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CNS & Neurological Disorders - Drug Targets, 2016, 15, 337-343 337
1871-5273/16 $58.00+.00 © 2016 Bentham Science Publishers
The Effects of Testosterone Supplementation on Cognitive Functioning in
Older Men
Eka J. Wahjoepramono1,2,§, Prita R. Asih1,2,3,§, Vilia Aniwiyanti2, Kevin Taddei1,3, Satvinder S. Dhaliwal5,
Stephanie J. Fuller3, Jonathan Foster6, Malcolm Carruthers1,7, Giuseppe Verdile1,3,4, Hamid R. Sohrabi1,3
and Ralph N. Martins*,1,3
1School of Medical Sciences, Faculty of Computing, Health, and Science, Edith Cowan University, Joondalup, WA,
Australia
2Medical Faculty, Pelita Harapan University, Neuroscience Centre, Siloam Hospitals, Lippo Karawaci, Tangerang,
Indonesia
3The Sir James McCusker Alzheimer’s Disease Research Unit, School of Psychiatry and Clinical Neurosciences,
University of Western Australia, Hollywood Private Hospital, Nedlands, WA, Australia
4School of Biomedical Sciences, Curtin University, Bentley, WA Australia
5School of Public Health, Curtin University of Technology, Bentley, WA, Australia
6School of Psychology and Speech Pathology, Curtin University of Technology, Bentley, WA, Australia
7Centre of Men’s Health, London, UK
Abstract: Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia.
Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer’s
disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and
low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various
measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the
baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone
treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B)
received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TèP), compared to
baseline, there was a modest (1 point) but significant improvement in general cognitive functioning as measured by the
Mini Mental State Examination (MMSE) following testosterone treatment. This improvement from baseline was sustained
following the washout period and crossover to placebo treatment. Similar Mini Mental State Examination (MMSE) scores
were observed when comparing testosterone treatment with placebo. In group B (PèT) a significant increase was observed
from baseline following testosterone treatment and a trend towards an increase when compared to placebo treatment.
Improvements in baseline depression scores (assessed by Geriatric Depression Scale) were observed following
testosterone/placebo treatment in both groups, and no difference was observed when comparing testosterone with placebo
treatment. Our findings indicate a modest improvement on global cognition with testosterone treatment. Larger clinical
trials with a longer follow- up and with the inclusion of blood and brain imaging markers are now needed to conclusively
determine the significance of testosterone treatment.
Keywords: Testosterone, Androgen, cognition, ageing, memory, dementia, depression, Apolipoprotein E, Alzheimer’s disease.
1. INTRODUCTION
Aging is associated with a gradual decline in sex
hormone levels in men, together with a deterioration in
general health, mood and cognitive abilities. In
epidemiological studies of healthy older men, higher
testosterone concentrations have been associated with better
global cognition, executive functions, and verbal memory
*Address correspondence to this author at the Suite 22, Hollywood Medical
Centre, 85 Monash Avenue, Nedlands, WA 6009, Australia; Tel: +61 8
9347 4200; Fax: +61 8 9347 4299; E-mail: r.martins@ecu.edu.au
§These authors have equally contributed to the manuscript preparation.
[1]. Most recently, testosterone levels have been associated
with an increase in the brain amyloid load, a major
Alzheimer’s disease (AD) pathological hallmark, in men at
risk of AD [2].
The potential benefits of testosterone replacement
therapy for the safety and physiological assessment has been
demonstrated in men with low testosterone levels and who
have subjective memory complaints at risk of cognitive
decline [3]. Even elderly men who are above 65 years old
with late onset hypogonadism benefit as much as the
younger men in terms of safety profile and increasing
testosterone levels [4]. With respect to cognition, although
cell culture and animal studies have provided support for
testosterone in having potential therapeutic benefits in AD
338 CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 3 Wahjoepramono!et al.
[5]. there have been relatively few studies that have trialed
testosterone supplementation in men with AD or mild
cognitive impairments (MCI) and none have evaluated
testosterone treatment in individuals that are pre-
symptomatic but at a greater risk of cognitive decline. These
studies have shown mixed outcomes with improvements in
certain cognitive domains [6], to no improvement [7, 8]. A
number of factors may account for the discrepancies in the
outcomes of these trials, including differences in type, mode
and dosage of treatment. Furthermore, modifying roles for
genetic factors such as the presence of the AD risk factor,
apolipoprotein E (APOE ε4) allele, may also influence
outcomes of trials and the benefits of testosterone on
cognition or AD like pathology [9]. In addition, testosterone
supplementation as potential prevention and/or therapeutics
prevention of AD should start at the earliest phase of the
disease when primary prevention may provide maximal
benefit. In the current study, the efficacy of testosterone
treatment on cognitive function and depression was assessed
during a six-month, double blind, cross-over treatment trial
in older men with subjective memory complaints and low
testosterone levels.
2. MATERIALS AND METHODS
2.1. Participants
This study was undertaken at the Siloam Hospital in
Lippo Karawaci, Tangerang, Indonesia. Ethics approval was
obtained from the Independent Human Ethics Committee,
Faculty of Medicine, University of Indonesia as well as from
Edith Cowan University, Western Australia. Informed
consent was obtained from all participants prior to the study.
Participants were recruited from all areas surrounding
Jakarta and Tangerang, Indonesia. The eligibility criteria
included: 1) Males aged ≥50 yrs old; 2) Presenting with
subjective memory complaints; 3) Testosterone levels of
300- 600 ng/dL (~10.4-20.8 nmol/L); 4) Normal prostate-
specific antigen (PSA) levels; 5) Normal blood pressure of
120/80 mmHg to 90/60 mmHg; 6) No diagnosis of diabetes
mellitus; 7) Normal liver and kidney enzyme function; 8) No
previous history of severe head injury and stroke ; 9) No
significant history of alcohol abuse ; 10) Normal cognitive
function, established using a score ≥24 on the Mini Mental
State Examination (MMSE); and 11) ≥6 years of education.
A clinical panel consisting of a neurologist and a
neuropsychologist reviewed each volunteer’s cognitive and
pathology blood results prior to recruitment into the study.
Fig. (1) depicts the participant recruitment and
randomization process and outlines number of participants
recruited from the initial screen and drop-outs during this
double blind, randomized study. A total of 44 men were
assigned to one of the two parallel, crossover groups, starting
with placebo (n=22) or testosterone (n=22) treatment and
transferred to testosterone and placebo after a 4 week wash-
out period. Assignment was random using stratification for
memory performance at baseline. Each participant had a total
of 11 clinic visits within the 52-week study period.
Intervention included applying a testosterone cream, namely
50 mg of AndroForte® 5% manufactured by Lawley
Pharmaceuticals, Perth, Australia, applied daily to the
scrotum via transdermal route for a period of 24 weeks. This
cream contains dl-α- tocopherol acetate (vitamin E) and
almond oil formulated to protect testosterone from oxidation.
It also contains cetomacrogol 1000, cetostearyl alcohol,
butylated hydroxytoluene, anhydrous citric acid,
triethanolamine, carbomer 940, B & J Phenonip® and
purified water. The placebo included dl-alpha tocopherol
acetate (vitamin E) only [without the active ingredient:
testosterone] and was applied in a similar manner to the
testosterone cream. Dose and site of application were
evaluated in a separate small pilot study as presented in
supplementary information.
2.2. Clinical and Neuropsychological Measures
Neuropsychological measurements were performed at
four different time points: week 0 (baseline), week 24 (1st
treatment period), week 28 (washout period) and week 52
(2nd treatment or cross-over period), while blood biomarker
measurements and apolipoprotein (APOE) genotyping were
performed as described previously [3]. Global cognitive
function was assessed using the Mini Mental State
Examination (MMSE) [10]. Verbal memory was assessed
using Rey Auditory Verbal Learning Test (RAVLT) [11].
Comparable, parallel Indonesian versions of the RAVLT
were administered at each time point to limit the practice and
learning effects. A standardized Indonesian translation of
Geriatric Depression Scale (GDS-30) with a cut off score of
≥11 was used to measure depressive symptoms [12].
Physicians, participants, and investigators were blind to the
treatment conditions.
2.3. Statistical Analysis
Statistical analysis was performed using the Statistical
Package for Social Sciences (SPSS version 21, SPSS Inc,
Chicago, IL). The Kolmogorov-Smirnov and Levene’s tests
for the MMSE, RAVLT, and GDS indicated normally
distributed data. To analyse each arm of the study
individually (testosterone to placebo “T!P” and placebo to
testosterone “P!T”) and overall, a mixed model ANOVA
analysis was used, consisted of fixed effects for treatment (to
compare testosterone and placebo treatments), treatment
period (testosterone or placebo), and sequence (testosterone
treatment first or placebo treatment first). Carry-over effects
were investigated by looking for differences between
baseline readings and readings at week 28 after the washout
period (weeks 24-28), was considered as the baseline reading
for the second treatment period. To analyse the results of
each treatment arms independently, one-way repeated
measures ANOVA was performed.
3. RESULTS
A total of 44 elderly men (32 APOE ε4 non carriers, 72%
and 12 APOE ε4 carriers) were randomized. Participants in
both T!P & P!T groups were comparable on age and
education (Age : T!P 59.2 + 7.2, P!T 62.9 + 8.2 ;
Education: T! P 13.9 + 2.8, P!T 13.7 + 3.3). There were
no significant differences in age or education between the
APOE ε4 carriers and non-APOE ε4 carriers.
Testosterone supplementation significantly increased the
serum levels of T and its metabolite DHT and reduced the
Testosterone and Cognitive Functions in Older Men CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 3 339
LH levels, when compared to baseline, placebo
administration or the washout period prior to crossover
treatment. Estradiol levels were similar following all
treatment periods (Tables 1 and 2). The results confirm that
the treatment regime was effective at increasing serum
testosterone and lowering LH levels.
3.1. Effects of Testosterone on Measures of Cognitive
Functioning and Depression
Compared to baseline MMSE scores, participants in the
testosterone then placebo (T!P) the treatment arm (Group
A) showed a modest but significant improvement with
testosterone supplementation (Table 1). The MMSE scores
of participants from the T!P arm remained at
approximately the same level for 52 weeks despite the fact
that testosterone treatment had been stopped at week 24 and
replaced with placebo at week 28 following the washout
period. In the P!T arm (started with placebo and transferred
to testosterone after the washout period, Group B) the
MMSE scores were only increased when they started the
testosterone application (Table 2). In both treatment arms, no
significant changes in MMSE scores were observed from
baseline following placebo treatment. In both groups, MMSE
scores were similar when comparing testosterone treatment
with placebo treatment. Also, no significant differences were
observed in verbal memory across treatment groups as
measured by immediate and delayed recall on the RAVLT
(Tables 1 and 2).
Depression scores significantly decreased following
testosterone treatment and the observed improvement
maintained during the washout and following crossover to
the administration of placebo compared to baseline in the
T!P treatment (Group A) (Table 1). Interestingly, the
placebo group showed a trend towards improvement in their
follow up depression scores compared to the baseline in the
P!T treatment (Group B) (Table 2). When compared to
placebo, testosterone treatment significantly decreased
depression scores in the T!P treatment, but not the P!T
treatment (Tables 1 and 2).
4. DISCUSSION
Our findings showed that significant improvements in
baseline MMSE scores occurred after testosterone treatment
in both arms of the study compared to baseline, consistent
with previous studies assessing testosterone in AD and MCI
subjects. In addition, when testosterone was administered
first, we saw an improvement in MMSE score at the end of
the washout and placebo phases. This finding suggests that
there may be carry-over effect of testosterone treatment.
These potentially lasting, beneficial effects of testosterone on
global cognition are in line with previous studies that
indicated changes in cognitive capacity following hormonal
manipulation do not return to baseline levels but are
preserved or continue to change in the same direction after
cessation of hormone treatment [7, 13]. This finding may
partially be a by-product of baseline hormonal state because
it has been indicated that baseline hormonal state may affect
ones response with carry-over effects [14]. A comparison
between placebo and testosterone treatment in group B
(commenced with placebo treatment), revealed no significant
differences (although a trend towards an increase was noted,
p=0.087). It is not clear why no differences were observed in
comparing placebo and testosterone. One potential
contributing factor maybe the similar ingredient that made
up the base of the cream. Both creams contained low doses
of dl-α-tocopherol acetate (Vitamin E) and almond oil to
allow greater systemic absorption of testosterone. Vitamin E
has shown to alter cognition in AD and MCI patients at
~2000 IU/day when consumed orally from 6 months to 4
years [15, 16]. In our study the cream contained less than 5%
of the dose of Vitamin E needed for clinical efficacy
(~111IU/day) and was administered topically, thus it is
Fig. (1). An outline of participant’s recruitment and randomization process [3].
340 CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 3 Wahjoepramono!et al.
unlikely that enough Vitamin E was systemically absorbed to
have cognitive enhancing effects.
There are, however, conflicting findings on the effects of
testosterone on global cognition with studies showing no
evidence of cognitive enhancing properties with testosterone.
A randomized double blind placebo controlled study by
Haren et al., 2005, showed no increase in MMSE scores in
76 men following 12 months of oral testosterone
undecanoate or placebo, after taking into the account of the
baseline hormone and MMSE levels [17]. Another study by
Kenny et al., 2004 also showed no significant changes in
global cognitive performance with 12 weeks of
intramuscular testosterone treatment in older men with early
cognitive decline and low testosterone levels [18].
Despite relatively modest improvements in baseline
global cognition with testosterone, our study showed no
beneficial effects on episodic verbal memory. This finding is
in accordance with those from another study that did not
show a consistent improvement across all cognitive domains
in relation to higher levels of testosterone [19]. While some
studies have found an association between testosterone and
verbal memory [20, 21], other studies have not reported
similar results [22, 23]. Moreover, the improvement on
verbal memory was found to last only for a short term, as
shown by Cherrier et al., 2015 that this improvement was
observed at 3 months and was not sustained at 6 months of
treatment [20]. It has been suggested that inconsistencies in
these studies could be explained by the concept of changes in
the optimal testosterone range and the possibility of a
curvilinear association between testosterone and cognitive
performance [19, 21]. For example, Cherrier et al. (2007)
reported that men with moderate increases in serum
testosterone and its metabolites showed significant
improvements in verbal and spatial memory, but that these
effects were not observed in men with larger or negligible to
low increases in testosterone concentration. In addition, men
who had higher levels of both testosterone and E2
subsequent to testosterone treatment showed better
performance on tests of verbal memory compared to pre-
treatment scores and compared to placebo treatment [21].
The E2 levels reached in our study (following transdermal
testosterone administration) may not have been sufficient to
improve memory. The peak serum levels of E2 in our study
Table 1. Cognitive scores and serum testosterone, DHT and estradiol for men that were administered Testosterone then Placebo
(Group A, n=22, Mean±SD).
Baseline (Week 0)
Testosterone (Week 24)
Wash Out
Placebo (Week 52)
MMSE1
27.3±1.7
28.3±1.5*
28.0±1.2*
28.2±1.3*
RAVLT2
Immediate Recall3
44.3±6.9
46.9±7.8
47.9±7.9
47.0±10.1
Delayed Recall
8.4±2.2
8.9±1.9
9.5±2.5
9.6±2.6
GDS4
7.1±5.5
4.5±3.3*#
3.5±3.1*
3.2±2.8*
Testosterone (nmol/L)
16.5±4.4
26.7±12.1*#
17.3±4.4
15.3±4.1
DHT (nmol/L)
1.84±0.9
9.1±4.9*#
1.8±1.7
1.7±0.8
Estradiol (pmol/L)
81.2±22.7
85.6±33.8
83.1±7.9
92.4±18.6
LH (U/L)
4.2±2.8
2.1±1.2*#
4.2±2.4
4.8±3.3
1Mini Mental State Examination; 2Rey Auditory Verbal Learning Test; 3RAVLT Learning Trial 1-5 total score; 4Geriatric Depression Scale. *p<0.05, values significantly different
compared to baseline; #p<0.05, values significantly different compared to placebo.
Table 2. Cognitive scores and serum testosterone, DHT and estradiol for men that were administered Placebo then Testosterone
(Group B, n=22, Mean±SD).
Baseline (Week 0)
Placebo (Week 24)
Wash Out
Testosterone (Week 52)
MMSE1
27.05±1.64
27.82±1.3
27.77±1.5
28.14±1.8*
RAVLT2
Immediate Recall3
42.4±9
44.1±8.2
47.4±8.6
46.7±10.2
Delayed Recall
8.5±3
8.1±3.2
9.8±2.8
9.7±3.5
GDS4
6.4±5.6
4.9±3.9
4.9±4.5
4.5±4*
Testosterone (nmol/L)
17.9±6.3
16.6±4.6
16.8±5.9
24.5±13.8*#
DHT (nmol/L)
2.8±0.8
1.7±0.9
1.7±1.6
8.4±5.7*#
Estradiol (pmol/L)
85.8±26.4
88.4±29.6
84.8±29.3
91.3±40.1
LH (U/L)
4.7±2.6
5.6±3.4
4.6±1.9
3.1±2.6* #
1Mini Mental State Examination; 2Rey Auditory Verbal Learning Test; 3RAVLT Learning Trial 1-5 total score; 4Geriatric Depression Scale. *p<0.05, values significantly different
from baseline; #p<0.05, values significantly different from placebo.
Testosterone and Cognitive Functions in Older Men CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 3 341
were in the lower one-third of the normal range for men. We
believe our mode of application of testosterone on the
scrotum explains the above finding with testosterone being
converted to DHT and thus not being susceptible to
aromatization which is usually observed in older men [24].
Our study shows that, albeit modestly, testosterone can
increase baseline global cognition following 24 weeks but
taken together with the above mentioned studies, it also
highlights the need for further validation studies. These may
involve a longer follow-up periods, reversing treatment to
placebo after the crossover completion or an open label study
following completion. As highlighted in a study of 500
elderly men that lower testosterone levels at baseline was
associated with a higher risk of cognitive decline at a 2 year
follow up [25]. Thus follow-up studies with larger
participants and longer treatment durations are required to
determine the efficacy of testosterone in preventing or
slowing down the progression of cognitive decline.
Depression symptoms can contribute to future cognitive
decline in older adults [26, 27]. Studies of testosterone
treatment in relation to depression levels have produced
conflicting results. It is likely that the relationship is complex
in nature and involves interaction between genetic,
environmental and lifestyle factors. Some studies have
shown no association between endogenous testosterone
levels and depressive symptoms [28] and may not be
beneficial for patients who have reached a clinical
depression state or are highly depressed [29]. However, a
significant improvement in depression following testosterone
treatment has been previously reported, with one study
observing the strongest effect in men with the lowest
baseline total testosterone [30]. It was shown that men with
sub-threshold levels of depression treated with testosterone
had greater reductions in symptoms of depression than
placebo treated men [31]. Furthermore, a recent study by
Cherrier et al. (2015) reported that men with MCI and low
testosterone levels had decreased depression symptoms
following 6 month transdermal testosterone gel treatment
[20]. In the present study, compared to baseline, depression
levels decreased following testosterone treatment in both
treatment arms. In T!P treatment (Group A), GDS scores
were reduced following administering testosterone, in the
wash-out period and following administering placebo. This
could be partially explained by the lasting benefits of
testosterone (similar to the effects on global cognition).
However, further reduction was observed when placebo at 52
weeks was compared to testosterone at 24 weeks. In
addition, in the P!T treatment (Group B), although not
significant, there was a trend towards a reduction when
placebo was administered with a further reduction following
testosterone treatment. Overall, these results may suggest a
placebo effect on reducing GDS scores. As discussed above
the low dose of Vitamin E within the creams is not likely to
confer benefits over the treatment period. Other factors may
contribute such as being active in the trial and engaging with
researchers on a regular basis.
It is also difficult to determine whether there is a placebo
effect in interpreting this result when the course of
development of AD is unknown in this cohort [32]. The
physician-patient relationship which resulted in the
expectations and motivations of the patient thus probably
also has modifying changes on the placebo response [33],
and where there is no untreated (control) group to define the
true placebo effect [33, 34].
CONCLUSION
Some limitations of the present study should be
acknowledged. Although larger than some of the previous
studies, this study was relatively underpowered with small
sample sizes (n=44) to conclusively determine testosterone
treatment on cognition. It is also possible that our memory
measure, the RAVLT, was not able to detect small or subtle
changes in cognitively intact participants even though we
used parallel forms to avoid the practice effect and the
RAVLT has proven to appropriately evaluate episodic verbal
memory [11]. Despite these limitations, this is the first
double blind randomized crossover placebo-controlled study
that evaluated the effect of short term testosterone treatment
on cognitive functioning in older men with low to low-
normal testosterone levels and who have a subjective
memory complaint. When combined with genetic risk
factors, brain amyloid imaging and other AD related
biomarkers, subjective memory complainers are at higher
risk of clinically defined cognitive decline than non-memory
complainers. We have also previously shown that in addition
to APOEε4, changes in hormone levels (LH) is strongly
correlated with greater brain amyloid load in subjective
memory complainers [2], providing further support that this
is an appropriate cohort to include in such a trial. Data from
our current study indicated that testosterone supplementation
lowered LH, investigating the impact on the association
between LH and brain amyloid load in subjective memory
complainers would be further warranted. Our findings of a
modest improvement from baseline in global cognition are
promising but require comprehensive larger longer term
studies to investigate the efficacy of testosterone treatment
on cognitive and clinical measures with the inclusion of
blood and brain imaging markers.
TRIAL REGISTRATION
The Australian New Zealand Clinical Trials Registry
(ANZCTR). Trial ID ACTRN12614000277640
LIST OF ABBREVIATIONS
AD = Alzheimer’s Disease
DHT = Dihydrotestosterone
GDS = Geriatric Depression Scale
LH = Luteinizing Hormone
MCI = Mild Cognitive Impairment
MMSE = Mini Mental State Examination
P = Placebo
PSA = Prostate Specific Antigen
RAVLT = Rey Auditory Verbal Learning Test
T = Testosterone
342 CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 3 Wahjoepramono!et al.
CONFLICT OF INTEREST
RNM is the founder and owns stock in Alzhyme. HRS
has received personal compensation for activities with Pfizer
and Wyeth and currently with Takeda Pharmaceuticals. The
Lawley Pharmaceuticals, Perth Western Australia, has kindly
provided the testosterone cream, namely AndroForte® 5%,
and the placebo, dl-alpha tocopherol acetate (vitamin E). The
Lawley Pharmaceuticals was not involved in any way or by
any means in the study design, data collection or data
analysis and data interpretation. There are no actual or
potential conflicts of interest.
ACKNOWLEDGEMENTS
We acknowledge Edith Cowan University and the
McCusker Alzheimer’s Research Foundation, Perth Western
Australia and Siloam Hospitals Lippo Village, Tangerang
Indonesia for generously funding this study. We would like
to thank the Lawley Pharmaceuticals, Perth Western
Australia for partially supporting this study by providing the
intervention drug and its placebo. We are indebted to the
Indonesian participants and research volunteers for making
this study possible. GV is supported by the NH&MRC
(APP1045507) and the Curtin University Senior Research
Fellowship (CRF140196).
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher’s
web site along with the published article.
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Received: June 8, 2015 Revised: September 16, 2015 Accepted: September 30, 2015
DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department
reserves the right to make minor modifications for further improvement of the manuscript.
PMID: 26553159
