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Cognitive Impacts of Estrogen Treatment in Androgen-Deprived Males: What Needs to be Resolved

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Background: Many prostate cancer (PCa) patients are on androgen deprivation therapy (ADT) as part of their cancer treatments but ADT may cause cognitive impairments. ADT depletes men of both androgen and estrogen. Whether estradiol supplementation can improve cognitive impairments in patients on ADT is understudied. Objective: To summarize data on the effects of estradiol treatment on cognitive function of androgen-deprived genetic male populations (PCa patients and male-to-female transsexuals) and castrated male animals. Method: Publications were identified by a literature search on PubMed and Google Scholar. Results: While some studies showed that estradiol improves cognitive function (most notably, spatial ability) for castrated rats, what remain uninvestigated are: 1) whether estradiol can improve cognition after long-term androgen deprivation, 2) how estradiol affects memory retention, and 3) how early vs. delayed estradiol treatment after castration influence cognition. For androgen-deprived genetic males, estradiol treatment may improve some cognitive functions (e.g., verbal and visual memory), but the findings are not consistent due to large variability in the study design between studies. Conclusion: Future studies are required to determine what the best estradiol treatment protocol is to maximize cognitive benefits for androgen-deprived genetic males. Tests that assess comparable cognitive domains in human and rodents are needed. What particularly under-investigated is how the effects of estradiol on cognitive ability intersect with other parameters; sleep, depression and physical fatigue. Such studies have clinical implications to improving the quality of life for both PCa patients on ADT as well as for male-to-female transsexuals.
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Cognitive Impacts of Estrogen Treatment in Androgen-Deprived Males:
What Needs to be Resolved
Erik Wibowo*
Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada
Abstract: Background: Many prostate cancer (PCa) patients are on androgen deprivation therapy
(ADT) as part of their cancer treatments but ADT may lead to cognitiv e impairments. ADT depletes
men of both androgen and estrogen. Whether estradiol supplementation can improve cognitive
impairments in patients on ADT is understudied.
Objective: To summarize data on the effects of estradiol treatment on cognitive function of
androgen-deprived genetic male populations (PCa patients and male-to-female transsexuals) and
castrated male animals.
Method: Publications were iden tified by a literature search on PubMed and Google S cholar.
Results: While some studies showed that estradiol improves cognitive function (most notably,
spatial ability) for castrated rats, what remains uninvestigated are: 1) whether estradiol can improve
cognition after long-term androgen deprivation, 2) how estradiol affects memory retention, and 3)
how early vs. delayed estradiol treatment after castration influences cognition. For androgen-
deprived genetic males, estradiol treatment may improve some cognitive functions (e.g., verbal and
visual memory), but the findings are not consistent due to large variability in the study design
between studies.
Conclusion: Future studies are required to determine the best estradiol treatment protocol to
maximize cognitive benefits for androgen-deprived genetic males. Tests that assess comparable
cognitiv e domains in human and rodents are needed. Wh at particularly under-investigated is how
the effects of estrad iol on cognitive ability intersect with other param eters; sleep, depression and
physical fatigue. Such studies have clinical implications to improve the quality of life for both PCa
patients on ADT as well as for male-to -female transsexuals.
Keywords: Estradiol, cognition, prostate cancer, androgen deprivation therapy, male-to-female transsexuals, verbal memory,
visual memory, spatial memory.
1. INTRODUCTION
Androgen deprivation therapy (ADT) is the primary
treatment for systemic prostate cancer (PCa), with more than
a half million men on ADT in North America [1]. ADT has
many deleterious side effects, including potential deficits in
cognitive function (reviewed in [2-4]). Furthermore, ADT
can also result in suboptimal sleep, fatigue, and depression
[5-12], all of which may contribute to cognitive decline.
The cognitive impairment after androgen loss is also ob-
served in animal models. Castration in rodents influences
*Address correspondence to this author at the Level 6, 2775 Laurel Street,
Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia,
V5Z 1M9, Canada; Tel: 604-875-4495, ext. 1; Fax: 604-875-4637;
E-mail: erik.w@dal.ca
both spatial [13-19] and non-spatial [15, 20-22] abilities. For
example, castrated rats are slower to acquire spatial working
memory [13, 14, 23, 24]. However, findings on how
castrated rats learn spatial reference memory have been
inconsistent [16, 17, 25, 26].
The cognitive impact of ADT may be associated with the
loss of both testosterone and estradiol (E2), which in males
is mainly derived from the aromatization of testosterone
[27]. Decline in gonadal hormones decreases ligand
bioavailability to bind to sex steroid receptors which are
present in various brain areas, including those involved in
cognition, such as the hippocampus and prefrontal cortex
[28-31]. The activation of brain sex steroid receptors plays a
role in normal cognitive functions. For example, without
functional androgen receptors, male rodents have deficits in
spatial reference memory [32, 33]. Furthermore, individuals
A R T I C L E H I S T O R Y!
Received: September 14, 2016
Revised: February 10, 2017
Accepted: March 08, 2017
DOI:
10.2174/1570159X15666170313122555!
1044 Current Neuropharmacology, 2017, Vol. 15, No. 7 Erik Wibowo
with androgen insensitivity syndrome [34] and idiopathic
hypogonadotropic hypogonadism [35] have reduced cogni-
tive ability (in the spatial domain).
Replacing testosterone is not considered a safe option for
PCa patients with androgen-sensitive PCa because testoster-
one can activate androgen receptor and stimulate PCa growth
[36]. Estrogen replacement therapy is currently being stud-
ied, though, in clinical trials for patients who are on ADT
[37, 38]. However, data on how E2 influences cognitive
function on androgen-deprived males are sparse, as com-
pared to data for hormone-deprived females (see the special
2015 issue on “Estradiol and Cognition” in Hormones and
Behavior vol. 74, and recent reviews [39, 40]). This
sex/gender disparity reflects the fact that E2 is the dominant
sex steroid in females and is present more than ten times the
concentrations in females than in males (for example, see
[41] vs. [42] for rodents data; and [43] vs. [44] for human
data).
Even in eugonadal males, there is no consensus on how
endogenous E2 modulates cognition. A few studies have
shown that men with higher E2 levels have better visual
[45], visuospatial [46] and verbal [47, 48] memory perform-
ances. However, most studies found that higher plasma E2
concentrations in older men have either no or negative asso-
ciation with cognitive functions [49]. The varying data on
the influence of endogenous E2 in eugonadal men could par-
tially be because serum E2 assessment may not reflect the
actual imp act of E2 in the brain. This is because neurons in
many brain areas-including those for cognitive functions-can
directly aromatize testosterone into E2 [50, 51]. Determining
the effects of endogenous E2 in eugonadal men is also con-
founded by the presence of endogenous androgens and sex
hormone binding globulin, which may affect the bioavail-
ability of gonadal steroids. Suffice to say, a few studies show
that reduced E2 bioavailability in male rodents due to aro-
matase-knock out [52] or administration of aromatase inhibi-
tor [53] impairs spatial task performances, though conflictin g
data have been reported [54, 55].
This paper reviews studies that have investigated the ef-
fects of E2 on cognitive function of androgen-deprived ge-
netic males of our species-i.e., PCa patients on ADT and
male-to-female transsexuals (MtFs) on hormone therapy
(HT)-as well as castrated male rodents. These studies help
isolate the effects of E2 on male cognition without the im-
pacts of endogenous testosterone. Many MtFs are androgen-
deprived due to surgical castration as part of sex reassign-
ment surgery or HT with a dose high enough to suppress
testosterone. Data from MtFs brings additional insight on
how HT affects cognition of genetic male population. Data
on castrated male rats are also reviewed because they served
as a preclinical model for men who are on ADT. Admittedly
there are limitations on animal research but they can provide
insights on how E2 modulates cognitive function in andro-
gen-deprived males. This paper points out areas that are un-
derstudied, but would be important to consider in the future
when researchers investigate cognitive impact of ADT on
PCa patients with or without E2 treatment. Studies in this
area are clinically relevant to other genetic male populations
who receive E2 treatment, such as MtFs [56, 57] and cas-
trated men [58, 59].
2. METHODS
PubMed and Google Scholar were searched for terms
including “estradiol”, “estrogen”, “cognition”, “male”,
“prostate cancer”, “androgen deprivation therapy”, “male-to-
female transsexuals”, and “cross-sex hormones”. From this
search I identified publications that investigated the impact
of E2 treatment on castrated male rats, PCa patients on ADT,
and MtFs on HT. Additional publications were located in
the references cited for papers found in the original search.
Findings on how E2 affects specific cognitive domains are
summarized on Tables 1 to 3. Experimental details, includ-
ing E2 dose and duration, are summarized in Supplementary
Tables 1 and 2.
3. STUDIES ON CASTRATED MALE RATS
3.1. Experimental Details
Ten studies have investigated how E2 influences the
cognitive performances of castrated male rats (Supplemen-
tary Table 1). In seven studies, the rats received E2 treatment
immediately after castration whereas, in the other three stud-
ies [23, 26, 60], the rats started E2 treatment at 1-2 weeks
after castration. Most studies administered E2 via a Silastic
capsule or slow-release E2 pellets. The only exceptions were
Hodosy et al. [26] and Lagunas et al. [23] who injected E2
intramuscularly and intraperitoneally respectively.
Plasma E2 levels were only measured in two studies [26,
61]. E2 levels were similar to female diestrus levels in both
studies, but Hodosy et al. [26] also treated one more group
of rats with a dose resulting in a plasma E2 levels almost
four times higher than female proestrus levels [see Butcher
et al. [41] for normal female E2 levels in estrus cycle]. Five
studies used the same E2 dose as the one in the Kritzer’s
study [62], which increased the plasma E2 levels to ~26.5
pg/mL (i.e., similar to diestrus levels in females). The re-
maining three studies used E2 doses that have been used by
other researchers for raising plasma E2 levels of female rats
to either diestrus [23] or proestrus [60, 63] levels. However,
whether such doses in fact increased plasma E2 levels to
those levels are not known. In my previous study [64], male
rats required higher E2 dose than female rats to achieve simi-
lar E2 levels [see Deurveilher et al. [65] for comparison].
Therefore, there is a possibility that the plasma E2 levels in
those studies [23, 60, 63] may be lower than expected. To
date, a dose of E2 that only brings plasma E2 levels into the
range of intact males (i.e., ~2 pg/mL [42, 61, 66]) has not
been tested in cognitive studies on castrated rats. As such, it
remains unknown as to how an E2 dose that raises the
plasma E2 levels to the levels of intact male rats would in-
fluence cognitive function for the castrated male rats.
One factor, which is rarely investigated in animal studies,
is how the interval between castration and the initiation of
E2 treatment (Supplementary Table 1) influences the effects
of E2 treatment on cognitive function. Except in three stud-
ies [23, 26, 60], the rodents started receiving E2 treatment
immediately after castration. In female rats, the effectiveness
of E2 in improving cognitive performance is known to be
sensitive to the time when the treatment begins after ovariec-
tomy [67]. Similar findings have also been observed in
Role of Estrogen in Male Cognition Current Neuropharmacology, 2017, Vol. 15, No. 7 1045
women, who receive E2 treatment after menopause [68]. It
remains unknown, though, how long-term hormone depriva-
tion affects male cognitive function, and when the best time
might be to start E2 treatment after castration to maximize
any cognitive benefit.
One possible factor that likely contributes to the time-
sensitive nature of E2’s effectiveness in restoring cognition
is the au toregulation of estrogen receptor α (ERα) in brain
areas for cognition. In female rats, early but not delayed E2
administration after ovariectomy increased ERα in the hip-
pocampus, and the opposite results were found in the pre-
frontal cortex [69]. Changes in ERα autoregulation in both
brain areas after prolonged hormone-deprivation have also
been observed in male rodents. In male rats, hippocampal
ERα decreases with early, but not delayed, E2 treatment after
castration [30]. The opposite was found in the prefrontal
cortex; i.e., ERα in the prefrontal cortex decreases with de-
layed E2 treatment [30]. How those results translate into
cognitive performances for male rats has not been assessed
(but see the discussion below on visual attention of andro-
gen-deprived PCa patients with and without E2), and there
may be other factors that may explain why the effect of E2
on cognition after hormone deprivation is time-sensitive.
Interestingly, the patterns of brain ERα autoregulation in
response to E2 treatment between sexes differ; i.e., down-
regulated in male [30] and upregulated in female [69] rats.
Additionally, a recent study [70] showed that how E2 induces
synaptic potentiation in the hippocampus is not the same in
males and females. Specifically, E2 can increase pre-synaptic
glutamate release probability in the hippocampus via ERα in
males, but via ERβ in females. That same study also found
that E2 can increase post-synaptic sensitivity to glutamate
via ERβ in males, but via the G-protein coupled ER-1. These
data suggest that there may be true sex differences in how E2
modulates cognition in males versus females.
3.2. Behavioural Findings
Among the reviewed studies, the cognitive domain that is
most commonly assessed is spatial ability (Table 1; Supple-
mentary Table 1). These include spatial learning, spatial
working memory, and spatial reference memory. Learning
tasks involving spatial memory in castrated rats are im-
proved by E2 treatment in some studies [23, 25, 61, 71] but
not in others [13, 15, 60]. Obviously, the type of testing ap-
paratus/mazes differs between studies, leading to variation in
the difficulty of the tasks in the different tests. As such, this
variation may contribute to discrepancy in findings on spatial
learning.
Spatial working memory of castrated rats is improved by
E2 treatment in some studies [23, 25, 63, 71], but not in
other studies [60, 61] (Table 1). Again, the variance in re-
sults could be because of the different testing apparatus. Un-
like the apparatus in other studies, the T-maze in the Gibbs’
study [61] was walled (5-inches high) so the rats may have
less extra-maze cues. In addition, the radial maze in the Lu-
ine and Rodriguez study [60] has 8 arms so performance on
this maze may have higher working memory demand. Nega-
tive impact of E2 on spatial working memory of castrated
rats was also reported in one study [26], but that study used
the Morris water maze, so their data cou ld be confounded by
stress due to water immersion [72].
Several studies have examined how E2 treatment affects
spatial reference memory (Table 1)-a type of long-term
memory that is constant from trial to trial [73, 74]. When
there are minimal d elays between testing, the acquisition of
spatial reference memory is not significantly different be-
tween castrated rats with and without E2 [25, 26, 60, 71].
However, when a time delay is introduced between testing
[25, 60], E2-treated castrated rats performed better on spatial
reference memory task than do castrated rats with no hor-
mone replacement. This suggests that a substantial delay
between tests may be necessary to assess the beneficial effect
of E2 on spatial reference memory. Future studies with such
delay would more closely reflect real life situations for men,
where the concern is on both previously learned and newly
acquired spatial tasks.
The effect of castration with and without E2 replacement
on non-spatial tasks has also been studied, but to a lesser
extent (Table 1). For example, Aubele et al. [21] assessed
object recognition memory, which requires visual memory,
and found that E2 does not improve object recognition memory
after castration. Kritzer et al. [15] also examined several
other non-spatial tasks, but the only two tasks in which they
found improvement with E2 treatment in castrated rats were
the learning of withholding response (holding back from
getting a reward) and motivational (motivation to get a re-
ward) tasks. Therefore, though only reported in one study
[15], E2 treatment in androgen-deprived males may also
have some benefits on non-spatial cognitive functions.
4. STUDIES ON ANDROGEN-DEPRIVED GENETIC
MALE HUMAN
4.1. Androgen-Deprived Men with Prostate Cancer
Three studies (total sample size = 41 patients; mean ages
= ~70 years old) have investigated how E2 treatments affect
cognitive functions for PCa patients on ADT (Supplemen-
tary Table 2). Serum testosterone levels of the patients were
in the castrate range in all studies. Patients received 0.6-1 mg
E2 daily for 4 to 12 weeks. Serum E2 levels reached supra-
physiological levels in one study [75], but not in the other
two [76, 77].
Compared to the performance of androgen-deprived PCa
patients without E2, scores on verbal memory tests of E2-
treated patients were better in the Beer et al. study [75], but
worse in the Matousek and Sherwin study [76] (Table 2).
Verbal memory was also assessed by Taxel et al. [77], but
by using a different test than the one used in the other two
studies. However, Taxel et al. did not find a significant dif-
ference in verbal memory performance between the E2- and
placebo-treated PCa patients. Considering that patients in the
Beer et al. study [75] had supraphysiological E2 levels, but
not in the other two studies, an E2 dose that yields supra-
physiological E2 levels may be required to benefit verbal
memory for androgen-deprived PCa patients.
Visual attention was tested with Trail tests in two
of these studies [75, 77]. E2 treatment improved visual
1046 Current Neuropharmacology, 2017, Vol. 15, No. 7 Erik Wibowo
Table 1. Summaries on the effects of E2 treatment on cognitive performance of castrated male rats. Data were compared to the
Control group, which consists of castrated rats without E2 treatment.
Cognitive Domain Tested
(Testing Apparatus)
Studies
Effects of E2
Treatment
Parameters Measured
Barnes maze
[71]
Changes in path length, latency to find a goal box, and number of errors on
Day 1 testing.
Barnes maze
[25]
Changes in path length, latency to find a goal box, and number of errors on
Day 1 testing.
Cross-maze
[23]
Percentage of correct choices between the first and fourth day of testing.
Operant conditioning chamber
[15]
0
Number of sessions to reach 25 correct choices in a single session; i.e., to alter-
nately press 2 levers for water reward.
T-maze
[61]
Percentage of trials with a correct response; i.e., to visit an arm in which the rats
previously received a food reward.
T-maze
[13]
0
Number of sessions to reach 7 correct choices in 9 tests; i.e., to visit alternating
baited (with water reward) arm consecutively.
Radial arm maze
[60]
0
Number of trials to obtain 7 correct choices in the first 8 visitsto get food
reward in 8 armsin 5 consecutive trials.
Barnes maze
[71]
on Day 1
0 on Day 2
Spatial working memory error was measured from the number of re-investigation
of incorrect holes.
Barnes maze
[25]
on Day 1
0 on Day 2
Spatial working memory error was measured from the number of re-investigation
of incorrect holes.
Open field with 2 identical ob-
jects
[63]
Time spent exploring moved and unmoved objects.
Morris water maze
[26]
with EB
0 with ED
Changes in escape latency between the final and first day of testing.
T-maze
[61]
0
Percentage of trials with a correct response (to visit an arm in which the rats
previously received a food reward) after the maze was rotated and inter-trial
delay was increased.
Radial arm maze
[60]
Data not shown
The number of re-entries into previously visited arm was collected (indicative of
working memory errors) but data were not shown.
Barnes maze
[71]
0
Path length an d latency to find a goal box on Day 2 (1 day de lay) testing. Sp atial
reference memory error was measured from the number of first-time investiga-
tion of incorrect holes.
Barnes maze
[25]
0 on Day 2
on Day 7
Path length an d latency to find a goal box on Day 2 (1 day de lay) and Day 7
(1 week delay) testing. Spatial reference memory error was measured from the
number of first-time investigation of incorrect holes.
Morris water maze
[26]
0
Escape latency (i.e., time to find a submerged platform).
Cross-maze
[23]
Averaged percentage of correct choices in 4 days of testing.
T-maze
[61]
0
Percentage of trials with a correct response; i.e., to visit an arm in which the rats
previously received a food reward.
Radial arm maze
[60]
0 with no delay
with delay
Number of correct choices (visits to baited arms) in the first 8 visits. Trials were
done with and without 1-hour delay between the 4th and 5th arm visits.
(Table 1) contd….
Role of Estrogen in Male Cognition Current Neuropharmacology, 2017, Vol. 15, No. 7 1047
Cognitive Domain Tested
(Testing Apparatus)
Studies
Effects of E2
Treatment
Parameters Measured
Open field with 2 objects
[21]
0
Time spent exploring novel and old objects.
Operant conditioning chamber
[15]
0
Number of sessions to reach 90% accuracy of a task; i.e., to press a lever wit h a
cue light in order to receive a water reward; another lever with unlit lamp was
present simultaneously.
Operant conditioning chamber
[15]
Percentage of impulsive lev er press over total lev er press.
Operant conditioning chamber
[15]
Number of water reward obtained.
Operant conditioning chamber
[15]
0
Number of sessions to reach 90% accuracy of a task; i.e., in a pair of testing
phases, rats needed to either press the same (match) or a different (non-match)
lever in the second test as that in the first test in order to get a water reward.
Operant conditioning chamber
[61]
0
Changes in the number of responses (i.e., to enter a food cup for reward) and
time to respond following a tone, light or both stimuli.
↑↓ = Significantly better or worse performance than castrated rats with no hormone treatment. 0 = No significant effect. E2 = Estradiol. EB = Estradiol benzoate. ED = Estradiol
dipropionate.
attention in the Taxel et al. study, but not in the Beer et al.
study. One possible reason for this inconsistency could be
because of the difference in the length of time between the
initiation of ADT and the onset of E2 treatment. Patients in
the Beer et al. study had been androgen-deprived for an
average of 5.32 years when they began E2 treatment. In con-
trast, patients in the Taxel et al. study had been androgen-
deprived for a shorter time; some had been on continuous
ADT for an average of 2.6 years, whereas others were only
on ADT for 3 weeks. Thus, E2 may not be able to improve
visual attention in men, who have been androgen-deprived
for a prolonged period of time. If this is true, such finding
will be consistent with the data in females (discussed in the
“Studies in Castrated Male Rats” section above), showing
that the effect of E2 treatment is sensitive to when the treat-
ment is started after hormone deprivation.
Visuospatial ability was tested in the Matousek and
Sherwin study [76], but E2 treatment did not improve per-
formance in visuospatial tests. This could be because the
men in that study were only androgen-deprived for 12
weeks. Similar lack of impact of E2 on visuospatial ability
was also found in healthy men [78] or PCa patients [79],
who were on ADT for less than 6 months. Currently, data on
visuospatial ability of PCa patients, who have been on ADT
for 9-12 months, have been inconsistent (see [80-83] vs. [83-
85]). How long-term ADT (i.e., >1 year) affects cognitive
functions has not been studied, but warrants investigation
because PCa patients with progressing systemic disease typi-
cally are on sustained ADT that can last for many years.
4.2. Male-to-Female Transsexuals
Seven studies have investigated the cognitive perform-
ances of MtFs, who are on HT (total sample size = 179
MtFs; mean ages vary between 22 and 40.3 years old). Ad-
mittedly, the participants of these studies are younger than
PCa population (Supplementary Table 2). HT regimens are
heterogeneous among studies (Supplementary Table 2);
MtFs received estrogen as oral ethinyl E2, transdermal E2 or
Premarin, and in some cases combined with progesteronic
compounds, such as cyproterone acetate. Most studies did
not measure plasma E2 levels, so the participants E2 con-
centrations are not known. Th e only exceptions are the stud-
ies by Schoning et al. [86] and Sommer et al. [87], but in
both cases the plasma E2 levels did not reach supraphysi-
ological levels. Whether higher E2 doses (i.e., as high as
female E2 levels at the peak of their menstrual cycle) have
different cognitive effects than lower dose treatments re-
mains to be determined.
Generally, there are many inconsistencies on how HT
affects cognitive performances for MtFs, which could be
partially attributed to the varying tests, doses and hormone
combinations used in the studies. For example, visual mem-
ory is improved after long-term HT [88], but that same study
also found that performance on a different visual memory
1048 Current Neuropharmacology, 2017, Vol. 15, No. 7 Erik Wibowo
test is better after HT is stopped for 8 weeks. Unfortu-
nately, no other studies on MtFs assessed visual memory so
the findings from the Miles et al. study [88] cannot be com-
pared.
Visuospatial ability of MtFs appears to be minimally
affected by HT. Van Goozen et al. [89] found worsening
performance on visuospatial ability after 3 months of HT.
However, such visuospatial ability deficit is not found when
assessed with a different test (i.e., mental rotation test) in
other studies. In contrast, better mental rotation ability was
observed after 14 weeks of HT [90], though the authors sug-
gested that this could be a learning effect, because non-MtFs
groups in the study also have similar improvements. In other
studies, HT does not significantly affect mental rotation abil-
ity of MtFs [86-88, 90-92].
Data on verbal ability of MtFs on HT were not consistent
across studies. In term of language skills, verbal reasoning
was not affected by HT [89-91], whereas verbal fluency was
better after HT in the Van Goozen et al. [89] study, but not
in other studies [88, 91]. Verbal memory appears to improve
for MtFs with HT [92] but, depending on the tests used, con-
flicting findings have also been reported [88, 89, 91, 92].
Potentially, the large heterogeneity between studies (e.g.,
type, dose, duration of HT, age) is the reason for the high
variability on the effects of E2 on MtFs’ verbal ability.
5. SEXUAL COGNITION
One domain that has not been well explored is how E2
influences sexual cognition. Eugonadal males may first look
at faces when viewing images of other humans, but their
visual attention quickly shifts to the torso and pelvic area,
when viewing sexually explicit images [93, 94]. Prolonged
fixation of one’s gaze on sexual images may lead to sexual
arousal [95-97], and men with sexual dysfunction may show
reduced visual attention to sexual images [95]. A recent pilot
study found that ADT may impair visual attention to sexual
(swimsuit models) images [98]. The Skead et al. study pro-
vides an objective way to measure how ADT diminishes
men’s attention to sexual stimuli. However, whether the de-
crease in attention to sexual images is due solely to androgen
deprivation or also due in part to estrogen deprivation was
not explored.
Whether E2 can improve visual attention to sexual stim-
uli in androgen-deprived men is not known, but warrants
further investigation. Other studies have shown that E2 helps
restore sexual interest in most castrated mammalian species
[99]. High dose E2 treatment in eugonadal men reduces sex-
ual desire but sexual interest appears to be higher in andro-
gen-deprived men with E2 treatment than those without E2
treatment [99, 100]. Finkelstein et al. [101] recently found
that testosterone improves sexual desire in androgen-
deprived men, but the effect is dampened when testosterone
is administered in combination with an aromatase inhibitor.
That affirms a role for E2 in raising libido in androgen-
deprived men. In addition, Handy et al. [58] provided inde-
pendent evidence of estrogen’s preservative effect on libido
for castrated men. That study showed that castrated men with
no hormonal treatment are more likely to be sexually inac-
tive than those on some form of estrogen treatment.
6. CLINICAL IMPLICATIONS AND FUTURE
DIRECTIONS
A clinical trial [38, 100] is currently underway, exploring
the use of high dose parenteral E2 as an alternative to the
Table 2. Summaries on the effects of E2 treatment on cogni-
tive performance of PCa patients who are on ADT.
Categories were from McGinty et al. [4]. The three
studies w ere longitudinal studies. Two studies [76,
77] were double blind RCTs, but one study [75] was
not a blinded and treatment assignment was not
randomized. More details can be found in Supple-
mentary Table 2.
Cognitive Domain Tested
(Test used)
Studies
Effects of E2
Treatment
Attention and working memory
Trail making test A
[77]
[75]
0
Digit span
[77]
0
Digit symbol test (WAIS-III)
[76]
0
Letter-number sequencing task
[76]
0
Subject-ordered pointing
[75]
0
Executive function
Stroop test
[77]
Trail making test B
[77]
[75]
0
0
Language
Controlled oral word association test
[77]
0
Verbal fluency test
[76]
0
Verbal memory
Logical memory task (WMS-R)
[76]
[75]
< ADT group
Verbal paired associates (WMS-R)
[76]
0
Rey auditory verbal learning test
[77]
0
Visual memory
Benton visual retention test
[77]
0
Visuomotor skill
Digit symbol test
[76]
0
Block design
[76]
0
Paper fo lding
[76]
0
Visuospatial ability
Mental rotation test
[76]
0
↑↓ = Significantly improved or worse performance at follow-up visit. ADT group =
patients on ADT but do not receive E2. RCT = Randomized controlled trial. WAIS-III
= Wechsler Adult Intellig ence Scale-Third Edition. WMS-R = Wechsler Mem ory Sc ale
- Revised.
Role of Estrogen in Male Cognition Current Neuropharmacology, 2017, Vol. 15, No. 7 1049
Table 3. Summaries on the effects of E2 treatment on cognitive performance of MtFs who are on HT. Some categories were from
McGinty et al. [4]. Two studies [86, 92] were cross-sectional studies, and the rest were longitudinal studies. All cases were
non-blinded studies. More details can be found in Supplementary Table 2.
Cognitive Domain Tested (Test used)
Studies
Effects of E2 Treatment
Attention and working memory
Digit span
[92]
[88]
0
after HT
Language
Controlled association test
[92]
[88]
0
0
Paced v erb generation test
[87]
0
Paced categorical decision test
[87]
0
Verbal fluency test (word production)
[89]
[91]
0
Verbal fluency test (sentence production)
[89]
[91]
[88]
0
0
Verbal reasoning test
[89]
[91]
[90]
0
0
0
Vocabulary
[92]
[88]
0
0
Verbal memory
Logical memory task (WMS-R)
[92]
[88]
0
after long-term HT
Verbal paired associates (WMS-R)
[92]
[88]
> MtFs group
after off HT
Visual memory
Visual reproduction test
[88]
0
Visual paired associate learning
[88]
0
after off HT for 8 weeks
Figural memory test
[88]
after long-term HT
Visual memory span
[88]
0
Object memory test
[88]
0
Location memory test
[88]
0
Visuomotor skill
Fine motor mov ement test
[91]
0
Targeted throwing
[90]
0
Visuospatial ability
Line orientation test
[90]
0
Judgment of line angle and position
[88]
0
Mental ro tation (2-dimensional)
[91]
[90]
at 3 months; but 0 post-SRS and 5 weeks off HT
but other groups too*
Mental ro tation (3-dimensional)
[86]
[87]
[92]
[91]
[90]
[88]
= MtFs group
0
0
0
but non-MtF groups too*
0
Mental ro tation (3D, same-different)
[90]
but non-MtF groups too*
Hidden figure test
[91]
at 3 months; but 0 post-SRS and 5 weeks off HT
Perceptual speed test
[91]
0
Card rotation test
[89]
↑↓ Significantly improved or worse performance at follow-up visit. 0 no significant difference at follow-up. HT = ho rmone therapy . MtFs group = MtFs who d o not receive HT. RCT
= Randomized c ontroll ed tria l. SRS = sex -reassignment surgery. WMS-R = Wechsler Memo ry Scale Rev ised. * = th e study included males and females with out gend er dysph oria.
1050 Current Neuropharmacology, 2017, Vol. 15, No. 7 Erik Wibowo
luteinizing hormone-releasing hormone (LHRH) agonists
and antagonists for androgen suppression in PCa patients. If
E2 treatment is shown to improve cognitive functions in
these PCa patients, it may help justify the use of high dose
E2 therapy for ADT or supplemental E2 therapy for patients
who are on ADT achieved with other drugs, such as the
LHRH drugs. However, one needs to also be aware of non-
cognitive effects associated with E2 treatment such as breast
and cardiovascular events as well as concerns on potential
breast and prostate cancer risks [38, 102, 103]. Certainly, in
the case of MtFs, breasts enlargement due to E2 treatment is
a desired effect, but may be bothersome to PCa p atients
[104].
Future researchers investigating the effects of E2 on cog-
nitive functions of PCa patients on ADT or MtFs on HT
needs to consider several factors in study design, such as the
type of cognitive tests used, E2 dose, treatment duration an d
follow-up time. Although short-term androgen deprivation
impairs various cognitive ability of male rodents, it remains
unclear why the cognitive deficits androgen-deprived PCa
patients and MtFs are more subtle. One possibility is that,
other than visual memory, most tests used in human studies
may not measure comparable cognitive domains as those in
the animal studies. As an example, spatial ability in rodents
are measured using spatial navigation tests; i.e., locating
object, rewards, or a goal hole (Table 1). However, visuospa-
tial tests that have been used in human participants only as-
sessed mental visualization ability (Tables 2 and 3). Other
human studies have utilized different techniques to assess
spatial memory, for example, by using virtual reality soft-
ware [105-107] or a real-life wayfinding task [108]. These
tests may more realistically reflect the spatial ability tests
used in animal studies. However, such methods have not
been used to examine how E2 treatment influences cognitive
function for androgen-deprived PCa patients or MtFs who
are on HT.
Two factors that need more investigations are E2 dosing
and the timing of follow-up assessment. Animal studies have
shown that an E2 dose higher than intact levels can have
positive cognitive effects, but whether a lower dose, that
raises E2 only to normal physiological levels, can still im-
prove cognition has not been explored. However, based on
the findings by Beer et al. [75], E2 may need to reach supra-
physiological levels in order to bring cognitive benefits in
androgen-deprived men. Furthermore, long-term studies of
E2 treatment for androgen-deprived men are necessary to
reflect the clinical reality that many PCa patients are on ADT
for years at a time. This is particularly relevant since, for
post-menopausal women (and in ovariectomized rodents
[67]), supplemental estrogens may have different risks and
benefits depending on how long they have been hormone-
deprived before starting estrogen therapy [68]. It is thus pos-
sible that cognitive responses to supplemental E2 treatment
will differ between androgen-deprived males with and with-
out E2 treatment, if the men are on ADT for a longer time or
the delay between E2 treatment and the onset of ADT is
short. If early E2 treatment preserves cognition better, it may
support the use of add-back E2 around the onset of ADT.
In addition, what needs to be explored in future studies is
other factors known to be linked to cognition, such as sleep
function. Based on self-reports from PCa patients, ADT re-
sults in sleep disturbance [5-8]. Using actigraphy, Hanisch et
al. [109] found that, on average, PCa patients on ADT re-
quired more than 30 minutes to fall asleep, slept for only
about 6 hours, and woke up 2.7 times per night. Not surpris-
ingly, ADT patients often reported daytime sleepiness and
took frequent naps [109]. However, whether the sleep prob-
lems correlate with cognitive impairment has not been ex-
plored.
Castration may also alter sleep-wake patterns in male
rodents. Increased period of rapid eye movement (REM)
sleep during the animals’ active period [110] and dampened
REM sleep recovery after acute sleep deprivation [64] are
found in castrated rats. However, other studies did not report
such findings [64, 111, 112]. Among these studies, how par-
tial sleep deprivation (i.e., not getting sufficient sleep on
consecutive nights) impacts sleep/wake behaviour have not
been studied in castrated animals, but will be important to
investigate for several reasons. First, such study reflects what
PCa patients on ADT experience in real life; i.e., havin g
sleep loss for days in a row. Second, increased allostatic load
(including metabolic, immune and neural changes) may oc-
cur with repeated sleep deprivation [113, 114], and may di-
rectly influence sleep-wake behaviour. Third, whether
chronic sleep deprivation can exacerbate other side effects of
androgen deprivationsuch as cognitive impairment, de-
pression and metabolic syndromehave not been explored.
Lastly, future clinical research that investigates how E2
influence cognition of PCa patients on ADT should also tak e
into account any effects of E2 on fatigue, depression and
anxiety. ADT has been shown to cause fatigue, depression
and anxiety [10, 11, 115, 116]. Preclinical research showed
that E2 has beneficial effects on these parameters [64, 117,
118], but those findings have not been explored in PCa pa-
tients on ADT. There are, though, some evidence that HT
may help reduce psychological symptoms (e.g., depression
and anxiety) symptoms in MtFs [56]. Changes in these be-
haviours may interlink between each other as well as with
cognitive function. Therefore, if E2 can alleviate one of these
symptoms, other symptom(s) may also be potentially im-
proved.
CONCLUSION
While some studies have suggested that E2 may have
some protective role in cognitive function of androgen-
deprived male rats and humans, there are still major knowl-
edge gaps on the roles of E2 in male cognition. This is partly
due to the fact that studies on genetic males treated with E2
are scarce, and there are large variations between studies
(e.g., type of cognitive tests, E2 treatment regimen). Future
studies need to explore which E2 treatment protocol can
most effectively improve cognitive functions in androgen-
deprived males. Such studies have important implications to
improving the quality of life of not just androgen-deprived
PCa patients, but also for MtFs.
Role of Estrogen in Male Cognition Current Neuropharmacology, 2017, Vol. 15, No. 7 1051
LIST OF ABBREVIATIONS
ADT = Androgen deprivation therapy
CA = Cyproterone acetate
DS = Digit span
E2 = Estradiol
EB = Estradiol benzoate
ED = Estradiol dipropionate
ER = Estrogen receptor
fMRI = Functional magnetic resonance imaging
FtMs = Female-to-male transsexuals
HT = Hormone therapy
LHRH = Luteinizing hormone-releasing hormone
MtFs = Male-to-female transsexuals
NMDA = N-methyl-d-aspartate
PAL = Paired associate learning
PCa = Prostate cancer
REM = Rapid eye movement
SRS = Sex-reassignment surgery
WMS-R = Wechsler Memory Scale-Revised
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
I thank Drs. Elizabeth Hampson, Sheila Garland, and
Richard Wassersug for providing critical feedback on the
draft manuscript.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher’s
web site along with the published article.
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... 6 Some animal and human studies suggest that E2 treatment might improve aspects of cognition in androgendeprived males. 7 However, in RCTs assessing broad domains of cognition with standard tests, no effects of T treatment on cognition in older men with low or low-to-normal serum T have been identified. [8][9][10] It has been reported that 69% of men receiving androgen deprivation therapy (ADT) for prostate cancer decline in at least one cognitive domain, 11 although not all studies agree. ...
... 19 A recent review called for additional studies of the effects of exogenous E2 on cognition in androgen-deprived males. 7 ADT represents the only situation in which an ethical requirement for T replacement is absent for prolonged periods, allowing any effects of exogenous E2 on cognition to be observed in the absence of T. We conducted a randomized placebo-controlled trial of transdermal E2 in men undergoing ADT, designed to assess the effect on fat mass and bone microarchitecture over 6 months. 20 This experimental design permitted us to observe the isolated effects of E2 on pre-defined domains of cognition, in the absence of T. We hypothesized that men randomized to receive E2, compared to those randomized to receive placebo, would have improved verbal learning and memory, and spatial problem solving over time. ...
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Objective: Roles for estradiol in modulating cognition in men remain uncertain. We assessed the isolated effects of estradiol on cognition in men in the absence of testosterone. Design: Randomised trial of transdermal estradiol 0.9mg daily, or matched placebo, for 6 months, hypothesizing that estradiol would improve verbal learning, verbal memory and spatial problem solving over time. Patients: Men receiving androgen deprivation therapy (ADT) for prostate cancer. Measurements: Cognition was assessed by a tablet-based cognitive battery (Cogstate) at baseline, month 1, month 3, and month 6. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale. Results: 78 participants were randomised. Baseline mean scores were 21.0 (sd 4.1) for the International Shopping List test (ISL), assessing verbal learning and memory (higher scores better), and 60.4 (sd 19.5) for the Groton Maze Learning test (GML), assessing spatial problem solving (lower scores better). There was no significant difference in performance over time for the estradiol group versus the placebo group for the ISL, mean adjusted difference (MAD) 0.7 (95% CI -1.2 - 2.5), p=0.36, or the GML, MAD -3.2 (95% CI -12.0 - 5.6), p-0.53. There was no significant difference between groups over time in performance in any other cognitive domain, or on depression or anxiety scores. Conclusions: We found no major effects of estradiol on cognition in men with castrate testosterone concentrations. Although the cognitive effects of ADT are debated, this study suggests that any such effects are unlikely to be prevented by administration of estradiol. This article is protected by copyright. All rights reserved.
... [42] Previous studies showed positive correlations between endogenous estrogen and testosterone levels, and cognition in older men. Older men with high serum estradiol levels performed better performance in working memory, [43] visual memory, [44] verbal memory, [45] spatial scan, [46] and global cognitive function. [47] Obesity and cognitive function based on sex have been studied before, with other studies also reporting differences between sexes. ...
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The prevalence of obesity as well as cognitive impairment increases with age. Previous studies showed that obesity is associated with an increased risk of cognitive impairment and dementia. Body composition changes occur as part of the aging process; therefore, the assessment of obesity in elderly populations should include body composition as well as body weight. This study investigated the relationship between body mass index (BMI), body composition, and cognitive function in a community-dwelling elderly Korean population.This cohort-based cross-sectional analysis included 2386 elderly participants aged between 70 and 84 years from the Korean Frailty and Aging Cohort Study for 2016 to 2017. To investigate the relationship between body composition and cognitive function in community-dwelling individuals, BMI and body composition, including total and trunk fat mass and fat-free mass, were measured by dual-energy X-ray absorptiometry. Fat mass index (FMI), trunk fat mass index (TFMI), and fat-free mass index (FFMI) were used to represent the body composition. A short form of the Korean version of the Consortium to Establish a Registry for Alzheimer disease was used to assess cognitive function. To evaluate the relationship between variables, simple and fully adjusted multivariable analyses were performed using generalized linear regression models.The mean ages were 76.8 years for males and 76.1 years for females. The BMI of male participants was significantly lower than that of females (23.9 ± 2.89 vs 24.7 ± 3.02 kg/m2, P < .001). Among body composition parameters, the differences in FMI (6.44 ± 1.97 vs 9.29 ± 2.3 kg/m2), TFMI (3.68 ± 1.33 vs 5.03 ± 1.43 kg/m2), and FFMI (17.4 ± 1.64 vs 15.3 ± 1.39 kg/m2) were statistically significant. In linear regression analyses, BMI, FMI, and TFMI showed significant positive correlations with mini-mental state examination in the Korean version of the CERAD assessment packet; wordlist memory, recall, and recognition; and frontal assessment battery only in males. The significant positive correlations persisted even after fully adjusting for age, education periods, location of residence, depression, marriage, annual income, presence of diabetes mellitus, dyslipidemia, and hypertension. However, no significant correlations in either sex were observed between FFMI and cognitive functions in the fully adjusted models.In this study, BMI, and fat mass-related indexes including FMI and TFMI showed a positive linear correlation with cognitive functions but not FFMI. Moreover, the findings were significant only in men. Besides the difference between sexes, the results of this study showed a more apparent correlation in fat mass than in fat-free mass that comprises body weight.
... However, there is evidence in rodents that prior reproductive experience, can ameliorate the effects of castration on engagement in mating, suggesting mating may involve learning. In fact, T actions at cognate androgen receptors (Edinger and Frye, 2007a), as well as actions of its metabolites, 3α-Diol and estradiol (E 2 ), can modulate cognitive behaviors (Osborne et al., 2009;Wibowo, 2017). Thus, reproductive behaviors and cognitive performance may both be modulated by androstane steroids in male rats. ...
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Engagement in sexual behavior can impact neurosteroidogenesis, in particular production of the prohormone testosterone (T) and likely its subsequent metabolism to 5α-androstane-3α-17β-Diol (3α-Diol) or aromatization to estradiol (E2). Androgens and their metabolites vary across the lifespan and impact many behaviors, including cognition, anxiety, and sexual behavior. Thus, we hypothesized that mating may alter cognitive performance via androstane neurosteroids in an age- and experience-dependent manner. We first investigated if exposure to mating during memory consolidation could enhance performance in the novel object recognition task (NOR). Male rats were trained in NOR and then immediately exposed to mating-relevant or control stimuli. Following a 4 h inter-trial interval (ITI), male rats were tested for object memory. Male rats that were exposed to a receptive female during the ITI had better performance in NOR. We then investigated if these effects were due to novelty associated with mating. Male rats were exposed to mating-relevant stimuli and identified as sexually responsive (SR) or sexually non-responsive (SNR) based on a median split of engagement in mating with the stimulus female. We found that a brief history (10 min session daily for five consecutive days) of sexual history substantially influenced performance in the NOR task, such that SR males had better performance in the NOR task, but only when presented with the opportunity to mate during the ITI. As T levels substantially decrease with age in male rodents, we investigated whether the effects of long-term sexual experience (10 months) influenced neurosteroids and NOR performance in mid-aged (12 months old) males. Mid-aged SR males maintain neural T; however, they have decreased neural E2 and decreased cognitive performance at 12 months compared to mid-aged SNR rats. In sexually experienced rats, those with better cognitive performance had greater levels of T metabolites (e.g., 3α-Diol in mated SR males, E2 in mid-aged SNR rats). While naïve males that were mated during the ITI had better cognitive performance, T metabolites were decreased compared to controls. These findings suggest that T metabolites, but not the prohormone, may influence learning dependent on sexual proclivity, experience, and proximate opportunity to mate.
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Men and women differ in their ability to evaluate options that vary in their rewards and the risks that are associated with these outcomes. Most studies have shown that women are more risk averse than men and that gonadal hormones significantly contribute to this sex difference. Gonadal hormones can influence risk-based decision making (i.e., risk taking) by modulating the neurobiological substrates underlying this cognitive process. Indeed, estradiol, progesterone and testosterone modulate activity in the prefrontal cortex, amygdala and nucleus accumbens associated with reward and risk-related information. The use of animal models of decision making has advanced our understanding of the intersection between the behavioral, neural and hormonal mechanisms underlying sex differences in risk taking. This review will outline the current state of this literature, identify the current gaps in knowledge and suggest the neurobiological mechanisms by which hormones regulate risky decision making. Collectively, this knowledge can be used to understand the potential consequences of significant hormonal changes, whether endogenously or exogenously induced, on risk-based decision making as well as the neuroendocrinological basis of neuropsychiatric diseases that are characterized by impaired risk taking, such as substance use disorder and schizophrenia.
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Purpose Although fatigue is a common problem for men with prostate cancer undergoing androgen deprivation therapy (ADT), there has been little systematic research on this issue. The present study examined changes in fatigue among prostate cancer patients receiving ADT compared to controls and predictors of heightened fatigue in ADT patients. Methods Prostate cancer patients treated with ADT (ADT+ group, n = 60) completed assessments of fatigue prior to or just after ADT initiation (baseline) and 6 and 12 months later. Prostate cancer patients treated with prostatectomy only (ADT− group, n = 85) and men without cancer (CA− group, n = 86) matched on age and education completed assessments at similar intervals. Results Group-by-time interactions for fatigue severity, interference, and duration were observed when comparing the ADT+ group to the controls. Groups did not differ at baseline; however, the ADT+ group reported worse fatigue at 6 and 12 months. The same pattern was observed for changes in the prevalence of clinically meaningful fatigue and the extent of clinically meaningful change in fatigue. Within the ADT+ group, higher baseline comorbidity scores were associated with greater increases in fatigue interference, and higher baseline Gleason scores were associated with greater increases in fatigue duration. Conclusions Prostate cancer patients receiving ADT demonstrate a trajectory of worsened fatigue during the first 12 months following treatment initiation relative to the controls. Greater comorbidities and higher Gleason scores at baseline appear to be risk factors for heightened fatigue during the first year following ADT initiation. Results highlight important time points for implementation of interventions aimed at fatigue reduction.
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Introduction: Some men seek castration outside a clear medical need. This study explored how their sexuality changed after castration. Aim: To explore changes in preferred gender(s) of sexual attraction, fantasy, and relationships in voluntarily castrated men with or without gonadal hormone therapy. Methods: A questionnaire was posted at http://www.eunuch.org that yielded data on men who had been voluntarily castrated physically (n = 198) or chemically (n = 96). Main Outcome Measures: Respondents were asked to report retrospectively on their sexuality, including their sexual activity and which gender(s) they were sexually attracted to, fantasized about, or had sexual relations with 6 months to 1 year before and after castration. Results: A substantial proportion of men remained sexually active after castration; 37% had sex at least several times per week. Most respondents did not report a change in preferred gender(s) of attraction (65%, n = 181), fantasies (62%, n = 169), or sexual relationships (66%, n = 163), although approximately 20% to 30% of respondents did report such changes and 8% to 11% became non-sexual after castration. Respondents who were attracted to and fantasized about “only men” or who had sexual relationship with “only women” before castration were the least likely to report a change subsequent to castration. Respondents who were taking neither supplemental testosterone nor estrogen were more likely to report (i) becoming attracted to no one, (ii) fantasizing about no one, and (iii) becoming sexually inactive. Conclusion: Sexual changes in voluntarily castrated men vary and can be influenced by various factors including the use of supplemental testosterone or estrogen therapy.
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Although eye tracking has been used for decades, it has gained popularity in the area of sex research only recently. The aim of this article is to examine the potential merits of eye tracking for this field. We present a systematic review of the current use of video-based eye-tracking technology in this area, evaluate the findings, and identify future research opportunities. A total of 34 relevant studies published between 2006 and 2014 were identified for inclusion by means of online databases and other methods. We grouped them into three main areas of research: body perception and attractiveness, forensic research, and sexual orientation. Despite the methodological and theoretical differences across the studies, eye tracking has been shown to be a promising tool for sex research. The article suggests there is much potential for further studies to employ this technique because it is noninvasive and yet still allows for the assessment of both conscious and unconscious perceptional processes. Furthermore, eye tracking can be implemented in investigations of various theoretical backgrounds, ranging from biology to the social sciences.
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231 Background: Eye-tracking research has demonstrated that heterosexual men with normal testosterone levels attend visually to features of women associated with fertility, notably their breast size and waist to hip ratio. As such, eye-tracking data can serve as an implicit measure of a man’s libido. Many treatments for prostate cancer (PCa)—in particular androgen deprivation therapy (ADT)—depress sexual interest in men, but there is no objective measure of the intensity of this effect. Here we explore whether eye-tracking can be used to quantify the impact of PCa treatments on men’s libido. Methods: We used an IRB-approved deception protocol to explore the validity of eye-tracking technology for assessing the level of sexual interest of PCa patients and normal controls. Three age-matched groups of heterosexual men aged 50 years and older were recruited. They were: PCa patients using ADT, PCa patients not using ADT, and healthy controls. Unaware that their eye movements were being tracked, all were exposed to photographs of female models, either fully clothed (neutral) or minimally clothed (sexy). Number and duration of eye fixations on target areas of the female models’ bodies were recorded. Results: Trends observed in our preliminary data suggest that men on ADT exhibit differential patterns of visual attention to sexual stimuli compared to men in the other two groups. Although confirmation with a larger sample size is required, such shifts in attention may provide an objective measure of the influence of cancer treatments on the libido of PCa patients. Conclusions: Eye-tracking technology may provide a reliable and objective technique for measuring the libido of cancer patients. Such data could help patients be better informed about psychological side effects when making treatment decisions. They could also lead to ways to both study and reduce the impact of PCa treatments on men’s sexual interest.
Article
Objectives: To compare quality-of-life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone-releasing hormone agonists (LHRHa) for androgen-deprivation therapy (ADT). Patients and methods: Men with locally advanced or metastatic prostate cancer participating in an ongoing randomised, multicentre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via three or four transcutaneous patches containing oestradiol 100 μg/24 h. LHRHa was administered as per local practice. Patients completed questionnaires based on the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORTC QLQ-C30) with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms. Results: In all, 727 men were enrolled between August 2007 and October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median (interquartile range) age of 74 (68-79) years and PSA level of 44 (19-119) ng/mL, and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than those on LHRHa (mean difference +4.2, 95% confidence interval 1.2-7.1; P = 0.006), less fatigue, and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynaecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to the tE2 arm. Conclusion: Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynaecomastia. The ongoing trial will evaluate clinical efficacy and longer term QoL. These findings are also potentially relevant for short-term neoadjuvant ADT.
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There is a growing interest in individual visuo-spatial skills and their role in environment learning from navigation because they can be key factors in explaining how navigation performance varies across individuals. The present study examined the role of visuo-spatial skills in navigation-based environment learning, focusing on rotation ability and visuo-spatial working memory (VSWM). A group of 83 females individually performed a series of visuo-spatial and verbal (control) tasks, and learned three routes through the same virtual environment. Their recall of each route (retraced in the same environment or reproduced separately in a drawing) and of the whole environment (in a drawing of all three routes and the identification of a shortcut) was assessed. Two path models were developed (using single route [Model 1] and whole environment [Model 2] recall performance as final dependent variables), inputting the rotation task as the initial predictor and VSWM between the predictor and the dependent variables. The results showed that the relationship between rotation ability and environment learning accuracy is indirect, through the intervention of VSWM. How individual visuo-spatial skills can work at different levels (as an interface and/or as a-priori abilities) is discussed.
Chapter
Sex differences in neurological disease exist in incidence, severity, progression, and symptoms and may ultimately influence treatment. Cognitive disturbances are frequent in neuropsychiatric disease with men showing greater cognitive impairment in schizophrenia, but women showing more severe dementia and cognitive decline with Alzheimer's disease. Although there are no overall differences in intelligence between the sexes, men, and women demonstrate slight but consistent differences in a number of cognitive domains. These include a male advantage, on average, in some types of spatial abilities and a female advantage on some measures of verbal fluency and memory. Sex differences in traits or behaviors generally indicate the involvement of sex hormones, such as androgens and estrogens. We review the literature on whether adult levels of testosterone and estradiol influence spatial ability in both males and females from rodent models to humans. We also include information on estrogens and their ability to modulate verbal memory in men and women. Estrone and progestins are common components of hormone therapies, and we also review the existing literature concerning their effects on cognition. We also review the sex differences in the hippocampus and prefrontal cortex as they relate to cognitive performance in both rodents and humans. There has been greater recognition in the scientific literature that it is important to study both sexes and also to analyze study findings with sex as a variable. Only by examining these sex differences can we progress to finding treatments that will improve the cognitive health of both men and women. © 2016 American Physiological Society. Compr Physiol 6:1295-1337, 2016.
Article
Unlabelled: Estradiol (E2) acutely potentiates glutamatergic synaptic transmission in the hippocampus of both male and female rats. Here, we investigated whether E2-induced synaptic potentiation occurs via presynaptic and/or postsynaptic mechanisms and which estrogen receptors (ERs) mediate E2's effects in each sex. Whole-cell voltage-clamp recordings of mEPSCs in CA1 pyramidal neurons showed that E2 increases both mEPSC frequency and amplitude within minutes, but often in different cells. This indicated that both presynaptic and postsynaptic mechanisms are involved, but that they occur largely at different synapses. Two-photon (2p) glutamate uncaging at individual dendritic spines showed that E2 increases the amplitude of uncaging-evoked EPSCs (2pEPSCs) and calcium transients (2pCaTs) at a subset of spines on a dendrite, demonstrating synapse specificity of E2's postsynaptic effects. All of these results were essentially the same in males and females. However, additional experiments using ER-selective agonists indicated sex differences in the mechanisms underlying E2-induced potentiation. In males, an ERβ agonist mimicked the postsynaptic effects of E2 to increase mEPSC, 2pEPSC, and 2pCaT amplitude, whereas in females, these effects were mimicked by an agonist of G protein-coupled ER-1. The presynaptic effect of E2, increased mEPSC frequency, was mimicked by an ERα agonist in males, whereas in females, an ERβ agonist increased mEPSC frequency. Thus, E2 acutely potentiates glutamatergic synapses similarly in both sexes, but distinct ER subtypes mediate the presynaptic and postsynaptic aspects of potentiation in each sex. This indicates a latent sex difference in which different molecular mechanisms converge to the same functional endpoint in males versus females. Significance statement: Some sex differences in the brain may be latent differences, in which the same functional endpoint is achieved through distinct underlying mechanisms in males versus females. Here we report a latent sex difference in molecular regulation of excitatory synapses in the hippocampus. The steroid 17β-estradiol is known to acutely potentiate glutamatergic synaptic transmission in both sexes. We find that this occurs through a combination of increased presynaptic glutamate release probability and increased postsynaptic sensitivity to glutamate in both sexes, but that distinct estrogen receptor subtypes underlie each aspect of potentiation in each sex. These results indicate that therapeutics targeting a specific estrogen receptor subtype or its downstream signaling would likely affect synaptic transmission differently in the hippocampus of each sex.
Article
There is ample empirical evidence to support the notion that the biological impacts of estrogen extend beyond the gonads to other bodily systems, including the brain and behavior. Converging preclinical findings have indicated a neuroprotective role for estrogen in a variety of experimental models of cognitive function and brain insult. However, the surprising null or even detrimental findings of several large clinical trials evaluating the ability of estrogen-containing hormone treatments to protect against age-related brain changes and insults, including cognitive aging, stroke, and traumatic brain injury, led to hesitation by both clinicians and patients in the use of exogenous estrogenic treatments for nervous system outcomes. That estrogen-containing therapies are used by tens of millions of women for a variety of health-related applications across the lifespan has made identifying conditions under which benefits with estrogen treatment will be realized an important public health issue. Here we provide a summary of the biological actions of estrogen and estrogen-containing formulations. We have devoted special attention to highlighting the notion that estrogen appears to be a conditional neuroprotectant whose efficacy is modulated by several interacting factors. By developing criteria standards for desired beneficial peripheral and neuroprotective outcomes among unique patient populations, we can optimize estrogen treatments for attenuating the consequences of, and perhaps even preventing, cognitive aging and brain injury.
Article
Objective: The aim of this study was to investigate the effects of hormone therapy (HT) on depression and depressive symptoms in prostate cancer patients undergoing 6 months of HT. Methods: One hundred two prostate cancer patients who had been prescribed HT completed the Zung Self-rating Depression Scale (SDS) and two questions about their sexual enjoyment and performance, plus a background questionnaire before HT, after 8 to 10 weeks of HT and again after 16 to 20 weeks of HT. Results: There was a significant increase in SDS scores from before to during HT. High depression score before HT was a significant predictor of later increases in depression during HT. Increases in depressive symptoms were restricted to 8 of the 20 SDS symptoms, the most powerful change being in sexual anhedonia, which was a result of decreased ability to perform during sexual activity. Conclusions: The association between HT and elevated depression is confirmed, but the relative influence of sexual anhedonia over other depressive symptoms expands the understanding of this association. The effects of decreased ability to perform during sex appear to dominate the increase in depression during HT. Copyright © 2016 John Wiley & Sons, Ltd.