT on depression. Two
control groups were included: men with PC who under-
went radical prostatectomy and men from the general
population. Both groups were matched by age and educa-
tion with the men who were receiving ADT. Men in the
radical prostatectomy cohort also were matched on time
since diagnosis within 6 months. Among men in the ADT
cohort, the rate of clinically significant depressive symp-
toms, measured by the Center for Epidemiologic Studies-
Depression scale (CES-D), increased significantly, and
their testosterone levels dropped dramatically 6 months
after the start of ADT. There was no increase in symptoms
for either control group over time. At the 6-month fol-
low-up assessment, rates of clinically significant depressive
symptoms were notably higher in the ADT group com-
pared with the radical prostatectomy and noncancer con-
trol groups (39% vs 9% vs 11%, respectively). The study
used a self-report assessment of depressive symptoms, not
a diagnostic interview; however, the CES-D contains
fewer somatic symptoms of depression and, thus, may be
less likely to reflect the effects of cancer and cancer treat-
ment. The 6-month follow-up interval was too short to
reveal the long-term effects of ADT, although the study’s
short timeframe was not dissimilar to the timeframe used
in the majority of studies to date. Despite these limita-
tions, findings from the study affirm the correlation
between ADT and depression.
It is possible that factors other than ADT actually
account for the depressive symptoms documented in the
study by Lee et al.78 Depression in men who are receiving
ADT may be secondary to uncontrolled pain or fatigue or
may be the result of functional impairments, such as sex-
ual dysfunction or urinary incontinence after radical pros-
tatectomy.83,91 This depression may reflect a composite
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Psychological Effects of ADT/Donovan et al
of the physical and emotional toll of a cancer diagnosis
that combines with reduced testosterone to induce depres-
sion.79 Finally, a cascade pattern of symptoms may link
ADT to depression. For examples, hot flashes resulting
from ADT may exacerbate sleep problems and may lead
to insomnia,92 which then leads to depression. Similarly,
weight gain, gynecomastia and breast tenderness, loss of
body hair, hot flashes, and/or genital shrinkage may
lead to strongly negative perceptions of body image,18
thus increasing the risk of depressive symptoms in men
receiving ADT.
Effect on partners
Many of the risk factors associated with depression in men
receiving ADT are consistent with the risk factors associated
with depression in men with PC in general.90 Thus, we
know that being married or living in a marriage-like
relationship reduces the risk of depression50,54,91,93 and
that depression impairs relationships.90 Often, a partner
becomes aware of the patient’s depressive symptomatology
before the patient. This awareness may either facilitate early
intervention or create conflict within the couple when there
is disagreement about the severity of the symptoms or how
to cope with them.94 Therefore, effective couple and self-
management strategies are crucial to overcoming the effects
of depression on men and their families.95,96 We also know
that, in PC, as in other cancers, the female partners’ risk for
depression is as high as or higher than the male patients’
risk.51,84,97,98 More research is needed about the impact on
same-sex couples. Although some might argue that the psy-
chological well being of the partner is outside the scope of
standard oncologic practice, recent research suggests that
ignoring the impact of ADT on the partner and the relation-
ship may adversely affect the physical and psychological
health and well being of the patient himself.99,100
Interventions
The complex relation between depression and ADT in men
with PC remains to be fully elucidated. Nevertheless, men
(and their partners) should be informed of the possibility of
ADT-related emotional lability and depression. They
should be encouraged to report any symptoms that arise
and advised of the interventions available to mitigate these
effects. In many men who receive ADT, the symptoms of
depression often are severe enough to warrant clinical inter-
vention. Thus, it is reasonable for all men who receive ADT
to be screened for depression and, if they screen positive,
to more fully assess them and intervene accordingly.101
Antidepressant medications and psychotherapy, especially
cognitive behavior therapy, are widely accepted treatments
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for depression in the general population and in cancer pop-
ulations. Therefore, they are likely to be efficacious for men
on ADT. Antidepressant medications are most effective for
patients who have more severe depression;102 whereas psy-
chotherapy, and cognitive behavior therapy in particular,
has been established as effective across the spectrum from
milder to moderately severe depression.103 Currently, there
are no evidence-based recommendations regarding the su-
periority of any antidepressant over another in patients with
cancer (or in other populations).104 The choice of which
antidepressant medication to prescribe requires the clinician
to consider several factors, including the current symptom
profile, medical comorbidities, potential drug interactions,
and the potential side-effect profile of the medication. SSRIs
and SNRIs may negatively affect sexual function, as noted
above; but some of these medications (eg, venlafaxine) are
also effective in reducing hot flashes. Certain antidepres-
sants, specifically mirtazapine and bupropion, are not typi-
cally associated with sexual dysfunction, and bupropion in
particular may have positive sexual effects.105 In any case,
the effective treatment of depression with SSRIs, SNRIs, or
other agents may actually increase overall sexual function
and/or sexual desire as psychological function and symptom
control improve. This may be especially true when depres-
sion arises, along with pain, fatigue, and sleep disturbance,
from the disease and its treatment.44
To date, there are relatively few psychosocial inter-
ventions for men with PC and their partners. A recent
Cochrane review106 identified 19 studies that compared
psychosocial interventions versus usual care in more than
3200 patients with PC. The interventions included cogni-
tive behavioral, psychoeducational, and supportive thera-
pies. Six of 19 studies included depression as an outcome.
Across studies, there were no significant differences in
self-reported depressive symptomatology between the
intervention groups and usual care at any of the time
points observed. Notably, the specific effect of the psycho-
social interventions on depression in men receiving ADT
was not examined, because there were no data regarding
treatment with ADT that could be extracted from the
studies.
Developing interventions to mitigate the psycho-
logical as well as physical effects of ADT is crucial to
improving the health and well being of men who receive
ADT for PC. To this end, a recent cross-sectional study
indicated that, in men who received ADT for PC, greater
adherence to national exercise guidelines was associated
with lower levels of depression and better quality of
life.107 More recently, a systematic review of exercise
interventions in men who were receiving ADT for PC
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demonstrated that supervised or unsupervised, structured
exercise interventions improved their quality of life.108
Only 1 study examined the benefits of exercise for
depression per se. Culos-Reed et al109 conducted a
randomized controlled trial of a 16-week, unsupervised
exercise intervention, consisting of a moderate-intensity
exercise program 3 to 5 times weekly, compared with a
once-weekly 90-minute group session. Depression scores
on the CES-D decreased in the intervention group and
increased in the control group over time, but the changes
from baseline were not statistically significant. This null
finding, combined with several identified limitations of
the evidence base to date, suggests that more research is
necessary to establish the most effective exercise program
for reducing depression in men who receive ADT.
Cognition
Many neural centers in the brain have both androgen
receptors and estrogen receptors, which are involved in in-
formation storage and learning (eg, the hippocampus) as
well as the consolidation of memory (eg, the amyg-
dala).110 Thus, from a neuroendocrinologic perspective,
ADT may impair memory and other cognitive processes
in men with PC simply because it suppresses the ligands
that bind to those receptors. Indeed, men who receive
ADT commonly complain about lapses in memory and
declines in their problem-solving skills.111 Other cogni-
tive complaints include changes in verbal memory,112,113
spatial memory, and visuospatial processing.114,115
In the last 2 decades, several reviews have refined our
understanding of the impact of ADT on various domains
of cognition.110,116,117 The domains explored to date
include working memory, attention, executive function,
language, verbal memory, visual memory, visuomotor
ability, and visuospatial ability. Whereas some studies
support the adverse effect of ADT on various cognitive
domains, others have failed to document any cognitive
effects of ADT.118-120 Additional studies have reported
mixed results across a wide range of domains,121,122 and
some have even suggested improvement in at least 1 do-
main.123,124 Consider, for example, the effects of ADT on
verbal memory. In the earliest studies,112,113 ADT report-
edly had an adverse effect on the verbal memory domain,
and that result has been widely cited by clinicians.114,115
However, larger and more recent studies failed to obtain
evidence of an association between ADT and verbal mem-
ory impairment.118,122
The diversity in cognitive domains that reportedly
are or are not affected by ADT may be a function of meth-
odological differences between studies. These include
Cancer December 15, 2015

differences in study designs (eg, whether a control group
was included and the nature of this control group), learn-
ing and practice effects in patients who served as their own
controls, sample sizes, and the assessment procedures
used. The diversity in findings also may reflect differences
in the age, education, health status, and baseline cognitive
abilities of participants.116,125 Nevertheless, a review by
Nelson et al116 estimated that between 47% and 69% of
men who receive ADT experience some degree of impair-
ment in at least 1 cognitive domain.
To date, the best controlled studies point to negative
effects of ADT on verbal and spatial memory. These effects
make intuitive sense, in that many studies in other popula-
tions have established that spatial processing is sensitive to
gonadal hormone titers.117,126 Furthermore, a few recent,
small pilot studies using functional magnetic resonance
imaging (fMRI) have endorsed the conclusions drawn
from the most recent reviews. The first, by Cherrier
et al,127 presents preliminary data indicating that ADT
reduces activity in the right parietal-occipital region of the
brain, a region associated with spatial representation of
objects and mental rotation. The other fMRI studies, by
Chao et al,126,128 report changes in the frontal and prefron-
tal cortical areas, which are known to be active in cognitive
control and executive functioning. Those authors point out
that ADT may have adverse effects on cerebral structures
and functions that are not apparent using conventional be-
havioral tests, such as the assessment instruments used in
any number of descriptive neurocognitive studies.
One of the most compelling arguments to date for
the adverse cognitive effects of ADT derives from a recent
and fairly definitive meta-analysis by McGinty et al.129
Those authors included 14 studies that recruited 417
patients who received ADT and concluded that the strong-
est demonstrable cognitive effect was on visuospatial tasks
involving coordinated visual perception and motor skills
(ie, visuomotor ability). That finding may not be surpris-
ing, because differences between the sexes in visuospatial
processing, as assessed by tests of mental rotation (ie, the
participant manipulating the image of an object in their
mind), consistently demonstrate a large effect size (Cohen
d 5 0.57).130,131 Visuospatial ability is also a cognitive do-
main in which testosterone titers in men have been linked
directly to performance superiority.132-135 It is noteworthy
that the findings from the recent meta-analysis are consist-
ent with the review by Jamadar et al117 and the results
from an fMRI study by Cherrier et al.127 In general, how-
ever, it is premature to conclude that visuospatial process-
ing is the only area in which ADT impairs cognitive
function. There may well be other cognitive domains, such
Cancer December 15, 2015
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Psychological Effects of ADT/Donovan et al
as verbal memory and executive function, which involve
cortical areas that are adversely affected by androgen depri-
vation.118,122 In 1 of the more recent studies to date, Yang
et al136 observed that ADT negatively affected attention,
memory, and information processing. Those results, com-
bined with existing studies, suggest defects in verbal mem-
ory and executive function. It is worth noting that
performance in these cognitive domains, as assessed by
Yang et al, was correlated with neural activity in the pre-
frontal areas that were identified by Chao et al126 as altered
by ADT. However, McGinty et al129 pointed out that the
effect sizes for studies of cognitive domains outside of
visuospatial processing were small (all Cohen d < 0.22). In
fact, there simply have not been investigations with large
enough samples and with rigorous enough study designs to
rule out impairment in other cognitive domains.
A yet-to-be-investigated cognitive domain
An area that particularly warrants investigation is the impact
of ADT on social signaling, awareness, sensitivity, and atten-
tion. Testosterone is first and foremost a social hormone, as
noted above (and we are an obligatory social species).9 How
individuals read and react to each other in general—ie, their
tendency toward empathy, egotism, competition, coopera-
tion, dominance, fair play, team play, etc—are known to be
influenced by testosterone11,135,137-141; thus, these social
abilities and interactions typically exhibit measurable sexual
differences.142,143 All of these aspects of neuroprocessing
and behavior fall under the broad area of social cognition.
Although there are various assessment instruments that mea-
sure aspects of social cognition,138,144 we know of no studies
that have used them to advance our understanding of the
impact of ADT on men with PC. We note, however, that
social cognition involves (among other neural centers) the
cortical areas that were identified as affected by ADT in the
fMRI studies by Chao et al.126,128 The absence of research
on this cognitive domain is somewhat surprising given the
burden that ADT often places on partners of men with
PC.50 Often, changes in social cognition materialize for
patients as changes in sociality with which others must deal.
A better understanding of the effect of ADT on social cogni-
tion might raise awareness for the need to assist men with
PC and their partners in adapting to the effects of ADT on
their lives as a couple.
Interventions
There is little doubt that ADT can affect some cognitive
processes in a subset of men with PC, but the effect sizes
are small, and the cognitive domains are not fully defined.
Thus, it is premature to promote interventions for
4293

Review Article
ameliorating the adverse effects of ADT on cognition in
men with PC. However, there are efforts underway to de-
velop cognitive rehabilitation programs for cancer
patients in general,145 and these efforts are likely to
inform efforts specific to ADT-related cognitive concerns.
In the meantime, patients with PC may be able to modify
their lifestyles in advance of starting on ADT to limit sub-
sequent problems in their lives by taking a prehabilitative
or preventative approach.146,147 Consistent with the
research to date, anecdotally, patients with PC often com-
ment on the problems they have with tasks that require
good visuospatial memory and visuomotor ability. Skills
in these areas are what we all use to order and organize
objects in time and space. Thus, men who are starting
ADT may be able to avoid future problems by preemp-
tively reducing clutter in their living space. They may be
able to mitigate some of the cognitive effects of ADT by
thoroughly organizing their desks, closets, drawers, and
storage areas before the side effects of ADT emerge.
The positive physical, psychological, and social ben-
efits of physical exercise and the correlation of these with
improved quality of life for individuals with a variety of
health conditions, including men who are receiving ADT
for PC, have been well documented.148-150 The specific
cognitive benefits of exercise for men receiving ADT are
under investigation.78,151 Whether a prehabilitative exer-
cise program for men who plan to receive ADT for PC
has benefits for cognitive function remains to be deter-
mined.152 Nevertheless, exercise has long been endorsed
as a means of alleviating several ADT side effects, includ-
ing sarcopenic obesity and depression.21,153-155 Further-
more, taking a prehabilitative approach may be especially
beneficial, because it may be particularly challenging to
initiate an exercise program once any of the more com-
mon physiologic side effects of ADT set in.
Another intervention with potentially positive effects
is computerized cognitive training (CCT). In a recent
meta-analysis of 52 studies of CCT encompassing 4885
older adult participants without dementia or other cogni-
tive impairments (who were not receiving ADT), Lampit
et al156 reported statistically positive effects of CCT on
verbal, nonverbal, and working memory. Although the
effect sizes were small (Hedges g < 0.22), the benefits of
CCT were greatest in processing speed (Hedges g 5 0.031)
and visuospatial skills (Hedges g 5 0.30). Visuospatial skills
constitute the cognitive domain in which McGinty and
colleagues’ recent meta-analysis129 identified the strongest
evidence for ADT-related cognitive impairment, as noted
above. This suggests that CCT may have considerable
potential as an intervention for men with ADT-related cog-
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nitive concerns. Lampit et al156 also observed that at-home,
unsupervised CCT programs were not effective, suggesting
that community-based or hospital-based CCT may have
the greatest potential for helping men maintain mental
acuity during ADT. Lampit et al156 further suggested com-
bining CCT with interventions like physical exercise and
memory strategy training to enhance executive function148
and verbal memory, respectively.150
Finally, researchers have suggested that the cognitive
problems associated with ADT may be because of the lack
of estradiol (E2), which is a metabolic product of testoster-
one, and not the lack of testosterone itself.110,134,157 Estro-
gen is well known for alleviating menopausal symptoms in
women, and some have suggested that it may do the same
for androgen-deprived men.67,154,158,159 Many neural cen-
ters in the brain, including those critical to cognitive proc-
esses, have estrogen receptors, as noted above.160-162 This
suggests that supplemental E2 may be of some benefit for
men on ADT.110,163,164 Estrogen taken orally increases the
risk of thromboembolic events and gynecomastia.67,165
However, the risk of thromboembolic events from estrogen
is greatly reduced with parenteral administration.166-168 E2
also promotes cancer cell growth in certain castrate-resistant
PC cell lines,169-171 so it should not be recommended for
patients who have advanced PC. To date, there is evidence
that E2 can help maintain bone mineral density, reduce hot
flashes, and, as previously noted, help preserve libido above
castrate levels in androgen-deprived men.67,154,158,172 It
remains to be determined whether E2 may mitigate the
effects of ADT on cognition in men with PC.111,119
Conclusions
ADT is the most common form of treatment for metastatic
and locally advanced PC. Although ADT is not curative, it
effectively enables many men with PC to live for many
years without the symptoms of metastatic disease. In addi-
tion to multiple adverse physical effects, ADT is associated
with adverse psychological effects. These effects include dif-
ficulties in multiple sexual domains, emotional lability,
depression, and cognitive impairment. The strongest evi-
dence exists for the effects of ADT on men’s sexual function
and the sexual relationship. Less is known about the nature
of the emotional or cognitive changes associated with ADT,
but evidence increasingly suggests that there are ADT-
associated impairments in multiple cognitive domains; and,
although the causal mechanisms for depression are debata-
ble, men on ADT are at increased risk of depression. Part-
ners may also be negatively affected by ADT-related effects.
The clinical implications of the adverse psychologi-
cal effects of ADT include the ethical responsibility of
Cancer December 15, 2015

clinicians who prescribe ADT to obtain informed con-
sent from their patients. Knowledge of how ADT affects
a man psychologically as well as physically may aid
patients in making treatment decisions with their part-
ners. Clinicians should monitor men on ADT for ED
and counsel them regarding reduced libido. Men should
also be monitored for significant depressive symptoms
and cognitive decline. Clinicians should screen for these
effects and offer treatment recommendations or make
referrals as appropriate. Regarding plausible interventions
to mitigate the effects of ADT, physical exercise appears
to have the greatest potential to address the psychological
effects of ADT both in the man with PC and in his part-
ner. The results from this review also highlight the need
for additional research assessing the natural history of
these effects using well designed, prospective studies.
Developing interventions to mitigate the psychological as
well as physical effects of ADT based on results from
such studies will be crucial to improving the health and
well being of men on ADT.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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