Treatment with oxandrolone and the durability of effects

in older men
E. Todd Schroeder, Ling Zheng, Kevin E. Yarasheski, Dajun Qian, Yolanda Stewart,
Carla Flores, Carmen Martinez, Michael Terk and Fred R. Sattler
J Appl Physiol 96:1055-1062, 2004. First published 24 October 2003;
doi: 10.1152/japplphysiol.00808.2003

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 J Appl Physiol 96: 1055–1062, 2004.
First published October 24, 2003; 10.1152/japplphysiol.00808.2003.

Treatment with oxandrolone and the durability

of effects in older men
E. Todd Schroeder,1,4 Ling Zheng,2 Kevin E. Yarasheski,3 Dajun Qian,2 Yolanda Stewart,2
Carla Flores,2 Carmen Martinez,2 Michael Terk,4,5 and Fred R. Sattler1,2,4
1
Division of Infectious Diseases, Department of Medicine, 2General Clinical Research Center, and 5Department of Radiology,
Keck School of Medicine, and 4Department of Biokinesiology and Physical Therapy, University of Southern California,
Los Angeles, California 90033; and 3Divisions of Metabolism, Endocrinology and Lipid Research and Cell Biology and
Physiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
Submitted 31 July 2003; accepted in final form 17 October 2003

Schroeder, E. Todd, Ling Zheng, Kevin E. Yarasheski, Dajun disposes older persons to accelerated atherosclerosis and Type
Qian, Yolanda Stewart, Carla Flores, Carmen Martinez, Mi- 2 diabetes.
chael Terk, and Fred R. Sattler. Treatment with oxandrolone and The contribution of age-associated hormonal alterations to

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the durability of effects in older men. J Appl Physiol 96: 1055–1062, these adverse health consequences is unclear. Both cross-
2004. First published October 24, 2003; 10.1152/japplphysiol.00808.
sectional (15, 28, 51) and longitudinal (17, 30) studies have
2003.—We investigated the effects of the anabolic androgen, oxan-
drolone, on lean body mass (LBM), muscle size, fat, and maximum shown that serum total and free concentrations of testosterone
voluntary muscle strength, and we determined the durability of effects decline with advancing age in men. Testosterone regulates
after treatment was stopped. Thirty-two healthy 60- to 87-yr-old men muscle and fat mass, but the relationship between gonadal
were randomized to receive 20 mg oxandrolone/day (n ⫽ 20) or hormone status and age-associated alterations in body compo-
placebo (n ⫽ 12) for 12 wk. Body composition [dual-energy X-ray sition, skeletal muscle strength, and metabolic disorders in
absorptiometry (DEXA), magnetic resonance imaging, and 2H2O older persons is uncertain. There is some evidence that bio-
dilution] and muscle strength [1 repetition maximum (1 RM)] were available testosterone levels (free and the fraction loosely
evaluated at baseline and after 12 wk of treatment; body composition bound to albumin) correlate with skeletal muscle mass and
(DEXA) and 1-RM strength were then assessed 12 wk after treatment muscle strength in different ethnic populations (3, 35).
was discontinued (week 24). At week 12, oxandrolone increased LBM
Testosterone treatment in hypogonadal young men increases
by 3.0 ⫾ 1.5 kg (P ⬍ 0.001), total body water by 2.9 ⫾ 3.7 kg (P ⫽
0.002), and proximal thigh muscle area by 12.4 ⫾ 8.4 cm2 (P ⬍ lean tissue (4, 7, 20, 45, 53, 54) and muscle strength (4, 54) and
0.001); these increases were greater (P ⬍ 0.003) than in the placebo decreases fat mass (4, 20, 54). Despite evidence that supple-
group. Oxandrolone increased 1-RM strength for leg press by 6.7 ⫾ mental testosterone increases myofibrillar protein synthesis
6.4% (P ⬍ 0.001), leg flexion by 7.0 ⫾ 7.8% (P ⬍ 0.001), chest press rate in older men (11, 52), its effects on body composition and
by 9.3 ⫾ 6.7% (P ⬍ 0.001), and latissimus pull-down exercises by muscle function in these men are less clear (22, 31, 44, 46, 50,
5.1 ⫾ 9.1% (P ⫽ 0.02); these increases were greater than placebo. 51). In the largest studies, in which older relatively hypogo-
Oxandrolone reduced total (⫺1.9 ⫾ 1.0 kg) and trunk fat (⫺1.3 ⫾ 0.6 nadal men received testosterone replacement for 1 and 3 yr,
kg; P ⬍ 0.001), and these decreases were greater (P ⬍ 0.001) than respectively, lean body mass (LBM) was only modestly in-
placebo. Twelve weeks after oxandrolone was discontinued (week creased (1.0 and 1.9 kg, respectively) (22, 46), and the effects
24), the increments in LBM and muscle strength were no longer on muscle strength were variable. Only three studies have
different from baseline (P ⬎ 0.15). However, the decreases in total
and trunk fat were sustained (⫺1.5 ⫾ 1.8, P ⫽ 0.001 and ⫺1.0 ⫾ 1.1
shown increases in lower extremity maximum voluntary force
kg, P ⬍ 0.001, respectively). Thus oxandrolone induced short-term (11, 22, 52). By contrast, in a controlled study of 108 older men
improvements in LBM, muscle area, and strength, while reducing randomized to receive placebo or testosterone (46), upper
whole body and trunk adiposity. Anabolic improvements were lost 12 extremity grip strength and lower extremity isokinetic strength
wk after discontinuing oxandrolone, whereas improvements in fat were unchanged with testosterone (50). Similarly, the effects of
mass were largely sustained. testosterone on fat mass have been variable with either no
lean body mass; muscle mass; dual-energy X-ray absorptiometry; change or only modest reductions achieved (11, 21, 31, 46,
magnetic resonance imaging 51, 52).
The variability in outcomes in older men may be related to
the different delivery strategies for testosterone (intramuscular
ADVANCING AGE IS ASSOCIATED with a progressive loss of muscle vs. transdermal delivery), dose (200 mg biweekly vs. 5 mg/
mass (sarcopenia), skeletal muscle strength, and physical func- day), change in testosterone levels in response to therapy,
tion (1, 2, 9, 14, 19). Sarcopenia increases the risk for frailty, duration of treatment (4 wk vs. 3 yr), different methods to
falls, fractures, dependency, and depression (34, 36). Advanc- assess body composition [bioelectrical impedance analysis,
ing age is also associated with increases in fat mass, particu- dual-energy X-ray absorptiometry (DEXA), magnetic reso-
larly central adiposity, which increases the risk for insulin nance imaging (MRI), hydrostatic weighing], as well as mea-
resistance, hypertension, dyslipidemia, and impaired fibrinoly- sures of muscle strength (handheld dynamometers, isokinetic
sis (metabolic syndrome) (37). The metabolic syndrome pre- dynamometers, free weights, or pneumatic resistance devices).

Address for reprint requests and other correspondence: F. R. Sattler, Uni- The costs of publication of this article were defrayed in part by the payment
versity of Southern California, Dept. of Medicine and Biokinesiology & of page charges. The article must therefore be hereby marked “advertisement”
Physical Therapy, 1540 East Alcazar St., CHP-155, Los Angeles, CA 90033. in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

http://www.jap.org 8750-7587/04 $5.00 Copyright © 2004 the American Physiological Society 1055
1056 ANDROGEN SUPPLEMENTATION AND DURABILITY OF EFFECTS

Moreover, with one exception, these studies did not directly weeks 6, 12, and 24. Additionally, liver function tests were obtained
assess changes in muscle mass or muscle cross-sectional area at weeks 3 and 9.
(CSA).
Body Composition by DEXA
Oxandrolone is a potent, oral anabolic androgen that is
approved for the treatment of weight loss due to known Whole body DEXA scans (Hologic QDR-4500, version 7.2 soft-
medical or unexplained causes (43, 48). We evaluated whether ware, Waltham, MA) were performed at baseline and weeks 12 and 24
the licensed dose of oxandrolone increases muscle mass and to quantify LBM and fat mass. One blinded, experienced technician
muscle strength and reduces body fat mass in older men at risk (C. Flores) performed and analyzed the scans. The coefficient of
for sarcopenia and metabolic complications. Moreover, we variation (CV) for repeated measures was ⬍1% for lean and fat mass.
followed these men for 12 wk after discontinuing oxandrolone Muscle CSA
to evaluate the durability of the alterations in body composition
and muscle strength. We hypothesized that oxandrolone would CSA of the dominant thigh muscles was assessed by using proton
increase LBM, muscle area, and muscle strength, and reduce MRI at baseline and week 12 (but not week 24). 1H-MRI was
whole body and central adiposity in older men, and that these performed by using a 1.5-T GE Signa-LX scanner with the body coil
used as both transmitter and receiver. Nine axial images of the thigh
benefits would not be fully sustained.
were acquired after obtaining a longitudinal relaxation time-weighted
METHODS coronal scout image (relaxation time-weighted longitudinal repetition
time/echo time 300/echo time) that was used to identify the exact

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Study Design anatomic location for the axial images. The slice thickness was 7.5
mm with a 1.5-mm gap. The field of view was 24 ⫻ 24 cm with a
This was a single-center, investigator-initiated, double-blind, pla- 254 ⫻ 128-pixel matrix. One signal average was used.
cebo-controlled investigation to determine the magnitude and dura- Thigh muscle CSA was measured at the junction of the proximal
bility of effects of a potent, convenient to administer anabolic andro- and middle third of the femur in the dominant leg, because greater
gen, oxandrolone (Oxandrin). The study was performed at the Uni- relative increases in CSA of the proximal quadriceps have been
versity of Southern California National Center for Research reported after anabolic interventions (32). Pixels associated with
Resources-funded General Clinical Research Center, with the excep- intramuscular fat, bone, and major arteries, veins, and nerves were
tion that skeletal muscle strength was assessed at the Clinical Exercise subtracted from the image (using Scion Image, version Beta 4.0.2
Research Center in the Department of Biokinesiology and Physical software, Scion). Muscle CSA was measured by setting a pixel
Therapy of the University. The study design and informed consent intensity threshold value that distinguished fat from muscle pixels.
were approved and annually reviewed by the Institutional Review This allowed adipose tissue to be differentiated from other more
Board of the Los Angeles County-University of Southern California optically dense lean tissue (muscle, nerve, and blood vessels). Total
Medical Center. thigh muscle CSA was calculated after area of the fat tissue was
removed automatically and area of the femur, nerve tissue, and blood
Study Population
vessels were removed manually. The same investigator (E. T.
Men ⱖ60 yr old were recruited from the Los Angeles communities Schroeder) blinded to treatment located the region of interest, set the
surrounding the University of Southern California Health Sciences threshold value and performed the image analyses. The CV for
Campus. To be eligible for the study, subjects had to have a body repeated measures of total thigh CSA was ⬍1%.
mass index ⱕ35 kg/m2, repeated resting blood pressure ⬍180/95
mmHg, prostate-specific antigen (PSA) ⱕ4.1 ng/ml, serum hematocrit Total Body Water
ⱕ50%, alanine aminotransferase (ALT) less than three times the Total body water (TBW) was determined at baseline and week 12
upper limit of normal, and serum creatinine ⬍2 mg/dl. Subjects with by using 2H2O dilution. Subjects ingested 2H2O (Cambridge Isotopes
untreated endocrine abnormalities (e.g., diabetes, hypothyroidism), Laboratory; 0.25 g/kg), and isotope dilution was estimated from
active inflammatory conditions, or cardiac problems (heart failure, plasma samples obtained at ⫺15 min, 0, 3, and 4 h. Our laboratory has
myocardial infarction, or angina) in the proceeding 3 mo were previously determined that steady-state 2H enrichment is achieved in
excluded. An incremental treadmill exercise test with 12-lead elec- plasma and maintained between 120 and 240 min (58). The dilution of
trocardiogram and blood pressure monitoring to achieve a heart rate tracer, corrected for the exchange of hydrogen with other body
ⱖ85% of age-predicted maximum was administered before resistance hydrogen pools (⬃4%), provides a measure of tracer dilution space,
exercise testing to identify subjects at possible risk for exercise which is equivalent to TBW volume. Plasma samples were analyzed
induced ischemia, abnormalities in cardiac rhythm, or abnormal blood for 2H2O abundance using proton magnetic resonance spectroscopy
pressure responses. and d9-tert-butanol as an internal standard (interassay CV ⫽ 6.3%)
Study Interventions (16). TBW was calculated from the average of the 3- and 4-h 2H
enrichments in plasma water by using the following formula: TBW ⫽
Eligible subjects were randomized in a 2:1 manner to receive either dose (16/18 ⫻ g of 2H2O)/deuterium enrichment, where TBW is
the licensed oral dose of oxandrolone (Oxandrin, Savient Pharmaceu- expressed as 2H dilution space/1.04 (57).
ticals, East Brunswick, NJ) of 20 mg/day (10 mg twice daily) or
matching placebo for 12 wk. Twenty milligrams were chosen because Evaluation of Muscle Strength
this is the Food and Drug Administration-licensed dose for treatment Maximal voluntary muscle strength was assessed by using the
of weight loss or inability to maintain normal body weight. Subjects one-repetition maximum (1-RM) method (13) at baseline and weeks
returned for a follow-up evaluation at study week 24 (12 wk after 12 and 24. The 1 RM was defined as the greatest resistance that could
stopping study treatment). Adherence was monitored by tablet count be moved through a defined range of motion with the use of proper
at each study visit. technique. Before strength testing, subjects warmed up on a cycle
Safety Monitoring ergometer or by walking for 5 min. Maximum voluntary strength was
determined for the bilateral leg press, leg flexion, latissimus pull-
Complete blood counts, comprehensive chemistries with tests of down, and chest press exercises on Keiser A-300 pneumatic equip-
renal and hepatic function, and PSA were measured at baseline and ment (Keiser, Fresno, CA). The leg press and chest press machines

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 ANDROGEN SUPPLEMENTATION AND DURABILITY OF EFFECTS 1057
only displayed units of measure in newtons. The newton measurement compared between oxandrolone and placebo groups by using an
of force cannot accurately be converted to kilograms, and therefore independent t-test. All statistical testing was performed at a two-sided
the strength data are reported in newtons for these two machines. To 5% level of significance (0.83% for each post hoc t-test) by using
accommodate for familiarization and learning of the testing proce- Statistical Analysis System version 8.0 (SAS Institute, Cary, NC).
dures, baseline strength was assessed twice within 1 wk before study
therapy was initiated. The greatest 1 RM measured for each exercise RESULTS
during the two pretreatment testing sessions was used as the baseline
value for maximal voluntary muscle strength. The technician was Subjects
blinded to the subjects’ treatment.
Thirty-four eligible subjects were enrolled and randomized
Nutritional Assessment to either oxandrolone (n ⫽ 22) or placebo (n ⫽ 12). One
subject randomized to receive oxandrolone elected not to
Subjects recorded dietary intake on 3 consecutive days, including 2 participate after providing informed consent; however, he did
weekdays and 1 weekend day in the week before baseline and weeks not start the study drug. A second subject randomized to
12 and 24. Subjects were counseled that the days should be chosen to receive oxandrolone completed study therapy through week 12
include usual activities and typical eating patterns. A licensed nutri- but did not return for follow-up at week 24. This subject could
tionist (C. Martinez) reviewed all dietary entries with the subjects.
This information was entered into the Nutritionist V software (First
not be contacted until well after he missed the week 24
Data Bank, San Bruno, CA) and analyzed for total energy intake, evaluation; he indicated that he had not had adverse events but

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macronutrients, and types of fat. Subjects were counseled not to had been too busy to make his appointment. Therefore, 32
change their routine dietary habits during the course of the study. subjects completed all aspects of the study and were included
in the final analysis. On the basis of tablet count, these subjects
Measurement of Hormones and C-Reactive Protein were adherent to their assigned treatment (94.0 ⫾ 7.4% of all
pills prescribed with no difference between the groups).
Total testosterone concentration (ng/dl) was measured by the Los
Angeles County-University of Southern California Medical Center
Baseline characteristics were similar in the two study groups
Clinical Diagnostic Laboratory (Endocrinology Section) by using (Table 1), except that serum PSA levels were greater (P ⫽
Diagnostic Products Coat-A-Count at baseline and week 24, 12 wk 0.009) in the oxandrolone group. Baseline energy, protein,
after the oxandrolone intervention was completed. This competitive carbohydrate, and fat intakes were similar between the two
radioimmunoassay uses a solid-phase polyclonal antibody. The CV groups.
for total testosterone was ⱕ7.7%. We did not measure testosterone
levels at week 12 because semisynthetic androgens, including oxan- Changes in Body Composition
drolone, cross-react in these testosterone assays. Luteinizing hormone
(LH) concentration (IU/ml) was measured by using a microparticle LBM. There was a significant (P ⬍ 0.001) group ⫻ time
enzyme immunoassay (AxSYM; Abbott Diagnostics), at baseline and interaction for total LBM. After 12 wk, LBM increased sig-
study weeks 12 and 24. The CV for LH was ⱕ4.9%. nificantly (P ⬍ 0.001) in the oxandrolone group (3.0 ⫾ 1.5 kg),
To assess for evidence of inflammation, we evaluated the changes and this increase in LBM was greater (P ⬍ 0.001) than the
in ultrasensitive C-reactive protein (CRP) at the University of South- small change (0.0 ⫾ 1.4 kg; P ⫽ 0.91) in the placebo group
ern California Pathology Reference Laboratory by using a latex (Fig. 1). At week 24, LBM (56.5 ⫾ 6.3 kg) had returned to
particle enhanced immunoturbidimetric assay, distributed by Equal baseline (56.0 ⫾ 5.9 kg) in the oxandrolone group (P ⫽ 0.15).
Diagnostics (Exton, PA) and manufactured by Kamiya Biochemical
(Seattle, WA). The CV for CRP was ⱕ7.1%.

Statistical Considerations Table 1. Baseline characteristics of the study population

The study was conservatively powered at 80% to detect a differ- Oxandrolone Placebo
ence in means between the oxandrolone and placebo group of 1.36 (n ⫽ 20) (n ⫽ 12) P Value*
times the common SD, using a two-sample t-test with a Bonferroni-
Age, yr 72.8⫾6.9 71.5⫾3.2 0.49
adjusted P ⫽ 0.0008, with 20 in oxandrolone group and 12 in placebo DEXA weight, kg 81.3⫾13.3 84.8⫾8.9 0.43
group. For total LBM by DEXA scanning, this sample size will be DEXA LBM, kg 56.5⫾5.6 58.3⫾5.9 0.47
able to detect a mean difference of 2 kg, assuming the common SD is DEXA fat mass, kg 23.5⫾7.7 23.7⫾4.4 0.51
1.47 kg. For the maximum voluntary skeletal muscle strength of the BMI, kg/m2 27.5⫾3.5 29.1⫾2.9 0.20
leg press exercise (which typically has the greatest variance of the Caloric intake, kcal/kg 25.8⫾6.3 25.6⫾4.5 0.87
exercises tested in this study), this sample size will be able to detect Intake of protein, g/kg 1.2⫾0.4 1.1⫾0.1 0.97
a mean relative difference of 6.8%, assuming the common standard Intake of carbohydrate, g/kg 3.0⫾0.6 3.2⫾0.7 0.47
deviation of 5.0%. Statistical analyses are presented in Tables 1–3 and Intake of fat, g/kg 1.0⫾0.3 1.0⫾0.3 0.94
Hematocrit, % 42.9⫾2.2 42.6⫾3.4 0.82
the text as means ⫾ SD.
Creatinine, mg/dl 1.5⫾1.3 1.2⫾0.4 0.34
For the main outcome variables, a two (oxandrolone and placebo Albumin, g/dl 4.0⫾0.2 4.2⫾0.2 0.07
group) by three (baseline, week 12, and week 24) repeated-measures ALT, U/l 38.0⫾7.0 38.0⫾4.4 0.83
ANOVA was used to statistically compare mean differences within Ultrasensitive CRP, mg/l 1.4⫾1.0 2.3⫾2.7 0.21
subjects and between groups. Greenhouse-Geisser adjustment was PSA, ng/ml 2.4⫾1.1 1.3⫾0.8 0.009
used to justify the assumption of sphericity. When a significant Total testosterone, ␮g/dl 369⫾147 357⫾153 0.83
group ⫻ time interaction was found, the changes from baseline to Luteinizing hormone, U/l 8.3⫾7.1 6.5⫾6.7 0.51
week 12 and the changes from baseline to week 24 between and within Total cholesterol, mg/dl 186⫾31 186⫾34 0.97
groups were compared by independent t-tests and paired t-tests, Values are means ⫾ 1 SD; n, number of subjects. DEXA, dual-energy X-ray
respectively. All post hoc tests were performed with Bonferroni absorptiometry; LBM, lean body mass; BMI, body mass index; ALT, alanine
adjustment for six possible comparisons. Baseline characteristic and aminotransferase; CRP, C-reactive protein; PSA, prostate-specific antigen. *P
the changes in safety evaluation from baseline to week 12 were value obtained by independent t-test.

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1058 ANDROGEN SUPPLEMENTATION AND DURABILITY OF EFFECTS

In the placebo group, the change from baseline in LBM was

not significant at either 12 or 24 wk.
Thigh muscle CSA. Oxandrolone increased the thigh muscle
area (12.4 ⫾ 8.4 cm2, P ⬍ 0.001; Fig. 2), whereas placebo did
not (1.4 ⫾ 6.9 cm2). After 12 wk, the increase in thigh muscle
area was greater in the oxandrolone group than in the placebo
group (P ⫽ 0.002). Thigh muscle area was not measured at
week 24.
TBW. Oxandrolone increased TBW (2.9 ⫾ 3.7 kg; P ⫽
0.002), whereas placebo did not (⫺0.6 ⫾ 2.8 kg; P ⫽ 0.47).
After 12 wk, the increase in TBW tended to be greater in the
oxandrolone group than in the placebo group (P ⫽ 0.07). TBW
was not measured at week 24.
Fat mass. There was a significant (P ⫽ 0.03) group ⫻ time Fig. 2. Absolute measures of cross-sectional area (CSA) by magnetic reso-
nance imaging at baseline (open bars) and study week 12 (solid bars) in the
interaction for total fat mass. Oxandrolone reduced whole body placebo (n ⫽ 12) and the oxandrolone (n ⫽ 20) study groups. Values are
fat mass (⫺1.9 ⫾ 1.0 kg, P ⬍ 0.001; Fig. 3A) and trunk fat means ⫾ SE. *Significant increase from baseline P ⬍ 0.001. † Significant
mass (⫺1.3 ⫾ 0.6 kg, P ⬍ 0.001; Fig. 3B), whereas placebo difference between study groups at week 12, P ⬍ 0.01.

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did not (whole body ⫽ ⫺0.2 ⫾ 1.0 kg, P ⫽ 0.58; trunk ⫽
0.0 ⫾ 0.7 kg; P ⫽ 0.87). The decreases in whole body and relative and absolute maximal voluntary strength were similar
trunk fat mass were greater in the oxandrolone group than in to baseline values in both the oxandrolone and placebo groups
the placebo group (P ⬍ 0.001). After oxandrolone was discon- (Table 2, Fig. 4).
tinued (week 24), whole body and trunk fat were still less than
baseline (⫺1.5 ⫾ 1.8 kg, P ⫽ 0.001; ⫺1.0 ⫾ 1.1 kg, P ⬍ Nutrition and Exercise
0.001, respectively).
Nutritional status, including total daily intake of energy,
Changes in Maximal Voluntary Strength protein, carbohydrate, and fat, was not different within or
There was a significant group ⫻ time interaction for chest
press (P ⬍ 0.001), leg press (P ⫽ 0.009), leg flexion (P ⫽
0.01), and latissimus pull-down (P ⫽ 0.04). After 12 wk, the
relative (Fig. 4) and absolute (Table 2) increases in maximal
voluntary muscle strength were greater for subjects receiving
oxandrolone. These increases were significantly different from
the placebo group for leg press and chest press and approached
significance for leg flexion and latissimus pull-down, even with
our very conservative Bonferroni adjustment. For leg press,
relative strength increased by 6.7 ⫾ 6.4% (P ⬍ 0.001), for leg
flexion by 7.0 ⫾ 7.8% (P ⬍ 0.001), for chest press by 9.3 ⫾
6.7% (P ⬍ 0.001), and for latissimus pull-down by 5.1 ⫾ 9.1%
(P ⫽ 0.02, not significant with Bonferroni adjustment) in the
group receiving oxandrolone (Fig. 4), whereas there were no
significant changes in the placebo group. By week 24, the

Fig. 1. Absolute change in lean body mass by dual-energy X-ray absorptiom- Fig. 3. Absolute change in total fat mass (A) and trunk fat (B) by dual-energy
etry from baseline to study week 12 (solid bars) and from baseline to study X-ray absorptiometry from baseline to study week 12 (solid bars) and from
week 24 (open bars) in the placebo (n ⫽ 12) and the oxandrolone (n ⫽ 20) baseline to study week 24 (open bars) in the placebo (n ⫽ 12) and the
study groups. Values are means ⫾ SE. *Significant increase from baseline, oxandrolone (n ⫽ 20) study groups. Values are means ⫾ SE. *Significant
P ⬍ 0.001. † Significant difference between study groups for change in lean decrease from baseline, P ⬍ 0.001. † Significant difference between study
body mass from 0 to 12 wk, P ⬍ 0.001. groups for change in fat mass from 0 to 12 wk, P ⬍ 0.001.

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 ANDROGEN SUPPLEMENTATION AND DURABILITY OF EFFECTS 1059
Table 3. Change in safety measures after 12 wk
of study therapy
Oxandrolone Placebo P Value*

Hematocrit % ⫺2.9⫾2.2 ⫺2.9⫾1.5 0.95

BUN, mg/dl ⫺1.0⫾3.6 2.0⫾4.8 0.06
Albumin, g/dl ⫺0.6⫾0.2 ⫺0.3⫾0.2 0.003
ALT, U/l 15⫾18 ⫺1⫾5 0.001
AST, U/l 8⫾8 ⫺1⫾4 0.001
Alkaline phosphatase, U/l ⫺24⫾13 ⫺7⫾12 ⬍0.001
Total serum bilirubin, mg/dl 0⫾0 0⫾0 0.93
Ultrasensitive CRP, mg/l 0.1⫾1.9 1.0⫾2.6 0.23
PSA, ng/ml ⫺0.6⫾0.9 0.1⫾0.5 0.004
Luteinizing hormone, U/l ⫺3.3⫾6.6 ⫺0.7⫾2.2 0.13
Total cholesterol, mg/dl 2⫾38 ⫺5⫾22 0.60
Fig. 4. Relative change in maximum voluntary muscle strength from baseline
Values are means ⫾ SD. BUN, blood urea nitrogen; AST, aspartate
to study week 12 (solid bars) and baseline to study week 24 (open bars) in the
aminotransferase. *P value obtained by independent t-test.
oxandrolone (n ⫽ 20) study group only. Values are means ⫾ SE. *Significant
increase from baseline with Bonferroni adjustment, P ⬍ 0.001. † Significant
difference between study groups at week 12 with Bonferroni adjustment, P ⬍

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0.001. #Approaching significant increase from baseline for lat pull-down, and drolone group, serum albumin and alkaline phosphatase levels
an approaching significant difference for leg flexion and lat pull-down between
study groups at week 12 with Bonferroni adjustment, P ⬍ 0.001.
decreased more than with placebo. The decline in albumin
could have reflected the new onset of subclinical inflammation,
but there was no change in ultrasensitive CRP levels at week 12
between groups over the 24-wk course of the study (P ⬎ 0.19 (Table 3) or week 24. There were minimal increments in the
by ANOVA for each; data not shown). Additionally, on entry liver transaminase levels that reached statistical significance,
into the study, subjects were instructed to maintain their but ALT was only increased beyond the normal range in two
habitual physical activity and not to engage in a new exercise subjects in whom it reached 71 and 99 U/l (ⱕ1.5 times the
routine during the course of the study. On the basis of self- upper limit of normal). Both subjects were asymptomatic
report at each study evaluation, subjects did not alter their without liver enlargement, and the ALT returned to normal in
physical activity levels. both at the week 24 evaluation. Finally, there was a small but
significant decrease in PSA in the oxandrolone group.
Safety Evaluation As described in METHODS, we only measured serum testos-
One serious adverse event occurred during the study. A terone levels at baseline and week 24. Oxandrolone and pla-
subject randomized to oxandrolone developed hypotension cebo groups had similar baseline (P ⫽ 0.28; Table 1) and week
(systolic blood pressure ⬍90 mmHg) when his primary doctor 24 testosterone levels (358 ⫾ 119 ng/dl in the oxandrolone
modified the patient’s antihypertensive medications at the group and 421 ⫾ 196 ng/dl; P ⫽ 0.26). There was a trend
subject’s request. His systolic blood pressure had been in the toward a greater decline in LH levels with oxandrolone, sug-
140- to 155-mmHg range before, and during the study and he gesting that oxandrolone treatment may have suppressed the
desired tighter control. Study therapy was suspended for 3 wk hypothalamic-pituitary-gonadal axis.
while his antihypertensive medications were adjusted; study DISCUSSION
therapy was then resumed without problem.
There were no new symptoms or physical findings that could These findings demonstrated that a relatively brief course of
be ascribed to oxandrolone. After 12 wk, there were only treatment with a potent anabolic androgen in men over 60 yr of
modest changes in blood chemistry (Table 3). In the oxan- age increased LBM as well as upper and lower body maximal

Table 2. Maximal voluntary skeletal muscle strength

P Value

Week 0 Week 12 Week 24 0 vs. 12 0 vs. 24

Leg press, N
Oxandrolone 1,245⫾132 1,357⫾189† 1,266⫾191 ⬍0.001* 0.81
Placebo 1,250⫾213 1,250⫾210 1,246⫾242 0.98 0.30
Leg flexion, kg
Oxandrolone 69.6⫾9.1 74.4⫾10.6 70.5⫾8.8 0.002* 0.58
Placebo 66.5⫾12.5 68.1⫾13.2 67.4⫾12.9 0.86 0.67
Chest press, N
Oxandrolone 212⫾41 233⫾40† 214.0⫾40.5 ⬍0.001* 0.89
Placebo 216⫾44 213⫾49 198⫾43 0.69 0.43
Latissimus pull-down, kg
Oxandrolone 52.8⫾9.9 55.5⫾11.0 52.4⫾10.3 0.02 0.48
Placebo 54.0⫾8.5 56.6⫾9.9 53.7⫾8.7 0.10 0.57
Values are means ⫾ SD. *P value significant at P ⬍ 0.05 with Bonferroni adjustment for within-group paired t-test. †P value significant at P ⬍ 0.05 with
Bonferroni adjustment for between-group comparison on the change from baseline to week 12.

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1060 ANDROGEN SUPPLEMENTATION AND DURABILITY OF EFFECTS

voluntary strength more than placebo. The increase of 3.0 ⫾ to maintain and enhance increases in LBM and muscle
1.5 kg in LBM in this study is approximately twofold greater strength. Other anabolic strategies with potentially better safety
than the increase in LBM reported by other investigators using profiles such as resistance training, a potent stimulus for
testosterone supplementation in older men (6, 21, 46, 51). The skeletal muscle protein synthesis in older persons (56), or
only other study of androgen therapy to achieve comparable specific androgen receptor modulators should be investigated
increases in LBM (4.2 ⫾ 0.6 kg) used a dose of testosterone for sustaining gains in muscle mass and strength during the
enanthate adjusted to produce nadir levels in the upper normal aging process.
range, suggesting that dosing was “supraphysiological” be- Another important and unique finding of this study was the
cause nadir levels were tested 2 wk after a prior intramuscular oxandrolone-induced decrease in total and trunk fat that was
dose (11). Moreover, subjects were treated for 24 wk compared largely sustained 12 wk after oxandrolone was stopped. In
with 12 wk in our study. These observations suggest that the younger hypogonadal men, testosterone decreased total body
formulation and potency of the androgen, dose, and duration of and abdominal fat mass (4, 20, 54). However, it is not clear
therapy may affect the changes in lean tissue achieved, which whether androgen therapy affects adipose tissue in eugonadal
is in keeping with a recent dose ranging study of testosterone men. Bhasin et al. (4) reported no change in fat mass with
in younger men (5). replacement doses of 125 mg testosterone weekly over 4 mo in
The significant increases in both upper and lower body eugonadal, healthy men, although much higher supraphysi-
maximal voluntary strength in subjects receiving oxandrolone ological doses reduced adipose tissue. Marin et al. (24) re-

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are noteworthy. In the few studies assessing the effects of ported that low-dose androgen therapy reduced abdominal fat
androgen supplementation in older men, muscle strength was in middle-aged men with central obesity. However, the effects
not tested (51) or was evaluated with either handgrip (31, 44) occurred primarily in subjects with low testosterone levels,
or isokinetic dynamometry (46, 52), which may measure dif- which is consistent with observations that intra-abdominal fat
ferent mechanistic aspects of strength [reviewed in Storer et al. is inversely correlated with free testosterone levels (42). Only
(47)]. Therefore, these evaluations may not be representative of five of our subjects had baseline total testosterone levels ⬍270
true changes in maximal strength for larger muscle groups ng/dl (lower limit of normal in our laboratory), but levels for
important for optimal physical function in older persons. More- the entire group were generally less than those of younger men.
over, only one study demonstrated substantial increases in Whether the relative hypogonadism (compared with younger
1-RM strength in both upper body and lower body muscle men) of our participants or the potency or structure of the
groups, although neuromuscular learning may have contributed synthetic androgen, oxandrolone, was primarily responsible for
to the gains in strength with testosterone because multiple the reductions in whole body and trunk fat is uncertain.
baseline trials of maximal strength were not assessed (11). These results do provide clarification as to whether metab-
However, older adults typically produce their best performance olism of testosterone by aromatase to estradiol (⬃40%) is
(highest force production) on the second or third 1-RM trial largely responsible for changes in fat mass when men are
(12, 40). Thus, studies to assess the affects of anabolic inter- treated with testosterone (18). The fact that adipocytes contain
ventions on maximal voluntary strength should test strength on estradiol receptors and the observation that estrogen receptor
at least two separate occasions before study therapy is initiated. knockout mice have increased adipose tissue have suggested
The increases in muscle strength and CSA in the oxan- that estrogen is important in downregulating fat mass (8).
drolone group suggest that a major portion of the anabolic However, oxandrolone is not aromatized to estrogen, suggest-
androgen-induced increase in LBM was due to increases in ing that the favorable declines in adipose tissue observed in the
muscle protein mass, because strength is closely related to present study were due to direct and specific actions of oxan-
muscle size (27). Oxandrolone and testosterone exert their drolone.
actions by enhancing the rate of mixed muscle (11, 52) and The discordant effects of oxandrolone on lean tissue and fat
myofibrillar protein synthesis (7), and by reducing the rate of mass 12 wk after study therapy was discontinued were puz-
muscle protein breakdown (43). However, our 2H2O dilution zling. According to 3-day food diaries and self-report of
measurements indicated a disproportionate increase in TBW exercise activity, subjects did not change their dietary or
(⬃2.9 kg) compared with the increase in DEXA-derived LBM habitual activity during the study. Thus the durability of the
(3 kg). If the entire increase in DEXA-derived LBM were effects of oxandrolone on adipose but not lean tissue likely
protein, we would have anticipated only ⬃2.3-kg increase in reflect the biological differences in these tissues and/or the
TBW. Also, the rapid loss of LBM (⬃2.5 kg) after oxan- effects of other concurrent regulators of metabolism. In a
drolone was discontinued suggests that tissue fluid was a population prone to obesity, it is remarkable that 80% of the
component of the oxandrolone-induced increase in LBM. Fu- reduction in total and central fat mass after a relatively short
ture studies should measure muscle amino acid balance after period of androgen therapy (12 wk) were sustained for at least
androgen administration in elderly men at risk for physical 3 mo after treatment was discontinued. The reductions in fat
frailty. mass observed in obese middle-aged men have been associated
To our knowledge, this is the first study to determine the with decreases in visceral adipose tissue, improvements in
durability of the effects achieved with androgen therapy after insulin sensitivity, and declines in cholesterol, triglycerides,
the treatment was discontinued. We speculated that at least and diastolic blood pressure (24, 25). These effects are consis-
some portion of the gains in LBM and strength would be tent with the known effects of androgens to decrease lipopro-
sustained 12 wk after treatment with oxandrolone. However, tein lipase and upregulate ␤-adrenergic receptors on adipo-
the fact that gains in both LBM and strength were largely lost cytes, which would inhibit the accumulation of lipid and
within 12 wk after treatment was discontinued suggests that enhance the efflux of lipid from these cells in response to
prolonged therapy with an anabolic androgen will be necessary catecholamines (26, 38, 55). Further studies will be necessary
J Appl Physiol • VOL 96 • MARCH 2004 • www.jap.org
 ANDROGEN SUPPLEMENTATION AND DURABILITY OF EFFECTS 1061
to assess whether the reductions in fat mass observed in our Stewart KJ, Cottrell E, St Clair C, Pabst KM, and Harman SM.
older men would be associated with beneficial measures of Growth hormone and sex steroid administration in healthy aged women
and men: a randomized controlled trial. JAMA 288: 2282–2292, 2002.
metabolism and health in an aging population. 7. Brodsky IG, Balagopal P, and Nair KS. Effects of testosterone replace-
A limitation of this study is that we assessed a 17-methylated ment on muscle mass and muscle protein synthesis in hypogonadal men–a
androgen and not generic testosterone. Thus we cannot extrap- clinical research center study. J Clin Endocrinol Metab 81: 3469–3475,
olate our findings to a dose of testosterone. Although we did 1996.
8. Cooke PS, Heine PA, Taylor JA, and Lubahn DB. The role of estrogen
not demonstrate short-term adverse clinical effects with oxan-
and estrogen receptor-alpha in male adipose tissue. Mol Cell Endocrinol
drolone, evaluation of anabolic androgens, including testoster- 178: 147–154, 2001.
one, as potential treatments for sarcopenia, must be investi- 9. Dutta C, Hadley E, and Lexell J. Sarcopenia and physical performance
gated in sufficiently powered studies of long-term treatment to in old age: overview. Muscle Nerve Suppl 5: S5–S9, 1997.
demonstrate their safety for prostate and cardiovascular health. 10. Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive Summary of The Third Report of The
In conclusion, substantial gains in LBM and muscle size National Cholesterol Education Program (NCEP) Expert Panel on Detec-
were achieved safely with a relatively short course of therapy tion, Evaluation, and Treatment of High Blood Cholesterol in Adults
with an anabolic androgen in 60- to 87-yr-old men. Moreover, (Adult Treatment Panel III). JAMA 285: 2486–2497, 2001.
these changes were associated with significant gains in maxi- 11. Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J,
mal voluntary strength in the large upper and lower body Achacosa A, Lieberman SA, Tipton K, Wolfe RR, and Urban RJ.
Testosterone administration to older men improves muscle function:
muscle groups, which are important for normal physical func- molecular and physiological mechanisms. Am J Physiol Endocrinol Metab

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

tion in older persons. However, the benefits were lost within 12 282: E601–E607, 2002.
wk after oxandrolone was discontinued, suggesting that pro- 12. Fiatarone MA, Marks EC, Ryan ND, Meredith CN, Lipsitz LA, and
longed androgen treatment would be needed to maintain these Evans WJ. High-intensity strength training in nonagenarians. Effects on
anabolic benefits. Thus the long-term safety and efficacy of skeletal muscle. JAMA 263: 3029–3034, 1990.
13. Fleck S and WJK. Designing resistance training programs. In: Human
androgen therapy in older men need to be established. In Kinetics (2nd ed.). Champaign, IL: Human Kinetics, 1997, p. 4, 98–100.
addition, whole body and trunk fat mass decreased signifi- 14. Frontera WR, Hughes VA, Fielding RA, Fiatarone MA, Evans WJ,
cantly during therapy, and the effects were largely sustained and Roubenoff R. Aging of skeletal muscle: a 12-yr longitudinal study.
after treatment was discontinued. Whether the reduction in J Appl Physiol 88: 1321–1326, 2000.
15. Gallagher D, Visser M, De Meersman RE, Sepulveda D, Baumgartner
central adiposity with androgen therapy has tangible health RN, Pierson RN, Harris T, and Heymsfield SB. Appendicular skeletal
benefits is uncertain. These observations, therefore, raise sev- muscle mass: effects of age, gender, and ethnicity. J Appl Physiol 83:
eral important questions that must be addressed before andro- 229–239, 1997.
gen therapy is widely prescribed as long-term therapy for 16. Halliday D and Miller AG. Precise measurement of total body water
sarcopenia in older individuals. using trace quantities of deuterium oxide. Biomed Mass Spectrom 4:
82–87, 1977.
ACKNOWLEDGMENTS 17. Harman SM, Metter EJ, Tobin JD, Pearson J, and Blackman MR.
Longitudinal effects of aging on serum total and free testosterone levels in
We thank the subjects who committed substantial time and efforts to make healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol
this study successful. We also appreciate the numerous helpful suggestions Metab 86: 724–731, 2001.
made by Colleen Azen, General Clinical Research Center (GCRC) statistician, 18. Herbst KL, Anawalt BD, Amory JK, Matsumoto AM, and Bremner
and the work of Xianghong Chen, who performed the 2H analyses in the WJ. The male contraceptive regimen of testosterone and levonorgestrel
Biomedical Mass Spectrometry Resource at Washington University Medical significantly increases lean mass in healthy young men in 4 wk, but
School [National Institutes of Health (NIH) National Center for Research attenuates a decrease in fat mass induced by testosterone alone. J Clin
Resources Grant RR-00954]. Endocrinol Metab 88: 1167–1173, 2003.
19. Holloszy JO. Workshop on sarcopenia: muscle atrophy in old age. J
GRANTS Gerontol Biol Med Sci 50A: 1–161, 1995.
20. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson
Support was provided in part from NIH GCRC Grant MOI RR-00043 and
EJ, and Klibanski A. Increase in bone density and lean body mass during
by a grant-in-aid from Savient Pharmaceuticals.
testosterone administration in men with acquired hypogonadism. J Clin
Endocrinol Metab 81: 4358–4365, 1996.
REFERENCES
21. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, and Raisz
1. Bassey EJ, Fiatarone MA, O’Neill EF, Kelly M, Evans WJ, and LG. Effects of transdermal testosterone on bone and muscle in older men
Lipsitz LA. Leg extensor power and functional performance in very old with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci
men and women. Clin Sci (Colch) 82: 321–327, 1992. 56: M266–M272, 2001.
2. Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield 22. Kenny AM, Prestwood KM, and Raisz LG. Short-term effects of
SB, Ross RR, Garry PJ, and Lindeman RD. Epidemiology of sarcope- intramuscular and transdermal testosterone on bone turnover, prostate
nia among the elderly in New Mexico. Am J Epidemiol 147: 755–763, symptoms, cholesterol, and hematocrit in men over age 70 with low
1998. testosterone levels. Endocr Res 26: 153–168, 2000.
3. Baumgartner RN, Waters DL, Gallagher D, Morley JE, and Garry 23. Lovejoy JC, Bray GA, Greeson CS, Klemperer M, Morris J, Parting-
PJ. Predictors of skeletal muscle mass in elderly men and women. Mech ton C, and Tulley R. Oral anabolic steroid treatment, but not parenteral
Ageing Dev 107: 123–136, 1999. androgen treatment, decreases abdominal fat in obese, older men. Int J
4. Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Obes Relat Metab Disord 19: 614–624, 1995.
Phillips J, Lee WP, Bunnell TJ, and Casaburi R. Testosterone replace- 24. Marin P. Testosterone and regional fat distribution. Obes Res 3, Suppl 4:
ment increases fat-free mass and muscle size in hypogonadal men. J Clin 609S–612S, 1995.
Endocrinol Metab 82: 407–413, 1997. 25. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G,
5. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Lindstedt G, and Bjorntorp P. The effects of testosterone treatment on
Chen X, Yarasheski KE, Magliano L, Dzekov C, Dzekov J, Bross R, body composition and metabolism in middle-aged obese men. Int J Obes
Phillips J, Sinha-Hikim I, Shen R, and Storer TW. Testosterone Relat Metab Disord 16: 991–997, 1992.
dose-response relationships in healthy young men. Am J Physiol Endocri- 26. Marin P, Oden B, and Bjorntorp P. Assimilation and mobilization of
nol Metab 281: E1172–E1181, 2001. triglycerides in subcutaneous abdominal and femoral adipose tissue in
6. Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-White- vivo in men: effects of androgens. J Clin Endocrinol Metab 80: 239–243,
head J, Stevens TE, Jayme J, O’Connor KG, Christmas C, Tobin JD, 1995.

J Appl Physiol • VOL 96 • MARCH 2004 • www.jap.org

1062 ANDROGEN SUPPLEMENTATION AND DURABILITY OF EFFECTS

27. Maughan RJ, Watson JS, and Weir J. Strength and cross-sectional area 44. Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, and Ross C.
of human skeletal muscle. J Physiol 338: 37–49, 1983. Testosterone replacement in older hypogonadal men: a 12-month random-
28. Melton LJ 3rd, Khosla S, Crowson CS, O’Connor MK, O’Fallon WM, ized controlled trial [see comments]. J Clin Endocrinol Metab 82: 1661–
and Riggs BL. Epidemiology of sarcopenia. J Am Geriatr Soc 48: 1667, 1997.
625–630, 2000. 45. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A,
29. Moldawer LL and Copeland EM 3rd. Proinflammatory cytokines, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson
nutritional support, and the cachexia syndrome: interactions and therapeu- LE, and Strom BL. Effects of testosterone replacement in hypogonadal
tic options. Cancer 79: 1828–1839, 1997. men. J Clin Endocrinol Metab 85: 2670–2677, 2000.
30. Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Morley PM, Stauber 46. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA,
PM, Vellas B, Baumgartner RN, and Garry PJ. Longitudinal changes Holmes JH, Dlewati A, Santanna J, Rosen CJ, and Strom BL. Effect
in testosterone, luteinizing hormone, and follicle-stimulating hormone in of testosterone treatment on body composition and muscle strength in men
healthy older men. Metabolism 46: 410–413, 1997. over 65 years of age. J Clin Endocrinol Metab 84: 2647–2653, 1999.
31. Morley JE, Perry HM, 3rd Kaiser FE, Kraenzle D, Jensen J, Houston 47. Storer TW, Magliano L, Woodhouse L, Lee ML, Dzekov C, Dzekov J,
K, Mattammal M, and Perry HM Jr. Effects of testosterone replace- Casaburi R, and Bhasin S. Testosterone dose-dependently increases
ment therapy in old hypogonadal males: a preliminary study. J Am Geriatr maximal voluntary strength and leg power, but does not affect fatigability
Soc 41: 149–152, 1993. or specific tension. J Clin Endocrinol Metab 88: 1478–1485, 2003.
32. Narici MV, Hoppeler H, Kayser B, Landoni L, Claassen H, Gavardi 48. Strawford A, Barbieri T, Van Loan M, Parks E, Catlin D, Barton N,
C, Conti M, and Cerretelli P. Human quadriceps cross-sectional area, Neese R, Christiansen M, King J, and Hellerstein MK. Resistance
torque and neural activation during 6 months strength training. Acta exercise and supraphysiologic androgen therapy in eugonadal men with
Physiol Scand 157: 175–186, 1996. HIV-related weight loss: a randomized controlled trial. JAMA 281: 1282–
33. Parry-Billings M, Bevan SJ, Opara E, and Newsholme EA. Effects of 1290, 1999.

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

changes in cell volume on the rates of glutamine and alanine release from 49. Taplin ME and Ho SM. Clinical review 134: the endocrinology of
rat skeletal muscle in vitro. Biochem J 276: 559–561, 1991. prostate cancer. J Clin Endocrinol Metab 86: 3467–3477, 2001.
34. Penninx BW, Guralnik JM, Ferrucci L, Simonsick EM, Deeg DJ, and 50. Tenover JS. Androgen replacement therapy to reverse and/or prevent
Wallace RB. Depressive symptoms and physical decline in community- age-associated sarcopenia in men. Baillieres Clin Endocrinol Metab 12:
dwelling older persons. JAMA 279: 1720–1726, 1998. 419–425, 1998.
35. Perry HM 3rd, Miller DK, Patrick P, and Morley JE. Testosterone and 51. Tenover JS. Effects of testosterone supplementation in the aging male.
leptin in older African-American men: relationship to age, strength, J Clin Endocrinol Metab 75: 1092–1098, 1992.
function, and season. Metabolism 49: 1085–1091, 2000. 52. Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR,
36. Rantanen T, Penninx BW, Masaki K, Lintunen T, Foley D, and Wolfe RR, and Ferrando A. Testosterone administration to elderly men
Guralnik JM. Depressed mood and body mass index as predictors of increases skeletal muscle strength and protein synthesis. Am J Physiol
muscle strength decline in old men. J Am Geriatr Soc 48: 613–617, 2000. Endocrinol Metab 269: E820–E826, 1995.
37. Reaven GM. Syndrome X: 6 years later. J Intern Med Suppl 736: 13–22, 53. Wang C, Alexander G, Berman N, Salehian B, Davidson T, McDonald
1994. V, Steiner B, Hull L, Callegari C, and Swerdloff RS. Testosterone
38. Rebuffe-Scrive M, Marin P, and Bjorntorp P. Effect of testosterone on replacement therapy improves mood in hypogonadal men–a clinical re-
abdominal adipose tissue in men. Int J Obes 15: 791–795, 1991. search center study. J Clin Endocrinol Metab 81: 3578–3583, 1996.
39. Ridker PM, Stampfer MJ, and Rifai N. Novel risk factors for systemic 54. Wang C, Swedloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunning-
atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocys- ham G, Matsumoto AM, Weber T, and Berman N. Transdermal
teine, lipoprotein(a), and standard cholesterol screening as predictors of testosterone gel improves sexual function, mood, muscle strength, and
peripheral arterial disease. JAMA 285: 2481–2485, 2001. body composition parameters in hypogonadal men. Testosterone Gel
40. Salem GJ, Wang M, and Sigward S. Measuring lower extremity strength Study Group. J Clin Endocrinol Metab 85: 2839–2853, 2000.
in older adults: the stability of isokinetic vs. 1RM measures. J Aging Phys 55. Xu XF, De Pergola G, and Bjorntorp P. Testosterone increases lipolysis
Act 10: 489–503, 2002. and the number of beta-adrenoceptors in male rat adipocytes. Endocrinol-
41. Sattler FR, Schroeder ET, Dube MP, Jaque SV, Martinez C, Blanche ogy 128: 379–382, 1991.
PJ, Azen S, and Krauss RM. Metabolic effects of nandrolone decanoate 56. Yarasheski KE, Pak-Loduca J, Hasten DL, Obert KA, Brown MB,
and resistance training in men with HIV. Am J Physiol Endocrinol Metab and Sinacore DR. Resistance exercise training increases mixed muscle
283: E1214–E1222, 2002. protein synthesis rate in frail women and men ⬎76 yr old. Am J Physiol
42. Seidell JC, Bjorntorp P, Sjostrom L, Kvist H, and Sannerstedt R. Endocrinol Metab 277: E118–E125, 1999.
Visceral fat accumulation in men is positively associated with insulin, 57. Yarasheski KE, Smith K, Rennie MJ, and Bier DM. Measurement of
glucose, and C-peptide levels, but negatively with testosterone levels. muscle protein fractional synthetic rate by capillary gas chromatography/
Metabolism 39: 897–901, 1990. combustion isotope ratio mass spectrometry. Biol Mass Spectrom 21:
43. Sheffield-Moore M, Urban RJ, Wolf SE, Jiang J, Catlin DH, Herndon 486–490, 1992.
DN, Wolfe RR, and Ferrando AA. Short-term oxandrolone administra- 58. Yarasheski KE, Zachwieja JJ, Campbell JA, and Bier DM. Effect of
tion stimulates net muscle protein synthesis in young men. J Clin Endo- growth hormone and resistance exercise on muscle growth and strength in
crinol Metab 84: 2705–2711, 1999. older men. Am J Physiol Endocrinol Metab 268: E268–E276, 1995.

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