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Musculoskeletal and Prostate Effects of Combined Testosterone and

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 Am J Physiol Endocrinol Metab 306: E433–E442, 2014.
First published December 10, 2013; doi:10.1152/ajpendo.00592.2013.

Musculoskeletal and prostate effects of combined testosterone and finasteride

administration in older hypogonadal men: a randomized, controlled trial
Stephen E. Borst,1,5 Joshua F. Yarrow,2,5 Christine F. Conover,2 Unyime Nseyo,4 John R. Meuleman,1
Judyta A. Lipinska,2 Randy W. Braith,5 Darren T. Beck,1,8 Jeffrey S. Martin,9 Matthew Morrow,3
Shirley Roessner,2 Luke A. Beggs,5 Sean C. McCoy,2,6 Darryl F. Cannady 2nd,2 and Jonathan J. Shuster7
1
Geriatric Research, Education and Clinical Center, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida;
2
Veterans Affairs Medical Center Research Service, Gainesville, Florida; 3Veterans Affairs Medical Center Pharmacy
Service, Gainesville, Florida; 4Veterans Affairs Medical Center Urology Service, Gainesville, Florida; 5Department of
Applied Physiology and Kinesiology, University of Florida, Gainesville, Gainesville, Florida; 6Department of Animal
Sciences, Gainesville, Florida; 7Department of Health Outcomes and Policy, Gainesville, Florida; 8Department of
Kinesiology, University of Rhode Island, Kingston, Rhode Island; and 9Department of Biomedical Sciences, Quinnipiac
University, Hamden, Connecticut
Submitted 24 October 2013; accepted in final form 5 December 2013

Borst SE, Yarrow JF, Conover CF, Nseyo U, Meuleman JR,
Lipinska JA, Braith RW, Beck DT, Martin JS, Morrow M, Roessner
S, Beggs LA, McCoy SC, Cannady DF 2nd, Shuster JJ. Musculosk-
eletal and prostate effects of combined testosterone and finasteride ad-
ministration in older hypogonadal men: a randomized, controlled trial.
Am J Physiol Endocrinol Metab 306: E433–E442, 2014. First published
December 10, 2013; doi:10.1152/ajpendo.00592.2013.—Testosterone
acts directly at androgen receptors and also exerts potent actions
following 5␣-reduction to dihydrotestosterone (DHT). Finasteride
(type II 5␣-reductase inhibitor) lowers DHT and is used to treat
benign prostatic hyperplasia. However, it is unknown whether ele-
vated DHT mediates either beneficial musculoskeletal effects or
prostate enlargement resulting from higher-than-replacement doses of
testosterone. Our purpose was to determine whether administration of
testosterone plus finasteride to older hypogonadal men could produce
musculoskeletal benefits without prostate enlargement. Sixty men
aged ⱖ60 yr with a serum testosterone concentration of ⱕ300 ng/dl or
bioavailable testosterone ⱕ70 ng/dl received 52 wk of treatment with
testosterone enanthate (TE; 125 mg/wk) vs. vehicle, paired with
finasteride (5 mg/day) vs. placebo using a 2 ⫻ 2 factorial design. Over
the course of 12 mo, TE increased upper and lower body muscle
strength by 8 –14% (P ⫽ 0.015 to ⬍0.001), fat-free mass 4.04 kg (P ⫽
0.032), lumbar spine bone mineral density (BMD) 4.19% (P ⬍ 0.001),
and total hip BMD 1.96% (P ⫽ 0.024) while reducing total body fat
⫺3.87 kg (P ⬍ 0.001) and trunk fat ⫺1.88 kg (P ⫽ 0.0051). In the
first 3 mo, testosterone increased hematocrit 4.13% (P ⬍ 0.001).
Coadministration of finasteride did not alter any of these effects. Over
12 mo, testosterone also increased prostate volume 11.4 cm3 (P ⫽
0.0051), an effect that was completely prevented by finasteride (P ⫽
0.0027). We conclude that a higher-than-replacement TE combined
with finasteride significantly increases muscle strength and BMD and
reduces body fat without causing prostate enlargement. These results
demonstrate that elevated DHT mediates testosterone-induced pros-
tate enlargement but is not required for benefits in musculoskeletal or
adipose tissue.
testosterone; hypogonadal; prostate enlargement
SOME STUDIES OF TESTOSTERONE TREATMENT in older, hypogonadal
men report substantial increases in muscle strength and bone
mineral density (BMD) (12, 21), whereas others report only
Address for reprint requests and other correspondence: S. Borst, VA Med-
ical Center, GRECC 182, 1601 SW Archer Rd., Gainesville FL 32608 (e-mail:
seborst@ufl.edu).
http://www.ajpendo.org
modest improvements (31, 41). Studies documenting substan-
tial effects typically employed intramuscular (im) doses of
ⱖ100 mg/wk im injection of long-acting testosterone esters
(12, 21). In contrast, lower doses of testosterone that result
from transdermal patch or gel administration produce only
modest myotrophic effects (31, 32, 41). Meta-analysis data
indicate that im testosterone produces a 4% increase in lumbar
spine BMD, while transdermal testosterone has no effect (39).
Unfortunately, higher doses of testosterone also increase the
risk of adverse events, including three that have been con-
firmed by meta-analysis: polycythemia, a small reduction in
HDL-cholesterol, and increased incidence of combined pros-
tate-related events (16, 20, 25). Currently, many question
whether the risk-to-benefit ratio is favorable enough to recom-
mend higher-than-replacement testosterone therapy for the
⬃20% of men aged over 60 yr who are at least moderately
hypogonadal (27).
Testosterone exerts direct effects at androgen receptors
(ARs) but also undergoes 5␣-reduction to dihydrotestosterone
(DHT), which mediates many of the developmental (42) and
androgenic effects of testosterone (44). Both finasteride (type
II 5␣-reductase inhibitor) and dutasteride (types I and II 5␣-
reductase inhibitor) are used clinically to treat benign prostatic
hyperplasia (BPH) and act by significantly reducing endoge-
nous DHT (3). However, it remains unclear whether elevated
DHT mediates the beneficial and/or adverse effects of admin-
istered testosterone. A single preliminary report indicates that
200 mg im testosterone enanthate (TE) biweekly plus 5 mg
finasteride/day improved total body fat-free mass and lumbar
spine and hip BMD and lessened the prostate enlargement
resulting from TE alone in older hypogonadal men. However,
this combination of TE plus finasteride failed to improve
lower-extremity maximal strength over 3 yr (33). Others have
reported that dutasteride (2.5 mg/day) does not limit the dose-
dependent TE-induced improvements in lean mass or muscle
function in younger eugonadal men who were administered a
GnRH agonist to suppress endogenous testosterone, although
dutasteride did not prevent TE-induced prostate enlargement in
this study (11). As such, questions remain regarding the safety
and efficacy of concomitant testosterone and steroid 5␣-reduc-
tase inhibitors.
E433
E434 TESTOSTERONE AND FINASTERIDE IN OLDER MEN

The primary purpose of this study was to determine whether
coadministration of higher-than-replacement TE (125 mg/wk)
and Proscar (5 mg finasteride/day) increases muscle strength,
fat-free mass, and hematocrit in older hypogonadal men while
limiting prostate enlargement. Secondary purposes were to
determine whether coadministration of higher-than-replace-
ment TE and finasteride improves BMD and body composition
without adversely affecting blood lipids.
METHODS
Study Design
This study was approved by the Institutional Review Board of the
University of Florida (UF). All participants gave written informed
consent. Potential participants underwent screening to determine eli-
gibility, including structured medical history, blood acquisition (per-
formed twice between 8:00 and 10:00 AM, separated by at least 30
min) to determine complete blood count, complete metabolic profile,
luteinizing hormone, lipid panel, total and bioavailable testosterone
(BioT), hematocrit (Hct), PSA, and a physical exam that included
prostate digital rectal examination (DRE) and transrectal ultrasound
sizing (TRUS), and American Urological Association International
Prostate Symptom Score (AUA/IPSS) (5). Participants were men aged
ⱖ60 yr, with a serum total testosterone ⱕ300 ng/dl or BioT ⱕ70
ng/dl. Two blood samples were obtained during screening, because
the Endocrine Society recommends repeated measurements to confirm
low testosterone prior to initiating testosterone treatment (9).
We excluded individuals who failed the Mini-Cog test (13) or who
had a history of prostate or breast cancer, severe BPH, AUA/IPPS
score ⱖ25, class 3 or 4 congestive heart failure, sleep apnea, Hct
⬎49%, PSA ⱖ2.6 ng/ml, BMI ⬎35, orthopedic limitations precluding
one-repetition maximum (1-RM) strength testing, or who had received
testosterone within 4 wk, finasteride/dutasteride within 6 mo, or who
were taking Coumadin. Participants were advised to maintain their
current level of physical activity.
A randomization table was prepared with RanPro release 1.1
(Applied Logic Associates, Houston, TX) to assign each qualifying
participants to one of four treatment groups: vehicle-placebo, TE-
placebo, vehicle-finasteride, or TE-finasteride (Fig. 1), using a 2 ⫻ 2

1,117 Assessed for Eligibility

1056 Excluded
188 Failed Screening
1 Diagnosed with Excluding
Medical Condition Between
Screening and
andomization

60 Randomized

16 Randomized to 13 Randomized to 14 randomized to 17 Randomized to

Vehicle + Placebo Vehicle + Finasteride Testosterone + Placebo Testosterone + Finasteride
16 Received Treatment 13 Received Treatment 14 Received Treatment 16 Received Treatment
as Assigned as Assigned as Assigned as Assigned

0 lost to follow-up 0 lost to follow-up 0 lost to follow up 0 lost to follow-up

4 discontinued study
3 for personal reasons
1 for adverse events
unrelated to the study
5 discontinued study
1 for elevated PSA
2 for personal reasons
2 for adverse events
unrelated to the study
7 discontinued study 4 discontinued study
1 for urinary symptoms 1 for elevated PSA
1 for sleep apnea 1 for urinary symptoms
1 for elevated hematocrit 2 for personal reasons
2 for personal reasons
2 for adverse events
unrelated to the study

12 completed the study 8 completed the study 7 completed the study 13 completed the study

40 participants completed 12 months of treatment. 9 participants dropped out for personal reasons, 5 were removed
for adverse events unrelated to treatment, and 6 for adverse events that were probably related to treatment. Across
all study groups, compliance was 98% for TE/vehicle (as assessed by record of injection) and 95%
for finasteride/placebo (as assessed by pill count).
Fig. 1. Flow of participants through the trial.

AJP-Endocrinol Metab • doi:10.1152/ajpendo.00592.2013 • www.ajpendo.org

 TESTOSTERONE AND FINASTERIDE IN OLDER MEN
factorial design. Treatment lasted 12 mo and consisted of Proscar (5
mg/day po finasteride) or placebo and Delatestryl (125 mg/wk im TE)
or vehicle. Proscar and matching placebo were donated by Merck,
Delatestryl was donated by Novartis, and matching vehicle was
prepared by WestLab Pharmacy (Gainesville, FL). Participants were
not paid for participation other than receiving reimbursement for
travel mileage. Study participants and investigators performing con-
senting, screening, drug administration, safety testing, and outcomes
testing were blinded to treatment. The only unblinded team members
were Research Pharmacy, the Laboratory Manager, who compared
safety testing values to removal criteria, and the Study Physician, who
assessed adverse events to determine participant removal criteria.
Protection from Risks
Participants underwent thorough health screenings every 3 mo
throughout the study, including all baseline measures described
above, with the exception of prostate TRUS (assessed every 6 mo).
Participants were removed from the study if the following occurred:
hematocrit ⱖ54%, serum PSA ⱖ4.0, increase in AUA/IPSS ⱖ4
points, or if gynecomastia or peripheral edema were noted at physical
exam (Fig. 1).
Outcomes
Outcome measures were performed at baseline and at 3-mo inter-
vals thereafter except dual X-ray absorptiometry (baseline and 12 mo
only) and prostate TRUS (every 6 mo).
Prostate DRE and TRUS. DRE and TRUS were performed by the
Urology Service, Malcom Randall VA Medical Center (VAMC),
Gainesville, FL. TRUS was performed using the General Electric
LOGICQ P5 scanning system with the highest sector transrectal
probe/transducer of 7 MHz. The GE LOGICQ has built-in software
for electronically calculating prostate volume (height ⫻ length ⫻
width ⫻ 0.52). The same operator performed testing for all partici-
pants.
1-RM strength testing. 1-RM strength testing was performed on
Cybex (Medway, MA) leg press, knee flexion, knee extension, chest
press, and triceps extension selectorized resistance exercise machines.
A 5-min warm-up preceded testing, and weights were gradually
increased to 1-RM. Testing was repeated within 2–7 days, and the
highest load completed was utilized.
Grip strength. Grip strength of the right hand was assessed using a
Jaymar hand-held dynamometer (Sammons Preston Roylan, Boling-
brook, IL).
Urinary symptoms. Urinary symptoms were assessed using the
AUA/IPPS questionnaire (5).
Hormone Assays
Serum samples were obtained 1 wk after TE/vehicle injection.
Clinical laboratory values, including total testosterone, were assessed
in the Clinical Laboratory, Malcom Randall VAMC. Testosterone was
assayed by Cobas electrochemoluminescence immunoassay. Separate
serum samples were stored at ⫺80°C and analyzed in duplicate in a
single assay for CTX-1 and osteocalcin by ELISA (Immunodiagnostic
Systems, Fountain Hills, AZ). Estradiol (E2) was assessed by ELISA
(American Laboratory Products, Salem NH). BioT and BioE2 were
assessed by ammonium sulfate precipitation of samples spiked with
[3H]testosterone or [3H]estradiol (40). DHT was assessed by LC-
MS-MS at Laboratory Corp of America (Calabasas Hills, CA).
Body Composition and Lumbar Spine and Hip BMD
These were assessed using a fan-bean densitometer (Lunar Prod-
igy; GE Medical Systems, Little Chalfont, Buckinghamshire, UK),
calibrated daily.
AJP-Endocrinol Metab • doi:10.1152/ajpendo.00592.2013 • www.ajpendo.org
E435
Statistical Methods
Descriptive statistics are given as means with standard deviations
(SD) or as means with 95% confidence intervals (CI), as appropriate.
P values ⬍ 0.05 (two-sided) were considered statistically significant.
Repeated-measures dependent variables were analyzed as linear
mixed models with participants as random effects, and time (3, 6, 9,
or 12 mo), testosterone, finasteride, interaction, and baseline value of
the dependent measures as fixed effects. We utilized an autoregressive
correlational structure, allowing measures closer in time to have
higher within-subject correlations than when farther apart. Missing at
random was presumed for our analyses, and we chose not to use
imputation, because it results in greater bias. For variables collected
only at baseline and 12 mo, we used a fixed-effects ANOVA model
with dependent variable as 12-mo minus baseline difference with the
same treatment-related independent variables as above. This coding
yields valid interpretable main effects even if interactions are present.
The main effect of testosterone, for example, represents the average
effect of testosterone under placebo and finasteride (weighted 50 –50).
In comparison, the interaction addresses whether or not the difference
between the means for treatment factors (e.g., testosterone vs. vehicle)
differ quantitatively according to the level of other treatment factors
(e.g., finasteride vs. placebo). The changes from baseline to 12 mo are
presented, but they estimate a different outcome than the mixed
model, which measures an average effect over the times after baseline.
The mixed model has two additional advantages over the simple 0- to
12-mo difference comparisons: 1) It uses all of the data, and 2) it is
more sensitive than the 0- to 12-mo comparison for effects that
increase early and decrease over time.
The study was powered around four end points: fat-free mass,
1-RM leg press, hematocrit, and prostate volume, although a wide-
range of variables were evaluated due to the systemic nature of
androgen-AR interactions and to ensure participant safety. We in-
tended to obtain 12 completers in each of the four arms. Allowing for
a 20% dropout rate, the goal was 60 randomized participants. Bhasin
et al. (1) reported that older men experience a ⱖ2␴ (␴ ⫽ SD) increase
in fat-free mass (4.2 ⫾ 0.6 SE, n ⫽ 12) and hematocrit (0.07 ⫾ 0.01
SE, n ⫽ 12) and 1.18␣ increase in 1-RM strength (28.0 ⫾ 6.8 SE, n ⫽
12) after 20 wk of 125 mg/wk TE, whereas Zitzmann et al. (46)
reported that testosterone replacement increased prostate volume
1.85␣ per year (6.1 ⫾ 3.3 SD). For each variable, a 2 ⫻ 2 factorial
study has 80% power to detect a 0.87␴ difference at P ⬍ 0.05
(two-sided), and 80% power to detect a 1.0␴ difference at P ⫽ 0.0125
(0.05/4). Importantly, 1-RM strength, fat-free mass, and hematocrit
were powered using data from changes occurring over a 20-wk period
of testosterone administration, whereas our study duration was 52 wk.
As such, we powered to achieve significance in the aforementioned
outcomes at the 6-mo time point of our study, which protects against
the adverse effects of an unexpectedly high participant dropout rate on
statistical power.
RESULTS
Primary Outcomes
Baseline values are reported in Table 1 and treatment effects
in Tables 2– 4 and Fig. 2. TE progressively increased 1-RM
strength over 12 mo (Table 2) by 12.9 kg for leg press, an
11.4% increase (P ⬍ 0.001; Table 2 and Fig. 2H), 6.00 kg for
knee extension (8.1%, P ⫽ 0.012), 5.42 kg for knee flexion
(12.5%, P ⫽ 0.0023), 6.47 kg for chest press (14.5%, P ⬍
0.001), 5.32 kg for triceps extension (9.5%, P ⬍ 0.001), and
0.77 kg for grip (11.3%, P ⫽ 0.015). TE also increased total
body fat-free mass 4.04 kg (P ⫽ 0.032; Table 3 and Fig. 2G)
and HCT 4.13% (P ⬍ 0.001; Table 2 and Fig. 2C), with most
of the Hct increase occurring in the first 3 mo of treatment.
Finasteride did not significantly affect muscle strength, fat-free
E436 TESTOSTERONE AND FINASTERIDE IN OLDER MEN

Table 1. Subjects’ baseline characteristics

Variable Vehicle-Placebo Vehicle-Finasteride TE-Placebo TE-Finasteride

Age, yr 70.8 ⫾ 9.7 69.5 ⫾ 9.2 69.2 ⫾ 8.0 64.2 ⫾ 4.8

BMI, kg/m2 30.4 ⫾ 3.4 28.8 ⫾ 3.9 29.4 ⫾ 4.6 31.1 ⫾ 2.5
Weight, kg 92.0 ⫾ 13.2 86.6 ⫾ 13.6 93.8 ⫾ 17.7 96.2 ⫾ 9.5
Fat-free mass, kg 56.1 ⫾ 5.8 55.7 ⫾ 6.1 58.0 ⫾ 9.5 59.9 ⫾ 6.6
Hematocrit, % 40.3 ⫾ 3.9 41.2 ⫾ 3.9 42.6 ⫾ 3.0 42.0 ⫾ 2.8
Prostate volume, cm3 36.9 ⫾ 15.6 29.7 ⫾ 12.7 26.4 ⫾ 8.4 37.1 ⫾ 16.3
PSA, ng/ml 0.98 ⫾ 0.53 1.1 ⫾ 0.59 0.78 ⫾ 0.64 1.4 ⫾ 0.79
AUA/IPPS score 7.8 ⫾ 5.6 7.7 ⫾ 5.1 7.5 ⫾ 5.4 8.1 ⫾ 4.9
Leg press 1-RM, kg 118.8 ⫾ 35.3 109.4 ⫾ 28.4 129.1 ⫾ 41.7 137.2 ⫾ 23.9
Knee extension 1-RM, kg 60.6 ⫾ 12.9 56.6 ⫾ 13.6 63.7 ⫾ 17.7 71.9 ⫾ 14.0
Knee flexion 1-RM, kg 39.3 ⫾ 10.4 32.0 ⫾ 9.5 43.5 ⫾ 11.0 43.2 ⫾ 9.9
Chest press 1-RM, kg 47.6 ⫾ 19.0 43.1 ⫾ 14.1 55.5 ⫾ 19.2 59.2 ⫾ 14.1
Triceps extension 1-RM, kg 36.2 ⫾ 8.5 32.8 ⫾ 9.3 35.8 ⫾ 10.1 38.8 ⫾ 6.6
Grip strength, kg 17.4 ⫾ 3.4 17.0 ⫾ 3.7 16.9 ⫾ 4.8 18.2 ⫾ 2.1
Testosterone, ng/dl 264 ⫾ 92 240 ⫾ 110 245 ⫾ 73 242 ⫾ 147
BioT, ng/dl 46 ⫾ 22 41 ⫾ 17 46 ⫾ 17 44 ⫾ 20
Estradiol, pg/ml 12.7 ⫾ 9.5 13.6 ⫾ 7.4 25.8 ⫾ 34.4 26.0 ⫾ 30.2
BioE2, pg/ml 4.7 ⫾ 3.1 4.7 ⫾ 2.1 11.0 ⫾ 17.2 9.8 ⫾ 9.2
DHT, ng/dl 25.2 ⫾ 15.1 18.9 ⫾ 12.7 21.4 ⫾ 6.3 21.9 ⫾ 22.4
Total body fat, kg 30.8 ⫾ 9.4 26.9 ⫾ 9.6 29.9 ⫾ 9.9 31.3 ⫾ 4.6
L2-L4 spine BMD, g/cm2 1.53 ⫾ 0.36 1.4 ⫾ 0.23 1.4 ⫾ 0.36 1.2 ⫾ 0.16
Rt total hip BMD, g/cm2 1.07 ⫾ 0.18 1.02 ⫾ 0.15 1.03 ⫾ 0.12 0.99 ⫾ 0.069
Values are means ⫾ SE. TE, testosterone enanthate; 1-RM, one-repetition maximum; BioT, bioavailable testosterone; BioE2, bioavailable estradiol; DHT,
dihydrotestosterone.

mass, or Hct. Additionally, TE increased prostate volume 5.33
cm3 (Table 2; main effect, P ⫽ 0.0051), and finasteride
reduced prostate volume by ⫺5.79cm3 (main effect, P ⫽
0.0027). These changes resulted in progressive prostate en-
largement of 11.4 cm3 (P ⫽ 0.0051) within the TE group, an
increase that was fully prevented by finasteride coadministra-
tion (P ⫽ 0.0027; Fig. 2D). Prostate volume remained similar
between TE-finasteride, vehicle-finasteride, and vehicle-pla-
cebo treatments.
Demographic and Blood Values
0.0051; data not shown), and android fat mass 0.42 kg (P ⬍
0.001; data not shown). Finasteride did not affect the above
measurements.
Prostate-Related Measures
TE elevated serum PSA, and finasteride reduced PSA (Table
2). The AUA/IPPS was not altered by treatment. Two partic-
ipants received prostate biopsies, prompted by DRE findings
(one each from the TE-placebo and TE-finasteride groups);
both were negative.

TE elevated nadir testosterone and BioT, representing 1.8- DISCUSSION

fold and 2.2-fold increases over baseline, respectively (Table 2
Testosterone exerts direct effects at ARs and can also induce
and Fig. 2A). Finasteride did not affect those increases. TE
indirect effects at ARs and/or estrogen receptors (ERs) follow-
elevated serum DHT, and finasteride lowered DHT (Table 2
ing the 5␣-reduction to DHT (44) or the aromatization to E2
and Fig. 2B). TE reduced LH to near-zero concentrations,
(28), respectively. However, the role of DHT in mediating
whereas finasteride modestly increased LH (Table 3). TE
beneficial and/or adverse effects of administered testosterone
elevated E2 1.7-fold and BioE2 2.2-fold (P ⬍ 0.001), whereas
has received little focus in the literature. We report that 12-mo
finasteride had no effect (Table 4). TE elevated hemoglobin
administration of higher-than-replacement TE (alone) or TE
with a time course similar to that of Hct (Table 4), whereas
plus finasteride increased fat-free mass, muscle strength, Hct,
finasteride had no significant effects on hemoglobin. TE low-
and lumbar spine and hip BMD while reducing fat mass in
ered HDL-cholesterol and triglycerides while increasing LDL-
older hypogonadal men. TE (alone) also elevated PSA and
cholesterol (Table 4). Finasteride significantly reduced LDL-
prostate volume, whereas coadministration of a clinically rel-
cholesterol while increasing triglycerides (Table 4). Neither
evant dose of finasteride completely prevented TE-induced
treatment altered total cholesterol. TE significantly decreased
increases in PSA and prostate volume.
CTX-1 but did not affect osteocalcin (Table 4). All clinical
In young and older men, testosterone dose-dependently
values remained within normal reference ranges throughout the
augments lean mass with high-dose TE (600 mg/wk for 10 wk)
study (Table 4).
increasing quadriceps area 7% and muscle strength 10 –12%
Body Composition (10). In contrast, low-dose testosterone (5 mg/day for 2 yr)
increased femoral neck BMD but did not alter muscle strength
TE increased lumbar spine BMD 4.19% (P ⬍ 0.001; Table in older men (31), suggesting that higher doses of testosterone
3 and Fig. 2E), lumbar spine BMC 3.94% (P ⫽ 0.0032), and may be required for improvements in muscle function (41). In
total hip BMD 1.96% (P ⫽ 0.024); BMC was not affected in support of this contention, moderate-dose TE (200 mg bi-
other regions. TE also reduced total body fat mass 3.87 kg weekly) improved lumbar spine and hip BMD, physical per-
(P ⬍ 0.001; Table 3 and Fig. 2F), trunk fat 1.88 kg (P ⫽ formance, and grip strength but did not increase leg strength

AJP-Endocrinol Metab • doi:10.1152/ajpendo.00592.2013 • www.ajpendo.org

 TESTOSTERONE AND FINASTERIDE IN OLDER MEN E437
Table 2. Treatment effects
Variable Group 0–12 mo Change Main Effect of T Main Effect of F Interaction

BMI, kg/m 2
Weight, kg
Fat-free mass, kg
Hct, %
Prostate volume, cm3
PSA, ng/ml
AUA/IPPS score
Leg press 1-RM, kg
Knee extension 1-RM, kg
Knee flexion 1-RM, kg
Chest press 1-RM, kg
Triceps extension 1-RM, kg
Grip strength, kg
T, testosterone; F, finasteride.
Vehicle-Placebo 0.75 (0.038 to 1.45) 0.49 (⫺0.031 to 1.02) ⫺0.40 (⫺0.916 to 0.12) ⫺0.378 (⫺1.44 to 0.68)
Vehicle-Finasteride ⫺0.073 (⫺0.92 to 0.77) P ⫽ 0.066 P ⫽ 0.13 P ⫽ 0.48
TE-Placebo 1.03 (⫺0.54 to 2.56)
TE-Finasteride 1.56 (⫺0.81 to 3.92)
Vehicle-Placebo 1.99 (⫺0.056 to 4.04) 1.38 (⫺0.068 to 2.82) ⫺1.00 (⫺0.42 to 1.71) ⫺1.18 (⫺4.00 to 0.98)
Vehicle-Finasteride 0.23 (⫺2.50 to 2.95) P ⫽ 0.063 P ⫽ 0.16 P ⫽ 0.41
TE-Placebo 2.272 (⫺2.51 to 6.97)
TE-Finasteride 0.65 (⫺1.85 to 3.14)
Vehicle-Placebo 0.45 (⫺1.07 to 1.9) 4.04 (0.43 to 7.64) 0.13 (⫺3.47 to 3.74) ⫺1.58 (⫺8.80 to 5.63)
Vehicle-Finasteride 0.086 (⫺1.76 to 1.93) P ⫽ 0.032 P ⫽ 0.94 P ⫽ 0.66
TE-Placebo 5.7 (0.26 to 11.1)
TE-Finasteride 3.21 (1.09 to 5.34)
Vehicle-Placebo ⫺0.19 (⫺1.66 to 1.28) 4.13 (3.07 to 5.18) 0.15 (⫺0.88 to 1.18) 0.14 (⫺1.93 to 2.21)
Vehicle-Finasteride ⫺1.18 (⫺3.50 to 1.15) P ⬍ 0.001 P ⫽ 0.77 P ⫽ 0.89
TE-Placebo 5.22 (3.01 to 7.42)
TE-Finasteride 4.17 (2.28 to 6.07)
Vehicle-Placebo ⫺2.81 (⫺8.62 to 2.83) 5.33 (1.73 to 8.94) ⫺5.79 (⫺9.40 to ⫺2.17) ⫺6.27 (⫺13.8 to 1.25)
Vehicle-Finasteride ⫺4.93 (⫺12.7 to 2.86) P ⫽ 0.0051 P ⫽ 0.0027 P ⫽ 0.10
TE-Placebo 11.4 (1.40 to 21.4)
TE-Finasteride ⫺1.72 (⫺5.26 to 1.80)
Vehicle-Placebo 0.123 (⫺0.24 to 0.49) 0.61 (0.32 to 0.90) ⫺0.34 (⫺0.65 to 0.040) 0.51 (⫺0.088 to 1.09)
Vehicle-Finasteride ⫺0.61 (⫺1.07 ⫺0.14) P ⬍ 0.001 P ⫽ 0.028 P ⫽ 0.090
TE-Placebo 0.43 (⫺0.09 to 0.96)
TE-Finasteride 0.24 (⫺0.76 to 1.24)
Vehicle-Placebo ⫺0.083 (⫺4.96 to 4.79) 0.89 (⫺0.64 to 2.43) 0.51 (⫺1.02 to 2.05) 2.38 (⫺0.66 to 5.43)
Vehicle-Finasteride ⫺2.00 (⫺4.75 to 0.75) P ⫽ 0.26 P ⫽ 0.51 P ⫽ 0.12
TE-Placebo ⫺2.00 (⫺4.66 to 0.66)
TE-Finasteride ⫺0.08 (⫺2.51 to 2.35)
Vehicle-Placebo 1.50 (⫺6.49 to 9.52) 12.9 (7.86 to 18.0) ⫺1.54 (⫺6.40 to 3.32) 2.00 (⫺7.70 to 11.7)
Vehicle-Finasteride 0.00 (⫺6.42 to 6.42) P ⬍ 0.001 P ⫽ 0.53 P ⫽ 0.68
TE-Placebo 14.7 (⫺7.62 to 37.2)
TE-Finasteride 12.5 (2.95 to 22.0)
Vehicle-Placebo 0.227 (⫺4.22 to 4.67) 6.00 (1.44 to 10.6 1.27 (⫺3.17 to 5.70) 1.22 (⫺7.75 to 10.2)
Vehicle-Finasteride 1.11 (⫺4.07 to 6.28) P ⫽ 0.012) P ⫽ 0.57 P ⫽ 0.79
TE-Placebo 5.17 (⫺14.5 to 24.8)
TE-Finasteride 9.44 (⫺1.24 to 20.1)
Vehicle-Placebo ⫺0.74 (⫺2.66 to 1.18) 5.42 (2.12 to 8.72) ⫺0.86 (⫺4.02 to 2.29) 1.12 (⫺5.17 to 7.42)
Vehicle-Finasteride ⫺3.79 (⫺8.99 to 1.40) P ⫽ 0.0023 P ⫽ 0.58 P ⫽ 0.72
TE-Placebo ⫺2.88 (⫺15.3 to 9.51)
TE-Finasteride 3.89 (⫺3.25 to 11.0)
Vehicle-Placebo 1.87 (⫺1.122 to 4.95) 6.47 (3.63 to 9.32) 0.29 (⫺2.40 to 2.99) 0.50 (⫺4.92 to 5.91)
Vehicle-Finasteride 0.68 (⫺2.31 to 3.67) P ⬍ 0.001 P ⫽ 0.83 0.85
TE-Placebo 8.05 (3.53 to 12.5)
TE-Finasteride 8.54 (1.94 to 15.2)
Vehicle-Placebo ⫺1.71 (⫺4.34 to 0.93) 5.32 (3.27 to 7.37) 1.22 (⫺0.83 to 3.28) ⫺0.78 (⫺4.91 to 3.36)
Vehicle-Finasteride 0.65 (⫺3.85 to 5.14) P ⬍ 0.001 P ⫽ 0.24 0.71
TE-Placebo 3.41 (1.32 to 5.50)
TE-Finasteride 5.78 (2.08 to 9.49)
Vehicle-Placebo 0.15 (⫺0.90 to 1.21) 0.77 (0.16 to 1.31) ⫺0.094 (⫺0.70 to 0.51) ⫺1.06 (⫺1.68 to ⫺0.44)
Vehicle-Finasteride 1.47 (⫺0.84 to 2.12) P ⫽ 0.015 P ⫽ 0.75 P ⫽ 0.088
TE-Placebo 1.91 (0.75 to 3.10)
TE-Finasteride 1.17 (0.38 to 1.97)

over 3 yr of treatment (4, 33). Importantly, equivalent results
were observed whether TE was administered alone or in
combination with finasteride (14, 23), indicating that elevated
DHT is not required for the beneficial skeletal responses to
testosterone in adults. We report similar findings, in that TE
plus finasteride markedly reduced DHT while increasing lum-
bar spine and hip BMD 2– 4% (via antiresorptive actions
indicated by reduced CTX-1) and total body fat-free mass ⬎3
kg. Additionally, we observed reductions in total body fat mass
of ⬃10% over 12 mo. We expand upon previous findings (33)
by demonstrating, for the first time, that coadministration of TE
and finasteride improves upper- and lower-body maximal
strength in older hypogonadal men. One difference between
these studies is that Page et al. (33) measured isokinetic
strength, whereas we measured 1-RM strength. Interestingly,
type I 5␣-reductase expression appears essential for normal
musculoskeletal development, as demonstrated by male 5␣-
reductase type I knockout (srd5a1⫺/⫺) mice that exhibit re-
duced bone mass and muscle force despite normal circulating
androgen concentrations (42). However, 5␣-reductase type I
activity is not essential for testosterone-induced myotrophic
effects in adult men. As evidence, Bhasin et al. (11) reported
that dutasteride did not inhibit TE-induced improvements in
lean mass or muscle function in young eugonadal men admin-

AJP-Endocrinol Metab • doi:10.1152/ajpendo.00592.2013 • www.ajpendo.org

E438 TESTOSTERONE AND FINASTERIDE IN OLDER MEN

A change in nadir serum testosterone

testosterone effect: p < 0.0001
B veh-plac
change in serum DHT
testosterone effect: p < 0.0001
C change in hematocrit
testosterone effect: p < 0.001
veh-finast veh-plac
finasteride effect: p = 0.39 test-plac finasteride effect: p < 0.0001 finasteride effect: p = 0.077
8 veh-finast
interaction: p = 0.78 test-finast interaction: p = 0.024 interaction: p = 0.79 test-plac
nadir serum testosterone

change in serum DHT

13 veh-plac test-finast
veh-finast 30 6

hematocrit (%)
test-plac
8
test-finast 4

(ng/dL)
(ng/ml)

10
2
3 -10
0

-2 -30 -2
0 6 12 0 6 12 0 3 6 9 12
months of treatment months of treatment months of treatment
D F
change in prostate volume
veh-plac
E % change in spine L2-L4 BMD change in total body fat
testosterone effect: p < 0.0001 veh-finast testosterone effect: p = 0.0007 testosterone effect: p < 0.0001

% change spine L2-L4 BMD

change in total body fat (kg)

change in prostate volume

20 finsteride effect: p = 0.028 test-plac 6 finasteride effect: p = 0.22 2 finasteride effect: p = 0.51
interaction: 0.090 test-finast interaction: p = 0.22 interaction: p = 0.39
15 1
4
10 veh-plac 0
veh-finast
(cm3)

test-plac veh-plac
5 2 -1
test-finast veh-finast
-2
test-plac
0
0 test-finast
-5 1 -3

-10 -2 -4
0 6 12
months of treatment

G change in fat-free mass H change in leg press

10 testosterone effect: p < 0.032 testosterone effect: p < 0.0001
change in leg press 1-RM (kg)
change in fat-free mass

finasteride effect: p = 0.94 finasteride effect: p = 0.53 veh-plac

8 interction: p = 0.66 interaction: p = 0.68 veh-finast
30 test-plac
6
20
(kg)

veh-plac
veh-finast
4 test-plac 10
test-finast
0
2
-10
0
1 -20 3 6 9 12
months of treatment
Fig. 2. Changes occurring from baseline to 12 mo in testosterone, dihydrotestosterone (DHT), hematocrit, prostate volume, lumbar spine bone miberal density
(BMD), total body fat, fat-free mass and one-repetition maximum (1-RM) leg press strength in participants receiving vehicle (veh)-placebo(plac), veh-
finasteride(finast), testosterone enanthate (test)-plac or test-finast. A: significant increase shown in nadir serum testosterone levels following testosterone-
enanthate (TE) administration. B: significant increase shown in serum DHT following TE administration and a significant decrease in DHT following finasteride
administration. C: significant increase shown in hematocrit following TE administration. D: significant increase shown in prostate volume following TE
administration and a significant decrease in prostate volume following finasteride administration. E: significant increase shown in lumbar spine BMD following
TE administration. F: significant decrease shown in fat mass following TE administration. G: significant increase shown in fat-free mass following TE
administration. H: significant increase shown in 1-RM leg press strength following TE administration. Values are means ⫾ SE; n ⫽ 7–13 per group. Effect and
interaction columns are derived from repeated-measures analysis for effects of T, F, and Interaction. These effects/interactions are indicative of the mean change
occurring over each individual 3-, 6-, 9-, and 12-mo time point, as applicable, with Main Effects representing the average of testosterone under placebo and
finasteride (weighted 50 –50) or finasteride under vehicle and testosterone (weighted 50 –50) and Interaction addressing whether or not the difference between
the means for the first treatment factor (e.g., testosterone vs. vehicle) differ quantitatively based on the level of the second treatment factor (e.g., finasteride vs.
placebo).

istered GnRH agonists to suppress testosterone despite a near- result in physiological serum concentrations) (19). As such, the
complete ablation of circulating DHT. Preclinical findings also possibility exists that the lipolytic and bone-protective effects
indicate that high-dose TE plus MK-434 (types I and II that we observed were, in part, mediated by elevated E2.
5␣-reductase inhibitor) (14, 15) and trenbolone [a highly po- However, this certainly does not preclude the possibility that
tent non-5␣-reducible and nonaromatizable testosterone analog androgens influence bone and adipose tissue through direct
(15, 30, 43)] protect against orchiectomy-induced muscle and AR-mediated mechanisms. In support of this contention, tren-
bone loss, although no clinical study has examined the skeletal bolone (a highly potent nonaromatizable and non-5␣-reducible
responses to TE plus dutasteride. testosterone analog) reduces adiposity and preserves bone mass
We also observed that TE treatment significantly elevated in several animal models of sex steroid deficiency (30, 43).
serum E2 and BioE2. In this regard, recent evidence indicates Additionally, human preadipocytes and mature adipocytes ex-
that the lipolytic (but not the muscular) effects of testosterone press ARs (35) and nonaromatizable androgens inhibit adipo-
may be influenced by the aromatization of testosterone to E2 genesis in human adipose tissue (17). Human osteoblasts also
(22). Additionally, E2 is a more potent bone antiresorptive express ARs at sites of bone formation (1), and physiological
agent than testosterone in older men undergoing experimental testosterone replacement maintains bone formation in older
sex steroid deficiency (at least when administered in doses that men undergoing experimental sex steroid deficiency (19). Re-

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 TESTOSTERONE AND FINASTERIDE IN OLDER MEN E439
Table 3. Treatment effects
Variable Group 0–12 mo Change Main Effect of T Main Effect of F Interaction

Testosterone, ng/dl Vehicle-Placebo 15 (⫺48 to 78) 479 (374 to 584) 45 (⫺59 to 152) 28 (⫺182 to 238)
Vehicle-Finasteride ⫺3.7 (⫺59 to 52) P ⬍ 0.001 P ⫽ 0.39 P ⫽ 0.79
TE-Placebo 229 (⫺27 to 485)
TE-Finasteride 323 (106 to 541)
BioT, ng/dl Vehicle-Placebo 7.3 (⫺11 to 25) 148 (114 to 184) 25 (⫺30 to 38) ⫺6.7 (⫺39 to 64)
Vehicle-Finasteride 3.0 (⫺9.4 to 15) P ⬍ 0.001 P ⫽ 0.89 P ⫽ 0.84
TE-Placebo 65 (⫺33 to 164)
TE-Finasteride 70 (21 to 118)
DHT, ng/dl Vehicle-Placebo ⫺1.67 (⫺10.35 to 7.02) 14.7 (8.80 to 20.6) ⫺23.3 (⫺29.2 to ⫺17.4) ⫺13.8 (⫺23.6 to ⫺1.94)
Vehicle-Finasteride ⫺15.7 (⫺24.8 to ⫺6.61) P ⬍ 0.001 P ⬍ 0.001 P ⫽ 0.024
TE-Placebo 12.3 (⫺3.59 to 28.2)
TE-Finasteride ⫺11.6 (⫺26.2 to 3.05)
LH, U/l Vehicle-Placebo ⫺0.29 (⫺2.41 to 1.83) [15] ⫺7.40 (⫺9.38 to ⫺5.42) 2.73 (0.74 to 4.72) ⫺0.47 (⫺4.52 to 3.58)
Vehicle-Finasteride 0.15 (⫺2.23 to 2.52) [8] P ⬍ 0.001 P ⫽ 0.0083 P ⫽ 0.81
TE-Placebo ⫺8.00 (⫺12.8 to ⫺3.24) [6]
TE-Finasteride ⫺5.89 (⫺12.12 to 0.38) [9]
Osteocalcin, ng/ml Vehicle-Placebo ⫺2.95 (⫺5.68 to ⫺0.22) [12] 1.28 (⫺0.92 to 2.38) ⫺0.64 (⫺2.82 to 1.58) ⫺5.60 (⫺7.87 to ⫺3.42)
Vehicle-Finasteride ⫺0.005 (⫺5.54 to 5.12) [7] P ⫽ 0.24 P ⫽ 0.56 P ⫽ 0.13
TE-Placebo ⫺0.934 (⫺6.87 to 5.00) [6]
TE-Finasteride ⫺1.55 (⫺4.53 to 1.44) [11]
CTX-1, pg/ml Vehicle-Placebo ⫺0.12 (⫺0.067 to 0.043) [12] ⫺0.81 (⫺0.13 to 0–0.029) ⫺0.0055 (⫺0.057 to 0.046) ⫺0.0088 (⫺0.13 to 0.095)
Vehicle-Finasteride 0.015 (⫺0.088 to 0.18) [7] P ⫽ 0.0028 P ⫽ 0.83 P ⫽ 0.86
TE-Placebo ⫺0.065 (⫺0.19 to 0.057) [6]
TE-Finasteride ⫺0.092 (⫺0.20 to 0.014) [11]

gardless of the mechanism, the biological significance of our
findings is profound given that we have demonstrated that the
desirable musculoskeletal and lipolytic effects of higher-than-
replacement testosterone can be obtained without deleterious
effects on prostate mass, which significantly improves the
safety profile of this clinically relevant treatment.
DHT mediates many of the androgenic effects of testoster-
one, including prostate enlargement, and may worsen prostate
cancer risk (29). Both finasteride and dutasteride are used
clinically to treat BPH due to their ability to reduce circulating
DHT (38). However, only two previous clinical studies (4, 11)
have examined whether elevated DHT mediates prostate en-
largement following testosterone administration, with some-
what conflicting results. Bhasin et al. (11) reported that graded
doses of TE (ranging from 50 to 600 mg/wk) increased prostate
volume ⬃2.5cm3 over 20 wk in young men and that dutas-
teride did not prevent this enlargement. Conversely, Amory et
al. (4) reported that TE (200 mg biweekly) increased prostate
volume 14 cm3 over 3 yr in older hypogonadal men and that
finasteride coadministration limited prostate enlargement to
only 5 cm3. Others reported that men receiving testosterone by
patch, gel, or injection experienced prostate volume increases
of 4.9 cm3/yr of treatment (46) and that coadministration of
transdermal testosterone (1% T gel) and dutasteride reduced
prostate size in older men with BPH (34). Similarly, we report
that the main effect of 125 mg/wk TE on prostate volume was
5.3 cm3 when administered to hypogonadal older men; how-
ever, this underestimates the actual 12-mo change in the
TE-placebo group (11.4 cm3), because finasteride coadminis-
tration completely prevented TE-induced prostate enlargement.
Testosterone dose-dependently increases hemoglobin and
hematocrit, possibly independently of erythropoietin, and this
effect is greater in older men compared with younger (18). We
observed a 4 –5 point Hct increase following administration of
either TE or TE plus finasteride; suggesting that elevated DHT
does not mediate this change. The Hct increase that occurs in
most older men receiving testosterone is not considered detri-
mental and may be beneficial (37), although this must be
weighed against the risk of polycythemia (25) and associated
cardiovascular risks (23).
Several meta-analyses (16, 25) have identified polycythe-
mia, combined incidence of prostate events (including elevated
PSA, increased urinary symptoms, number of prostate biop-
sies, and prostate cancer), and a modest reduction in HDL-
cholesterol as the three proven adverse events resulting from
testosterone administration. Rates of adverse events were sim-
ilar between groups in our study, although we observed that TE
lowered HDL by ⬃10%, an effect not altered by finasteride.
TE also increased LDL 29% and reduced triglycerides. Con-
versely, finasteride coadministration reduced LDL-cholesterol
but did not alter triglycerides. The clinical ramifications of
these blood lipid changes remains unknown (36). Additionally,
several putative adverse events are associated with testosterone
administration, including worsening of sleep apnea, edema,
gynecomastia, increased incidence of cardiovascular events,
acceleration of underlying prostate cancer, and liver-related
side effects (6, 7, 25). In this regard, coadministration of
testosterone plus finasteride has some advantages, including
lessening of androgen-induced prostate enlargement, and some
potential disadvantages compared with treatment with testos-
terone alone, including altering the clinical usefulness of PSA
measurements (29). However, the value of PSA testing has
come into question, especially in men aged ⱖ70 yr (8).
Testosterone administration combined with 5␣-reductase inhi-
bition may also alter prostate cancer risk or severity, given that
finasteride alone reduces the incidence of prostate cancer while
increasing the number of prostate cancers with Gleason scores
of 7–10 (38). Similarly, testosterone-stimulated prostate cancer
growth in culture is ablated by dutasteride (2), perhaps through
mechanisms involving upregulation of testosterone-sensitive
tumor suppressors (24).

AJP-Endocrinol Metab • doi:10.1152/ajpendo.00592.2013 • www.ajpendo.org

E440 TESTOSTERONE AND FINASTERIDE IN OLDER MEN

Table 4. Treatment effects

Group Baseline Value 0–12 mo Change Main Effect of T Main Effect of F Interaction
Vehicle-Placebo 13.4 (12.8 to 14.2) [16] 0.00 (⫺0.44 to 4.4) [12] 1.13 (0.68 to 1.56) 0.28 (0.07 to 0.49) 0.31 (⫺0.15 to 1.14)
Vehicle-Finasteride 13.8 (12.9 to 14.7) [13] ⫺0.28 (⫺0.95 to 0.40) [8] P ⬍ 0.001 P ⫽ 0.18 P ⫽ 0.46
TE-Placebo 14.7 (13.9 to 15.5) [13] 1.06 (⫺0.31 to 2.43) [5]
TE-Finasteride 14.6 (14.1 to 15.1) [17] 1.31 (0.45 to 2.16) [11]
Vehicle-Placebo 2.30 (0.91 to 3.6) [16] 0.062 (⫺0.12 to 0.24) [12] 0.54 (0.34 to 0.75) 0.12 (⫺0.08 to 0.32) ⫺0.10 (⫺0.50 to 0.30)
Vehicle-Finasteride 2.45 (1.2 to 3.7) [13] ⫺0.030 (⫺0.56 to 0.50) [6] P ⬍ 0.001 P ⫽ 0.24 0.62
TE-Placebo 2.76 (1.2 to 4.3) [13] 0.055 (⫺0.67 to 0.78) [6]
TE-Finasteride 2.86 (1.2 to 4.5) [17] 0.30 (⫺0.18 to 0.78) [10]
Vehicle-Placebo 1.33 (⫺0.022 to 2.6) [16] 0.056 (⫺0.19 to 0.30) [12] 0.77 (0.51 to 1.03) 0.034 (⫺0.22 to 0.29) ⫺0.17 (⫺0.67 to 0.33)
Vehicle-Finasteride 1.39 (⫺0.040 to 2.8) [13] ⫺0.057 (⫺0.80 to 0.69) [6] P ⬍ 0.001 P ⫽ 0.79 P ⫽ 0.51
TE-Placebo 1.75 (⫺0.21 to 3.7) [13] 0.18 (⫺0.58 to 0.94) [6]
TE-Finasteride 1.88 (0.018 to 3.7) [17] 0.45 (⫺0.078 to 0.97) [10]
Vehicle-Placebo 160.2 (145.2 to 175.3) [16] 0.17 (⫺13.2 to 13.5) [12] ⫺0.81 (⫺12.0 to 10.4) ⫺4.9 (⫺16.1 to 6.30) ⫺20.5 (⫺42.9 to 1.89)
Vehicle-Finasteride 160.5 (143.9 to 177.2) [13] ⫺9.25 (⫺35.0 to 16.5) [8] P ⫽ 0.88 P ⫽ 0.40 P ⫽ 0.074
TE-Placebo 161.2 (140.0 to 182.2) [13] 17.5 (⫺25.5 to 60.2) [6]
TE-Finasteride 173.6 (149.3 to 198.0) [17] ⫺4.46 (⫺18.6 to 9.65) [11]
Vehicle-Placebo 89.8 (75.2 to 104.3) [16] ⫺2.58 (⫺14.3 to 9.14) [12] 10.5 (0.54 to 20.4) ⫺11.5 (⫺18.9 to ⫺1.5) ⫺21.7 (⫺41.6 to ⫺1.87)
Vehicle-Finasteride 85.8 (72.6 to 99.0) [13] ⫺20.9 (⫺44.1 to 2.36) [8] P ⫽ 0.041 P ⫽ 0.026 P ⫽ 0.037
TE-Placebo 84.5 (64.4 to 104.5) [13] 25.3 (⫺22.2 to 72.8) [6]
TE-Finasteride 94.1 (75.1 to 113.0) [17] ⫺0.82 (⫺9.87 to 8.23) [11]
Vehicle-Placebo 144.0 (111.1 to 176.9) [16] 4.33 (⫺18.7 to 27.4) [12] ⫺42.8 (⫺71.2 to ⫺14.3) 42.6 (14.1 to 71.0) ⫺17.1 (⫺74.0 to 39.9)
Vehicle-Finasteride 148.1 (114.2 to 182.0) [13] 46.4 (⫺7.4 to 100.1) [8] P ⫽ 0.0051 P ⫽ 0.0046 P ⫽ 0.55
TE-Placebo 154.6 (100.8 to 208.4) [13] ⫺16.5 (⫺39.2 to 6.22) [6]
TE-Finasteride 183.4 (135.1 to 231.8) [17] ⫺2.72 (⫺58.7 to 53.2) [11]
Vehicle-Placebo 1.10 (0.97 to 1.26) [16] ⫺0.01 (⫺0.59 to 0.04) [12] 0.072 (0.018 to 0.13) 0.019 (⫺0.031 to 0.068) ⫺0.11 (⫺0.15 to 0.022)
Vehicle-Finasteride 1.08 (0.84 to 1.32) [13] 0.10 (⫺0.01 to 0.21) [8] P ⫽ 0.010 P ⫽ 0.45 P ⫽ 0.034
TE-Placebo 0.97 (0.89 to 1.04) [13] 0.083 (0.004 to 0.16) [6]
TE-Finasteride 0.88 (0.77 to 1.01) [17] 0.091 (0.004 to 0.18) [11]
Vehicle-Placebo 24.9 (21.1 to 28.7) [16] ⫺0.50 (⫺4.62 to 3.62) [12] 1.19 (⫺2.59 to 4.93) 1.89 (⫺1.88 to 5.66) ⫺1.02 (⫺8.56 to 6.52)
Vehicle-Finasteride 23.6 (17.1 to 30.1) [13] 2.13 (⫺2.35 to 6.60) [8] P ⫽ 0.53 P ⫽ 0.32 P ⫽ 0.78
TE-Placebo 24.9 (19.9 to 29.9) [13] 1.33 (⫺1.53 to 4.20) [6]
TE-Finasteride 46.8 (16.3 to 77.2) [17] ⫺9.82 (⫺28.2 to 8.56) [11]
Vehicle-Placebo 21.9 (18.3 to 25.4) [16] ⫺0.67 (⫺4.55 to 3.22) [12] 0.075 (⫺5.31 to 5.46) 4.16 (⫺1.23 to 9.54) 1.72 (⫺9.02 to 12.5)
Vehicle-Finasteride 21.8 (15.6 to 28.1) [13] 1.75 (⫺3.28 to 6.78) [8] P ⫽ 0.98 P ⫽ 0.13 P ⫽ 0.75
TE-Placebo 23.3 (19.1 to 27.5) [13] ⫺2.67 (⫺8.40 to 3.07) [6]
TE-Finasteride 58.0 (17.7 to 98.3) [17] ⫺11.2 (⫺35.8 to 13.4) [11]
Vehicle-Placebo 67.1 (54.6 to 79.7) [16] 3.33 (⫺1.38 to 8.05) [12] ⫺6.88 (⫺11.5 to 2.28) 2.76 (⫺1.94 to 7.46) 3.43 (⫺6.07 to 12.9)
Vehicle-Finasteride 89.5 (63.5 to 115.6) [13] 1.00 (⫺10.7 to 8.68) [8] P ⫽ 0.0044 P ⫽ 0.24 P ⫽ 0.47
TE-Placebo 79.4 (62.4 to 96.3) [13] ⫺8.50 (⫺22.5 to 5.47) [6]
TE-Finasteride 72.1 (60.2 to 83.9) [17] ⫺6.46 (⫺14.0 to 1.06) [11]

As with all studies, several limitations exist with our data
set, including a relatively small sample size and a slightly
higher than expected non-completion rate. In this regard, the
2 ⫻ 2 factorial design that we utilized is the most powerful
study design to detect outcomes resulting from a combination
pharmacological therapy and allows for adequate power with
smaller sample sizes. To ensure an appropriate sample size, we
powered to detect differences in three of four primary out-
comes (i.e., 1-RM strength, fat-free mass, and Hct) at the 6-mo
time point despite the 12-mo duration of our study. In this
regard, we met our expected non-completion rate of 20% at 6
mo, whereas the 12-mo noncompletion rate in our study (i.e.,
33%) was slightly higher than anticipated. Importantly, non-
completion was similar among all groups (␹2 P value ⫽ 0.48,
indicating no differences) and was comparable to the non-
completion rates of 27–29% in other long-term testosterone
studies (4, 11, 26). Additionally, our non-completion rate was
not exceedingly high, given that once-weekly visits to the
hospital were required for 52 consecutive weeks and that we
observed a significant main effect for testosterone in each of
our primary and secondary outcomes and a significant interac-
tion for prostate volume (the only primary outcome powered
on 12-mo data), as hypothesized. Indeed, we detected all a
priori hypotheses for primary and secondary outcomes. How-
ever, it remains theoretically possible that we did not observe
significant interactions (at the 12-mo time point) because our
noncompletion rate resulted in a slightly lower than expected
power to detect such outcomes. We believe this to be highly
unlikely given that the 0- to 12-mo changes and point estimates
(i.e., 95% CI) for the vast majority of our data were direction-
ally similar and of a comparable magnitude in the 1) testos-
terone-placebo and testosterone-finasteride groups and 2) ve-
hicle-placebo and vehicle-finasteride groups. Regardless, when
one is interpreting our data, nonsignificant interactions should
not be used to infer that an interaction was not present. In
addition to the above mentioned limitations, some nonsignifi-
cant differences also existed between groups at baseline. To
account for this random variability, baseline values were in-
cluded in our statistical model as fixed effects. Additionally we
examined the baseline characteristics of the randomized cohort
(n ⫽ 60) and of the completers (n ⫽ 40) and observed no
differences between cohorts, indicating that completers were
representative of the overall randomized cohort. Irrespective of
these limitations, we report significance in each of our primary
and secondary outcomes, demonstrating the robustness of our
data and that our study achieved appropriate power to detect all
desired outcomes.
In conclusion, our results add to the growing number of
preclinical (24 –26) and clinical trials (4, 11, 33) reporting that
musculoskeletal and lipolytic improvement can be obtained

AJP-Endocrinol Metab • doi:10.1152/ajpendo.00592.2013 • www.ajpendo.org

 TESTOSTERONE AND FINASTERIDE IN OLDER MEN
without prostate enlargement when higher-than-replacement
testosterone is coadministered with finasteride (an inhibitor of
the type II 5␣-reductase enzyme). These findings indicate that
elevated DHT is not required for the benefits of exogenous
testosterone and support the contention that finasteride ablates
prostate enlargement associated with higher-than-replacement
TE administration. As such, our findings provide a rationale for
larger and more comprehensive clinical trials examining the
safety and efficacy of higher-than-replacement testosterone
plus finasteride/dutasteride treatment in hypogonadal elderly
men.
ACKNOWLEDGMENTS
We thank Dr. Keith Kaufman at Merck for editorial comments; Warren
Reed, Tom Cornwell, and the Urology Service from the Malcom Randall
VAMC for assistance with urological exams; and Helen Dunn and Linda
Sawka, The Living Well Center at the University of Florida, for allowing use
of resistance exercise equipment. Trial registration: Clinical trials.gov identi-
fier NCT00475501.
GRANTS
This study was upported by a Veteran’s Health Administration Clinical
Services R&D Merit Award to S. E. Borst, by Grant 1UL1 TR-000064 from
the National Center for Advancing Translational Science, National Institutes of
Health, and in part by the Merck-Investigator-Initiated Studies Program
(Merck & Co.).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: S.E.B., U.N., and M.M. conception and design of
research; S.E.B., J.F.Y., C.F.C., U.N., J.R.M., J.A.L., R.W.B., D.T.B., J.S.M.,
M.M., S.R., L.A.B., S.C.M., and D.F.C. performed experiments; S.E.B.,
J.F.Y., C.F.C., U.N., J.A.L., R.W.B., D.T.B., J.S.M., L.A.B., D.F.C., and J.J.S.
analyzed data; S.E.B., J.F.Y., C.F.C., U.N., R.W.B., D.T.B., J.S.M., L.A.B.,
and S.C.M. interpreted results of experiments; S.E.B. and J.F.Y. prepared
figures; S.E.B., J.F.Y., R.W.B., D.T.B., J.S.M., M.M., L.A.B., S.C.M., D.F.C.,
and J.J.S. drafted manuscript; S.E.B., J.F.Y., C.F.C., U.N., J.R.M., J.A.L.,
R.W.B., D.T.B., J.S.M., M.M., S.R., L.A.B., S.C.M., D.F.C., and J.J.S. edited
and revised manuscript; S.E.B., J.F.Y., C.F.C., U.N., J.R.M., J.A.L., R.W.B.,
D.T.B., J.S.M., M.M., S.R., L.A.B., S.C.M., D.F.C., and J.J.S. approved final
version of manuscript.
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