Treatment with Oxandrolone and the Durability of Effects in Older Men
E. Todd Schroeder, PhD1, 4
Ling Zheng, MS2
Kevin E.Yarasheski, PhD3
Dajun Qian, PhD2
Carmen Martinez, MS, RD2
Michael Terk, MD4,5
Fred R. Sattler, MD1, 2, 4
Running Title: Androgen Supplementation and Durability of Effects
Department of Medicine and Division of Infectious Diseases1, General Clinical Research
Center2, and the Department of Radiology5 of the Keck School of Medicine
and the Department of Biokinesiology and Physical Therapy4
of the University of Southern California, Los Angeles, California
Department of Internal Medicine, Divisions of Metabolism, Endocrinology and Lipid Research
and Cell Biology and Physiology3,
Washington University School of Medicine, St. Louis, Missouri
Address for inquiries and Reprints:
Fred Sattler, MD
University of Southern California
Departments of Medicine and Biokinesiology & Physical Therapy
1540 East Alcazar St. CHP-155
Los Angeles, CA 90033
Copyright (c) 2003 by the American Physiological Society.
Articles in PresS. J Appl Physiol (October 24, 2003). 10.1152/japplphysiol.00808.2003
We investigated the effects of the anabolic androgen, oxandrolone, on lean body mass (LBM),
muscle size, fat, and maximum voluntary muscle strength, and determined the durability of
effects after stopping treatment. Thirty-two healthy 60-87 year old men were randomized to
receive 20 mg oxandrolone/day (n = 20) or placebo (n = 12) for 12 weeks. Body composition
(DEXA, MRI and D2O dilution) and muscle strength (1-repetition maximum; 1-RM) were
evaluated at baseline and after 12 weeks of treatment; body composition (DEXA) and 1-RM
strength were then assessed 12 week after discontinuing treatment (week 24). At week 12,
oxandrolone increased LBM 3.0±1.5kg (P<0.001), total body water 2.9±3.7kg (P=0.002),
proximal thigh muscle area 12.4±8.4cm2 (P<0.001); these increases were greater (P<0.003) than
in the placebo group. Oxandrolone increased 1-RM strength for leg press 6.7±6.4% (P<0.001),
leg flexion 7.0±7.8% (P<0.001), chest press 9.3±6.7% (P<0.001), and latissimus pull-down
5.1±9.1% (P=0.02) exercises; these increases were greater than placebo. Oxandrolone reduced
total (-1.9±1.0kg) and trunk fat (-1.3 ±0.6kg; P<0.001) and these decreases were greater
(P<0.001) than placebo. Twelve weeks after discontinuing oxandrolone (week 24), the
increments in LBM and muscle strength were no longer 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±1.1kg,
P<0.001, respectively). Thus, oxandrolone induced short-term improvements in lean body mass,
muscle area, and strength, while reducing whole-body and trunk adiposity. Anabolic
improvements were lost 12 weeks after discontinuing oxandrolone, while improvements in fat
mass were largely sustained.
Key Words: Oxandrolone, Lean Body Mass, Muscle Mass, DEXA, MRI
Advancing age is associated with a progressive loss of muscle mass (sarcopenia), skeletal muscle
strength, and physical function (2, 3, 10, 14, 19). Sarcopenia increases the risk for frailty, falls,
fractures, dependency and depression (34, 36). Advancing age is also associated with increases
in fat mass, particularly central adiposity, which increases the risk for insulin resistance,
hypertension, dyslipidemia, and impaired fibrinolysis (Metabolic Syndrome) (37). The Metabolic
Syndrome predisposes older persons to accelerated atherosclerosis and type II diabetes.
The contribution of age-associated hormonal alterations to these adverse health consequences is
unclear. Both cross-sectional (15, 28, 51) and longitudinal (17, 30) studies have shown that
serum total and free concentrations of testosterone decline with advancing age in men.
Testosterone regulates muscle and fat mass, but the relationship between gonadal hormone status
and age-associated alterations in body composition, skeletal muscle strength, and metabolic
disorders in older persons is uncertain. There is some evidence that bioavailable testosterone
levels (free and the fraction loosely bound to albumin) correlate with skeletal muscle mass and
muscle strength in different ethnic populations (4, 35).
Testosterone treatment in hypogonadal young men increases lean tissue (5, 8, 20, 45, 53, 54),
and muscle strength (5, 54) and decreases fat mass (5, 20, 54). Despite evidence that
supplemental testosterone increases myofibrillar protein synthesis rate in older men (11, 52), its
effects on body composition and muscle function in these men are less clear (22, 31, 44, 46, 50,
51). In the largest studies, in which older relatively hypogonadal older men received testosterone
replacement for one and three years, respectively, lean body mass (LBM) was only modestly
increased (1.0 and 1.9 kg, respectively) (22, 46) and the effects on muscle strength were variable.
Only three studies have shown increases in lower extremity maximum voluntary force (11, 22,
52). By contrast, in a controlled study of 108 older men randomized to receive placebo or
testosterone (46), upper extremity grip strength and lower extremity isokinetic strength were
unchanged with testosterone (50). Likewise, the effects of testosterone on fat mass have been
variable with either no change or only modest reductions achieved (11, 21, 31, 46, 51, 52).
The variability in outcomes in older men may be related to the different delivery strategies for
testosterone (intramuscular versus transdermal delivery), dose (200 mg biweekly versus 5
mg/day), change in testosterone levels in response to therapy, duration of treatment (four weeks
versus three years), different methods to assess body composition (bioelectrical impedance
analysis, DEXA, MRI, hydrostatic weighing) as well as measures of muscle strength (hand held
dynamometers, isokinetic dynamometers, free weights or pneumatic resistance devices).
Moreover, with one exception, these studies did not directly assess changes in muscle mass or
muscle cross-sectional area.
Oxandrolone is a potent, oral anabolic androgen that is approved for the treatment of weight loss
due to known medical or unexplained causes (43, 48). We evaluated whether the licensed dose of
oxandrolone increases muscle mass and muscle strength, and reduces body fat mass in older men
at risk for sarcopenia and metabolic complications. Moreover, we followed these men for 12
weeks after discontinuing oxandrolone to evaluate the durability of the alterations in body
composition and muscle strength. We hypothesized that oxandrolone would increase lean mass,
muscle area, and muscle strength, and reduce whole-body and central adiposity in older men and
that these benefits would not be fully sustained.
This was a single center, investigator initiated, double blind, placebo-controlled investigation to
determine the magnitude and durability of effects of a potent, convenient to administer anabolic
androgen, oxandrolone (Oxandrin). The study was performed at the University of Southern
California NCRR-funded General Clinical Research Center with the exception that skeletal
muscle strength was assessed at the Clinical Exercise Research Center in the Department of
Biokinesiology and Physical Therapy of the University. The study design and informed consent
were approved and annually reviewed by the Institutional Review Board of the Los Angeles
County-University of Southern California Medical Center.
Men >60 years old were recruited from the Los Angeles communities surrounding the University
of Southern California Health Sciences Campus. To be eligible for the study, subjects had to
have a body mass index (BMI) 35 kg/m2, repeated resting blood pressure <180/95 mm Hg,
prostate specific antigen (PSA) 4.1 ng/ml, serum hematocrit 50%, alanine aminotransferase
(ALT) less than three times the upper limit of normal (ULN), and serum creatinine < 2 mg/dL.
Subjects with untreated endocrine abnormalities (e.g. diabetes, hypothyroidism), active
inflammatory conditions, or cardiac problems (heart failure, myocardial infarction, or angina) in
the proceeding three months were excluded. An incremental treadmill exercise test with 12-lead
electrocardiogram and blood pressure monitoring to achieve a heart rate 85% of age predicted
maximum was administered prior to resistance exercise testing to identify subjects at possible
risk for exercise induced ischemia, abnormalities in cardiac rhythm, or abnormal blood pressure
Eligible subjects were randomized in a 2:1 manner to receive either the licensed oral dose of
oxandrolone (Oxandrin, Savient Pharmaceuticals, Inc., East Brunswick, NJ) of 20 mg/day (10
mg twice daily) or matching placebo for 12 weeks. Twenty milligrams was chosen since this is
the FDA licensed dose for treatment of weight loss or inability to maintain normal body weight.
Subjects returned for a follow-up evaluation at study week 24 (12 weeks after stopping study
treatment). Adherence was monitored by tablet count at each study visit.
Complete blood counts, comprehensive chemistries with tests of renal and hepatic function, and
prostate specific antigen were measured at baseline and weeks 6, 12, and 24. Additionally, liver
function tests were obtained at weeks 3 and 9.
Body Composition by Dual-energy X-ray Absorptiometry (DEXA)
Whole-body DEXA scans (Hologic QDR-4500, version 7.2 software, Waltham, MA) were
performed at baseline and weeks 12 and 24 to quantify LBM and fat mass. One blinded,
experienced technician (CF) performed and analyzed the scans. The coefficient of variation for
repeated measures was <1% for lean and fat mass.
Muscle Cross-Sectional Area
Cross sectional area (CSA) of the dominant thigh muscles was assessed using proton magnetic
resonance imaging (MRI) at baseline and week 12 (but not week 24). 1H-MRI was performed
using a 1.5 Tesla GE Signa-LX scanner with the body coil used as both transmitter and receiver.
Nine axial images of the thigh were acquired after obtaining a T1-weighted coronal scout image
(T1-weighted TR/TE 300/TE) that was used to identify the exact anatomical location for the
axial images. The slice thickness was 7.5 mm with a 1.5 mm gap. The field of view was 24 X
24 cm with a 254 X 128 pixel matrix. One signal average was used.
Thigh muscle CSA was measured at the junction of the proximal and middle third of the femur
in the dominant leg, because greater relative increases in CSA of the proximal quadriceps have
been reported following anabolic interventions (32). Pixels associated with intramuscular fat,
bone, and major arteries, veins, and nerves were subtracted from the image (using Scion Image,
version Beta 4.0.2 software, Scion Corp.). Muscle CSA was measured by setting a pixel
intensity threshold value that distinguished fat from muscle pixels. This allowed adipose tissue to
be differentiated from other more optically dense lean tissue (muscle, nerve, and blood vessels).
Total thigh muscle CSA was calculated after area of the fat tissue was removed automatically
and area of the femur, nerve tissue, and blood vessels were removed manually. The same
investigator (ETS) blinded to treatment located the region of interest, set the threshold value, and
performed the image analyses. The coefficient of variation for repeated measures of total thigh
CSA was <1%.
Total Body Water
Total body water (TBW) was determined at baseline and week 12 using 2H2O dilution. Subjects
ingested 2H2O (Cambridge Isotopes Laboratory; 0.25g/kg) and isotope dilution was estimated
from plasma samples obtained at –15 min, 0, 3 and 4 hr. We have previously determined that
steady state 2H-enrichment is achieved in plasma and maintained between 120-240 minutes (58).
The dilution of tracer, corrected for the exchange of hydrogen with other body hydrogen pools
(~4%), provides a measure of tracer dilution space, which is equivalent to TBW volume. Plasma
samples were analyzed for 2H2O abundance using proton magnetic resonance spectroscopy and
d9-tert-butanol as an internal standard (interassay CV=6.3%) (16). TBW was calculated from the
average of the three and four hour 2H-enrichments in plasma water using the formula: TBW =
Dose (16/18 x g of 2H2O)/deuterium enrichment (D/H ratio in water) where TBW is expressed as
2H-dilution space/1.04 (57).
Evaluation of Muscle Strength
Maximal voluntary muscle strength was assessed using the one-repetition maximum (1-RM)
method (13) at baseline and weeks 12 and 24. The 1-RM was defined as the greatest resistance
that could be moved through a defined range of motion using proper technique. Prior to strength
testing, subjects warmed up on a cycle ergometer or by walking for five minutes. Maximum
voluntary strength was determined for the bilateral leg press, leg flexion, latissimus pull-down,
and chest press exercises on Keiser A-300 pneumatic equipment (Keiser Corp., Fresno, CA).
The leg press and chest press machines only displayed units of measure in Newtons. The Newton
measurement of force cannot accurately be converted to kilograms and therefore the strength
data are reported in Newtons for these two machines. To accommodate for familiarization and
learning of the testing procedures, baseline strength was assessed twice within one week prior to
initiating study therapy. The greatest 1-RM measured for each exercise during the two pre-
treatment testing sessions was used as the baseline value for maximal voluntary muscle strength.
The technician was blinded to the subjects’ treatment.
Subjects recorded dietary intake on three consecutive days, including two weekdays and one
weekend day in the week prior to baseline and weeks 12 and 24. Subjects were counseled that
the days should be chosen to include usual activities and typical eating patterns. A licensed
nutritionist (CM) reviewed all dietary entries with the subjects. This information was entered into
the Nutritionist V software (First Data Bank, San Bruno, CA) and analyzed for total energy
intake, macronutrients, and types of fat. Subjects were counseled not to change their routine
dietary habits during the course of the study.
Measurement of Hormones and C-Reactive Protein
Total testosterone concentration (ng/dL) was measured by the Los Angeles County-University of
Southern California Medical Center Clinical Diagnostic Laboratory (Endocrinology Section)
using Diagnostic Products Corporation Coat-A-Count at baseline and week 24, 12 weeks after
completing the oxandrolone intervention. This competitive radioimmunoassay uses a solid-phase
polyclonal antibody. The coefficient of variation for total testosterone was < 7.7%. We did not
measure testosterone levels at week 12 because semisynthetic androgens, including oxandrolone,
cross-react in these testosterone assays. Luteinizing hormone (LH) concentration (IU/mL) was
measured using a microparticle enzyme immunoassy (AxSYM; Abbott Diagnostics), at baseline
and study weeks 12 and 24. The coefficient of variation for LH was < 4.9%.
To assess for evidence of inflammation, we evaluated the changes in ultrasensitive C-reactive
protein (CRP) at the University of Southern California Pathology Reference Laboratory using a
latex particle enhanced immunoturbidimetric assay distributed by Equal Diagnostics (Exton, PA)
and manufactured by Kamiya Biochemical Company (Seattle, WA). The coefficient of variation
for CRP was < 7.1%.
The study was conservatively powered at 80% to detect a difference in means between the
oxandrolone and placebo group of 1.36 times the common standard deviation, using a two-
sample t-test with a Bonferroni-adjusted P=0.0008, with 20 in oxandrolone group and 12 in
placebo group. For total LBM by DEXA scanning, this sample size will be able to detect a mean
difference of 2 kg, assuming the common standard deviation is 1.47 kg. For the maximum
voluntary skeletal muscle strength of the leg press exercise (which typically has the greatest
variance of the exercises tested in this study), this sample size will be able to detect a mean
relative difference of 6.8%, assuming the common standard deviation of 5.0%. Statistical
analyses are presented in the tables and text as mean ± one standard deviation (SD).
For the main outcome variables, a two (oxandrolone and placebo group) by three (baseline, week
12 and week 24) repeated measure analysis of variance (ANOVA) was used to statistically
compare mean differences within subjects and between groups. Greenhouse-Geisser adjustment
was used to justify the assumption of sphericity. When a significant group by time interaction
was found, the changes from baseline to week 12 and the changes from baseline to week 24
between and within groups were compared by independent t-tests and paired t-tests respectively.
All post hoc tests were performed with Bonferroni adjustment for six possible comparisons.
Baseline characteristic and the changes in safety evaluation from baseline to week 12 were
compared between oxandrolone and placebo group using an independent t-test. All statistical
testing was performed at a two-sided 5% level of significance (0.83% for each post hoc t-test)
using Statistical Analysis System version 8.0 (SAS Institute, Inc. Cary, NC).
Thirty-four eligible subjects were enrolled and randomized to either oxandrolone (n=22) or
placebo (n=12). One subject randomized to receive oxandrolone elected not to participate after
providing informed consent; however, he did not start study drug. A second subject randomized
to receive oxandrolone completed study therapy through week 12 but did not return for follow-
up at week 24. This subject could not be contacted until well after he missed the week 24
evaluation; he indicated that he had not had adverse events but had been too busy to make his
appointment. Therefore, 32 subjects completed all aspects of the study and were included in the
final analysis. On the basis of tablet count, these subjects were adherent to their assigned
treatment (94.0±7.4% of all pills prescribed with no difference between the groups).
Baseline characteristics were similar in the two study groups (Table 1), except that serum
prostate-specific antigen levels were greater (P = 0.009) in the oxandrolone group. Baseline
energy, protein, carbohydrate, and fat intakes were similar between the two groups.
Changes in Body Composition
Lean body mass (LBM). There was a significant (P<0.001) group by time interaction for total
LBM. After 12 weeks, LBM increased significantly (P<0.001) in the oxandrolone group
(3.0±1.5 kg), and this increase in LBM was greater (P<0.001) than the small change (0.0±1.4 kg;
P=0.91) in the placebo group (Figure 1). At week 24, LBM (56.5±6.3 kg) had returned to
baseline (56.0±5.9 kg) in the oxandrolone group (P=0.15). In the placebo group, the change
from baseline in LBM was not significant at either 12 or 24 weeks.
Thigh muscle cross-sectional area. Oxandrolone increased the thigh muscle area (12.4±8.4 cm2,
P<0.001; Figure 2), while placebo did not (1.4±6.9 cm2). After 12 weeks, 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.
Total body water. Oxandrolone increased TBW (2.9±3.7 kg; P=0.002), while placebo did not
(-0.6±2.8 kg; P=0.47). After 12 weeks, the increase in total body water tended to be greater in the
oxandrolone group than in the placebo group (P=0.07). Total body water was not measured at
Fat mass. There was a significant (P=0.03) group by time interaction for total fat mass.
Oxandrolone reduced whole body fat mass (-1.9±1.0 kg, P<0.001; Fig 3a) and trunk fat mass
(-1.3±0.6 kg, P<0.001; Fig 3b), while placebo 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 trunk fat mass were greater in the
oxandrolone group than in the placebo group (P<0.001). After discontinuing oxandrolone
(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<0.001, respectively).
Changes in Maximal Voluntary Strength
There was a significant group by 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 weeks, the relative (Figure 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 (Figure 4), while there were no
significant changes in the placebo group. By week 24, the relative and absolute maximal
voluntary strength were similar to baseline values in both the oxandrolone and placebo groups
(Table 2 and Figure 4).
Nutrition and Exercise
Nutritional status, including total daily intake of energy, protein, carbohydrate and fat was not
different within or between groups over the 24-week course of the study (P>0.19 by ANOVA for
each; data not shown). Additionally, upon entry into the study subjects were instructed to
maintain their habitual physical activity and not to engage in a new exercise routine during the
course of the study. Based on self-report at each study evaluation, subjects did not alter their
physical activity levels.
One serious adverse event occurred during the study. A subject randomized to oxandrolone
developed hypotension (systolic blood pressure <90 mm Hg) when his primary doctor modified
the patient’s antihypertensive medications at the subject’s request. His systolic blood pressure
had been in the 140-155 mm Hg range prior to and during the study and he desired tighter
control. Study therapy was suspended for three weeks while his anti-hypertensive medications
were adjusted; study therapy was then resumed without problem.
There were no new symptoms or physical findings that could be ascribed to oxandrolone. After
12 week, there were only modest changes in blood chemistry (Table 3). In the oxandrolone
group, serum albumin and alkaline phosphatase levels 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 (Table 3) or week 24. There were minimal
increments in the liver transaminase levels that reached statistical significance, but ALT was
only increased beyond the normal range in two subjects where it reached 71 and 99 U/L (1.5
times the upper limit of normal). Both subjects were asymptomatic without liver enlargement
and the ALT returned to normal in both at the week 24 evaluation. Finally, there was a small
but significant decrease in PSA in the oxandrolone group.
As described above, we only measured serum testosterone levels at baseline and week 24.
Oxandrolone and placebo groups had similar baseline (P=0.28; Table 1) and week 24
testosterone levels (358±119 ng/dL in the oxandrolone group and 421±196 ng/dL; P=0.26).
There was a trend towards a greater decline in LH levels with oxandrolone, suggesting that
oxandrolone treatment may have suppressed the hypothalamic-pituitary-gonadal axis.
These findings demonstrated that a relatively brief course of treatment with a potent anabolic
androgen in men over 60 years of age increased LBM as well as upper and lower body maximal
voluntary strength more than placebo. The 3.0±1.5 kg increase in LBM in this study is
approximately two-fold greater than the increase in LBM reported by other investigators using
testosterone supplementation in older men (7, 21, 46, 51). The only other study of androgen
therapy to achieve comparable increases in LBM (4.2±0.6 kg) used a dose of testosterone
enanthate adjusted to produce nadir levels in the upper normal range, suggesting that dosing was
“supraphysiologic” since nadir levels were tested two weeks after a prior intramuscular dose
(11). Moreover, subjects were treated for 24 weeks compared to 12 weeks in our study. These
observations suggest that the formulation and potency of the androgen, dose, and duration of
therapy may affect the changes in lean tissue achieved, which is in keeping with a recent dose
ranging study of testosterone in younger men (6).
The significant increases in both upper and lower body maximal voluntary strength in subjects
receiving oxandrolone are noteworthy. In the few studies assessing the effects of androgen
supplementation in older men, muscle strength was not tested (51), evaluated with either hand-
grip (31, 44) or isokinetic dynamometry (46, 52), which may measure different mechanistic
aspects of strength (reviewed in Storer et al)(47). Therefore, these evaluations may not be
representative of true changes in maximal strength for larger muscle groups important for
optimal physical function in older persons. Moreover, only one study demonstrated substantial
increases in 1-RM strength in both upper body and lower body muscle groups, although
neuromuscular learning may have contributed to the gains in strength with testosterone since
multiple baseline trials of maximal strength were not assessed (11). However, older adults
typically produce their best performance (highest force production) on the second or third 1-RM
trial (40) (12). Thus, studies to assess the affects of anabolic interventions on maximal voluntary
strength should test strength on at least two separate occasions prior to initiating study therapy.
The increases in muscle strength and cross-sectional area in the oxandrolone group suggest that a
major portion of the anabolic androgen-induced increase in LBM was due to increases in muscle
protein mass, because strength is closely related to muscle size (27). Oxandrolone and
testosterone exert their actions by enhancing the rate of mixed muscle (11, 52) and myofibrillar
protein synthesis (8) , and by reducing the rate of muscle protein breakdown (43). However, our
D2O dilution measurements indicated a disproportionate increase in TBW (~2.9 kg) when
compared to the increase in DEXA-derived LBM (3kg). If the entire increase in DEXA-derived
LBM were protein, we would have anticipated only ~2.3 kg increase in TBW. Also, the rapid
loss of LBM (~2.5 kg) after oxandrolone was discontinued suggests that tissue fluid was a
component of the oxandrolone-induced increase in LBM. Future studies should measure muscle
amino acid balance following androgen administration in elderly men at risk for physical frailty.
To our knowledge, this is the first study to determine the durability of the effects achieved with
androgen therapy after the treatment was discontinued. We speculated that at least some portion
of the gains in LBM and strength would be sustained 12 weeks after treatment with oxandrolone.
However, the fact that gains in both LBM and strength were largely lost within 12 weeks after
discontinuing treatment suggests that prolonged therapy with an anabolic androgen will be
necessary to maintain and enhance increases in LBM and muscle strength. Other anabolic
strategies with potentially better safety profiles such as resistance training, a potent stimulus for
skeletal muscle protein synthesis in older persons (56), or specific androgen receptor modulators
should be investigated for sustaining gains in muscle mass and strength during the aging process.
Another important and unique finding of this study was the oxandrolone-induced decrease in
total and trunk fat that were largely sustained 12 weeks after stopping oxandrolone. In younger
hypogonadal men, testosterone decreased total body and abdominal fat mass (5, 20, 54).
However, it is not clear whether androgen therapy affects adipose tissue in eugonadal men.
Bhasin et al reported no change in fat mass with replacement doses of 125 mg testosterone
weekly over four months in eugonadal, healthy men, although much higher supraphysiologic
doses reduced adipose tissue (5). Marin et al, reported that low dose androgen therapy reduced
abdominal fat in middle aged men with central obesity (24). However, the effects occurred
primarily in subjects with low testosterone levels, which is consistent with observations that
intra-abdominal fat is inversely correlated with free testosterone levels (42). Only five of our
subjects had baseline total testosterone levels <270 ng/dL (lower limit of normal in our
laboratory), but levels for the entire group were generally less than those of younger men.
Whether the relative hypogonadism (compared to younger men) of our participants or the
potency or structure of the synthetic androgen, oxandrolone, was primarily responsible for the
reductions in whole-body and trunk fat is uncertain.
These results do provide clarification as to whether metabolism of testosterone by aromatase to
estradiol (approximately 40%) is largely responsible for changes in fat mass when men are
treated with testosterone (18). The fact that adipocytes contain estradiol receptors and the
observation that estrogen receptor knockout mice have increased adipose tissue has suggested
that estrogen is important in down regulating fat mass (9). However, oxandrolone is not
aromatized to estrogen suggesting that the favorable declines in adipose tissue observed in the
present study were due to direct and specific actions of oxandrolone.
The discordant affects of oxandrolone on lean tissue and fat mass 12 weeks after study therapy
was discontinued were puzzling. According to 3-day food diaries and self-report of exercise
activity, subjects did not change their dietary or habitual activity during the study. Thus, the
durability of the effects of oxandrolone on adipose but not lean tissue likely reflect the biological
differences in these tissues and/or the effects of other concurrent regulators of metabolism. In a
population prone to obesity, it is remarkable that 80% of the reduction in total and central fat
mass after a relatively short period of androgen therapy (12 weeks) were sustained for at least
three months after treatment was discontinued. The reductions in fat mass observed in obese
middle aged men have been associated with decreases in visceral adipose tissue, improvements
in insulin sensitivity, and declines in cholesterol, triglycerides and diastolic blood pressure (24,
25). These effects are consistent with the known effects of androgens to decrease lipoprotein
lipase and upregulate beta adrenergic receptors on adipocytes which would inhibit the
accumulation of lipid and enhance the efflux of lipid from these cells in response to
catecholamines (26, 38, 55). Further studies will be necessary to assess whether the reductions in
fat mass observed in our older men would be associated with beneficial measures of metabolism
and health in an aging population.
A limitation of this study is that we assessed a 17-methylated androgen and not generic
testosterone. Thus, we cannot extrapolate our findings to a dose of testosterone. Although we
did not demonstrate short-term adverse clinical effects with oxandrolone, evaluation of anabolic
androgens, including testosterone, as potential treatments for sarcopenia, must be investigated in
sufficiently powered studies of long-term treatment to demonstrate their safety for prostate and
In conclusion, substantial gains in lean body mass and muscle size were achieved safely with a
relatively short course of therapy with an anabolic androgen in 60-87 year old men. Moreover,
these changes were associated with significant gains in maximal voluntary strength in the large
upper- and lower-body muscle groups, which are important for normal physical function in older
persons. However, the benefits were lost within 12 weeks after oxandrolone was discontinued,
suggesting that prolonged androgen treatment, would be needed to maintain these anabolic
benefits. Thus, the long-term safety and efficacy of androgen therapy in older men need to be
established. In addition, whole-body and trunk fat mass decreased significantly during therapy
and the effects were largely sustained after treatment was discontinued. Whether the reduction
in central adiposity with androgen therapy has tangible health benefits is uncertain. These
observations, therefore, raise several important questions that must be addressed before androgen
therapy is widely prescribed as long term therapy for sarcopenia in older individuals.
ACKNOWLEDGEMENTS: We thank the subjects who committed substantial time and
efforts to make this study successful. We also appreciate the numerous helpful suggestions made
by Colleen Azen, MS, GCRC statistician and the work of Ms. Xianghong Chen who performed
the 2H-analyses in the Biomedical Mass Spectrometry Resource at Washington University
Medical School (NIH NCRR RR00954). Support was provided in part from the National
Institutes of Health GCRC MOI RR00043 and by a grant-in-aid from Savient Pharmaceuticals.
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Figure 1. Absolute change in lean body mass by DEXA from baseline to study week 12 (solid
bars) and baseline to study week 24 (open bars) in the placebo (n=12) and the oxandrolone
(n=20) study groups. The whiskers are ± one standard error. * Represents a significant (p<0.001)
increase from baseline. † Represents a significant (p<0.001) difference between study groups for
change in lean body mass from 0-12 week.
Figure 2. Absolute measures of cross-sectional area (cm2) by magnetic resonance imaging at
baseline (open bars) and study week 12 (solid bars) in the placebo (n=12) and the oxandrolone
(n=20) study groups. The whiskers are ± one standard error. * Represents a significant (P<0.001)
increase from baseline. † Represents a significant (P<0.01) difference between study groups at
Figure 3a. Absolute change in total fat mass by DEXA from baseline to study week 12 (solid
bars) and baseline to study week 24 (open bars) in the placebo (n=12) and the oxandrolone
(n=20) study groups. The whiskers are ± one standard error. * Represents a significant (P<0.001)
decrease from baseline. † Represents a significant (P<0.001) difference between study groups for
change in total fat mass from 0-12 week.
Figure 3b. Absolute change in trunk fat by DEXA from baseline to study week 12 (solid bars)
and baseline to study week 24 (open bars) in the placebo (n=12) and the oxandrolone (n=20)
study groups. The whiskers are ± one standard error. * Represents a significant (P0.001)
decrease from baseline. † Represents a significant (P<0.001) difference between study groups for
change in total fat mass from 0-12 week.
Figure 4. Relative (%) change in maximum voluntary muscle strength from baseline to study
week 12 (solid bars) and baseline to study week 24 (open bars) in the oxandrolone (n=20) study
group only. The whiskers are ± one standard error. * Represents a significant increase from
baseline with Bonferroni adjustment. † Represents a significant difference between study groups
at week 12 with Bonferroni adjustment. # Represents an approaching significant increase from
baseline for lat pull, and an approaching significant difference for leg flexion and lat pull
between study groups at week 12 with Bonferroni adjustment.
Change in Lean Body Mass (kg)
Total Thigh Muscle CSA (cm2)
Change in Total Fat Mass (kg)
Change in Trunk Fat Mass (kg)
Relative (%) Change in Strength
Leg Press Leg Flexion Chest Press Lat Pull
Table 1. Baseline Characteristics of the Study Population
Oxandrolone Placebo P Value*
n 20 12
Age, yr 72.8±6.9 71.5±3.2 0.49
DEXA weight, kg 81.3±13.3 84.8±8.9 0.43
DEXA LBM, kg 56.5±5.6 58.3±5.9 0.47
DEXA fat mass, kg 23.5±7.7 23.7±4.4 0.51
BMI, kg/m227.5±3.5 29.1±2.9 0.20
Caloric intake, kcal/kg 25.8±6.3 25.6±4.5 0.87
Intake of protein, g/kg 1.2±0.4 1.1±0.1 0.97
Intake of carbohydrate, g/kg 3.0±0.6 3.2±0.7 0.47
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
Creatinine, mg/dl 1.5±1.3 1.2±0.4 0.34
Albumin, g/dl 4.0±0.2 4.2±0.2 0.07
ALT, U/l 38±7.0 38±4.4 0.83
Ultrasensitive CRP, mg/l 1.4±1.0 2.3±2.7 0.21
PSA, ng/ml 2.4±1.1 1.3±0.8 0.009
Total testosterone, µg/dl 369±147 357±153 0.83
Luteinizing hormone, U/l 8.3±7.1 6.5±6.7 0.51
Total cholesterol, mg/dl 186±31 186±34 0.97
Values are means ± 1 standard deviation; n = number of subjects; DEXA, dual-energy x-ray
absorptiometry; LBM, lean body mass; BMI, body mass index; ALT, alanine aminotransferase;
CRP, C-Reactive Protein; PSA, prostate-specific antigen.
*P-value obtained by independent t-test.
Table 2. Maximal Voluntary Skeletal Muscle Strength
Week 0 Week 12 Week 24 P value
0 v 12 0 vs 24
Leg Press, N
Oxandrolone 1245±132 1357±189†1266±191 <0.001* 0.81
Placebo 1250±213 1250±210 1246±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±40.5 <0.001* 0.89
Placebo 216±44 213±49 198±43 0.69 0.43
Lat 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 ± 1 standard deviation.
* 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.
Table 3. Change in Safety Measures After 12 Weeks 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±50.001
AST, U/l 8±8-1±40.001
Alkaline phosphatase, U/l -24±13 -7±12 <0.001
Total serum bilirubin, mg/dl 0±0 0±00.93
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
Values are means ± SD. BUN, blood urea nitrogen; AST, aspartate aminotransferase.
*P-value obtained by independent t-test.