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Treatment with oxandrolone and the durability of effects in older men

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We investigated the effects of the anabolic androgen, oxandrolone, on lean body mass (LBM), muscle size, fat, and maximum voluntary muscle strength, and we determined the durability of effects after treatment was stopped. Thirty-two healthy 60- to 87-yr-old men were randomized to receive 20 mg oxandrolone/day (n = 20) or placebo (n = 12) for 12 wk. Body composition [dual-energy X-ray absorptiometry (DEXA), magnetic resonance imaging, and (2)H(2)O dilution] and muscle strength [1 repetition maximum (1 RM)] were evaluated at baseline and after 12 wk of treatment; body composition (DEXA) and 1-RM strength were then assessed 12 wk after treatment was discontinued (week 24). At week 12, oxandrolone increased LBM 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 cm(2) (P < 0.001); these increases were greater (P < 0.003) than in the placebo group. Oxandrolone increased 1-RM strength for leg press by 6.7 +/- 6.4% (P < 0.001), leg flexion by 7.0 +/- 7.8% (P < 0.001), chest press by 9.3 +/- 6.7% (P < 0.001), and latissimus pull-down exercises by 5.1 +/- 9.1% (P = 0.02); these increases were greater than placebo. Oxandrolone reduced total (-1.9 +/- 1.0 kg) and trunk fat (-1.3 +/- 0.6 kg; P < 0.001), and these decreases were greater (P < 0.001) than placebo. Twelve weeks after oxandrolone was discontinued (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 +/- 1.1 kg, P < 0.001, respectively). Thus oxandrolone induced short-term improvements in LBM, muscle area, and strength, while reducing whole body and trunk adiposity. Anabolic improvements were lost 12 wk after discontinuing oxandrolone, whereas improvements in fat mass were largely sustained.
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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
Yolanda Stewart2
Carla Flores2
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
Phone: 323-442-2498
Facsimile: 323-442-1515
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.
Study Design
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.
Study Population
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
Study Interventions
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.
Safety Monitoring
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.
Nutritional Assessment
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%.
Statistical Considerations
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
week 24.
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.
Safety Evaluation
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
cardiovascular health.
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
week 12.
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.
Figure 1
Placebo Oxandrolone
Change in Lean Body Mass (kg)
0-12 wk
0-24 wk
Figure 2
Placebo Oxandrolone
Total Thigh Muscle CSA (cm2)
Week 12
Figure 3
Change in Total Fat Mass (kg)
0-12 wk
0-24 wk
0-12 wk
0-24 wk
Placebo Oxandrolone
Placebo Oxandrolone
Figure 4
Relative (%) Change in Strength
0-12 wk
0-24 wk
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±1891266±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±40214±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.
... A previous study has shown that the coefficient of variation for serum testosterone measured by this method was 7.7%. 46 Blood analysis was performed throughout the study, monitoring pituitary hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), prostate-specific antigen (PSA), alanine aminotransferase (ALT), hematocrit, hemoglobin, and white blood cell at 2 weeks preoperatively, 1 day preoperatively, and 2, 6, 12, and 24 weeks postoperatively. Informed consent documentation included a discussion of the possible but uncommon risks of testosterone such as allergic reactions, liver function test alterations, breast tenderness, hair growth or loss, polycythemia, and mood or mental changes. ...
... Lean mass was measured by wholebody dual-energy x-ray absorptiometry using the Lunar iDXA system (General Electric Healthcare). 44,46 Lean body mass was measured to the nearest one-tenth of a kilogram (kg), and previous studies evaluating the precision of the Lunar iDXA system have demonstrated a coefficient of variation <1% for total lean body mass measurements. 40 Tests of maximal extensor strength were performed on the participants' affected and unaffected legs using a NORM dynamometer (Cybex) following the standard protocol for concentric extension at a speed of 60 deg/s. ...
... Preliminary data were taken from a study that found a change in lean mass of 3.0 ± 1.5 kg in healthy men receiving testosterone. 46 Using a significance level of 0.05 and a power of 0.80, a sample size of 6 participants per group was calculated to observe similar effects. Assuming a dropout rate of 20%, it was estimated that 14 patients would be needed in total. ...
Full-text available
Background Rehabilitation after repair of the anterior cruciate ligament (ACL) is complicated by the loss of leg muscle mass and strength. Prior studies have shown that preoperative rehabilitation may improve muscle strength and postoperative outcomes. Testosterone supplementation may likewise counteract this muscle loss and potentially improve clinical outcomes. Purpose The purpose was to investigate the effect of perioperative testosterone administration on lean mass after ACL reconstruction in men and to examine the effects of testosterone on leg strength and clinical outcome scores. It was hypothesized that testosterone would increase lean mass and leg strength and improve clinical outcome scores relative to placebo. Study Design Randomized controlled trial; Level of evidence, 1. Methods Male patients (N = 13) scheduled for ACL reconstruction were randomized into 2 groups: testosterone and placebo. Participants in the testosterone group received 200 mg of intramuscular testosterone weekly for 8 weeks beginning 2 weeks before surgery. Participants in the placebo group received saline following the same schedule. Both groups participated in a standard rehabilitation protocol. The primary outcome was the change in total lean body mass at 6 and 12 weeks. Secondary outcomes were extensor muscle strength, Tegner activity score, and Knee injury and Osteoarthritis Outcome Score. Results There was an increase in lean mass of a mean 2.7 ± 1.7 kg at 6 weeks postoperatively in the testosterone group compared with a decrease of a mean 0.1 ± 1.5 kg in the placebo group (P = .01). Extensor muscle strength of the uninjured leg also increased more from baseline in the testosterone group (+20.8 ± 25.6 Nm) compared with the placebo group (–21.4 ± 36.7 Nm) at 12 weeks (P = .04). There were no significant between-group differences in injured leg strength or clinical outcome scores. There were no negative side effects of testosterone noted. Conclusion Perioperative testosterone supplementation increased lean mass 6 weeks after ACL reconstruction, suggesting that this treatment may help minimize the effects of muscle atrophy associated with ACL injuries and repair. This study was not powered to detect differences in strength or clinical outcome scores to assess the incidence of testosterone-related adverse events. Clinical Relevance Supraphysiological testosterone supplementation may be a useful adjunct therapy for counteracting muscle atrophy after ACL reconstruction. Further investigation is necessary to determine the safety profile and effects of perioperative testosterone administration on leg strength and clinical outcomes after surgery. Registration NCT01595581 (
... Previous investigations of the effects of AAS administration on strength, functional performance, and quality of life are inconclusive (32,33,42). Muscle strength is multifactorial, with muscle mass being only one variable that can influence strength. ...
... Without the use of a no-treatment control group and one receiving oxandrolone only, it is impossible to determine whether oxandrolone alone could increase muscle strength or functional performance in this particular cohort of older frail women. Oxandrolone administration has been shown to elicit gains in strength (33), and thus, appropriately designed studies are warranted to investigate whether administration of oxandrolone alone is sufficient to increase muscle strength in older frail women. In addition, a disproportionate increase in total body water compared with DXA-derived increase in lean tissue has been noted with oxandrolone administration (33), and this could affect DXA-derived lean tissue estimates (37). ...
... Oxandrolone administration has been shown to elicit gains in strength (33), and thus, appropriately designed studies are warranted to investigate whether administration of oxandrolone alone is sufficient to increase muscle strength in older frail women. In addition, a disproportionate increase in total body water compared with DXA-derived increase in lean tissue has been noted with oxandrolone administration (33), and this could affect DXA-derived lean tissue estimates (37). Furthermore, DXA is unable to quantify visceral versus subcutaneous abdominal fat, and thus, image analysis techniques such as computed tomography scanning or magnetic resonance imaging would be needed to determine specific oxandrolone-induced changes in these compartments relative to PRT, which has been associated with reductions in visceral fat (15). ...
Sarcopenia is disproportionately present in older women with disability, and optimum treatment is not clear. We conducted a double-blind, randomized, placebo-controlled trial to determine if oxandrolone administration in elderly women improves body composition or physical function beyond that which occurs in response to progressive resistance training. Twenty-nine sedentary women (aged 74.9±6.8yrs; 5.9±2.8 meds/day) were randomized to receive high intensity progressive resistance training (3 times/week for 12 weeks) combined with either oxandrolone (10 mg/day) or an identical placebo. Peak strength was assessed for leg press, chest press, triceps, knee extension and knee flexion. Power was assessed for leg press and chest press. Physical function measures included static and dynamic balance, chair rise, stair climb, gait speed and six-minute walk test. Body composition was assessed using dual energy X-ray absorptiometry. Oxandrolone treatment augmented increases in lean tissue for the whole body (2.6kg; 95% CI 1.0, 4.2kg; p=0.003); arms (0.3kg; 95% CI 0.1, 0.5kg; p=0.001); legs (0.8kg; 95% CI 0.1, 1.4kg; p=0.018) and trunk (1.4kg; 95% CI 0.4, 2.3kg; p=0.004). Oxandrolone also augmented loss of fat tissue of the whole body (-1kg; 95% CI -1.6, -0.4, p=0.002), arms (-0.2kg; 95% CI -0.5, -0.02kg; p=0.032), legs (-0.4kg; 95% CI -0.6, -0.1; p=0.009) and tended to reduce trunk fat (-0.4kg; 95% CI -0.9, 0.04; p=0.07). Improvements in muscle strength and power, chair stand, and dynamic balance were all significant over time (p<0.05), but not different between groups (p>0.05). Oxandrolone improves body composition adaptations to progressive resistance training in older women over 12 weeks without augmenting muscle function or functional performance beyond that of PRT alone.
... Of nineteen current AAS users recruited, only six verbalised intensions for complete removal of AAS for ≥18 weeks post usage and only five were sampled on a second visit. A 3.9 -4.7 kg decrease in FFM from four returning participants who all ceased AAS usage ≤2 weeks prior to their first visit with 19-28 weeks between visits corroborates with previous research showing that LBM decreases post AAS usage in young [220] and older men [281]. RP1 and RP2 exhibited decrements in CSA whilst myonuclei per fibre values remained relatively similar between visits. ...
... testosterone administration studies have shown FFM can be gained from supraphysiological doses of testosterone. However, there is limited data regarding how much FFM can be lost after AAS exposure [220,281]. A 3.9 -4.7 kg decrease in FFM from four returning participants who all ceased AAS usage ≤2 weeks prior to their first visit with 19-28 weeks between visits corroborates with this previous research that LBM decreases post AAS exposure. ...
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Anabolic Androgenic Steroid (AAS) doping pervasiveness, identified retrospectively through International Olympic Committee (IOC) re-tests of the 2004-2012 summer Olympic Games (OG) threatened weightlifting's place at the 2024 OG. Despite this, analysing doping practices in weightlifting and an investigation of IOC re-test efficacy, across all summer OG sports, is outstanding. AAS induce human hypertrophy via increasing myonuclei, and mice data suggests myonuclei permanency causing a "memory" of exposure and long-term advantage. However, limited human data exists on past AAS users and there is no longitudinal data post AAS exposure. Furthermore, RNA-Seq has yet to be conducted on human samples exposed to AAS. Chapter 1 outlines an introduction and Chapter 2 methodologies. Chapter 3 provides results of analysing weightlifting doping practices from 2008-2019 and identified continental differences in detected substances. Chapter 4 analysed doping that impacted medal results for the 1968-2012 summer OG and showed most doping (74% of medals impacted by doping) was identified retrospectively, either from events prior to OG (17%) or IOC re-tests of 2004-2012 (57%). Chapter 5 describes the males recruited for cross-sectional observational research on AAS and myonuclear permanency and Chapter 6 their transcriptome data. Fifty-six men aged 20-42 years were recruited: Non-resistance-trained (C), resistance-trained (RT), RT currently using AAS (RT-AS), of which if AAS usage ceased for ≥18 weeks resampled as Returning Participants (RP) or RT previously using AAS (PREV). There were no significant differences between C (n = 5), RT (n = 15), RT-AS (n = 17), and PREV (n = 6) for trapezius myonuclei per fibre data. Three of 5 returning participants (RP1-3) were sampled longitudinally. Fibre cross-sectional area decreased for RP1 and RP2 between visits, whilst myonuclei per fibre remained similar, congruent with the memory mechanism. However, these values increased for RP3 and self-declared AAS regimens varied. For RNA-Seq, RT-AS was divided to participants who ceased exposure ≤2 or ≥10 weeks prior to sampling. For validation, RNA-Seq was conducted twice but cross-comparison of whole blood datasets showed no differential expression between RP time points or comparisons of RT-AS≤2 to other groups. In both muscle datasets, nine differentially expressed genes overlapped with RT-AS≤2 vs RT and RT-AS≤2 vs C, but were not differentially expressed with RT vs C, possibly suggesting they are from acute doping alone, but differential training routines is a confounder. This thesis identified geographical differences in weightlifting doping, demonstrated retrospective doping testing efficacy and contributed data on AAS regarding muscle memory and the human transcriptome.
... Although three isoforms exist (TGF-β1-3), mainly TGF-β1 has been associated with the pathology of different muscle-wasting disorders. TGF-β1 plays an important role in wound healing and regulation of the immune system and is a key pro-fibrotic factor [219]. In addition, it is known that TGF-β inhibits myogenic differentiation of myoblasts in vitro [220,221]. ...
... In this category is included oxandrolone, a synthetic anabolic androgen. Treatment with this compound had advantages like improvements in lean body mass and fat mass and also in muscle strength [219] but had significant disadvantageous consequences on plasmatic lipid profiles. ...
Low back pain is one of the most common pain disorders defined as pain, muscle tension, or stiffness localized below the costal margin and above the inferior gluteal folds, sometimes with accompanying leg pain. The meaning of the symptomatic atrophy of paraspinal muscles and some pelvic muscles has been proved. Nowadays, a need for new diagnostic tools for specific examination of low back pain patients is posited, and it has been proposed that magnetic resonance imaging assessment toward muscle atrophy may provide some additional information enabling the subclassification of that group of patients.
... Taking into consideration the real bodybuilding scenario, i.e., competition without doping tests, the loss of muscle mass under high doses of T and associated AASs with high anabolic potential (e.g., nandrolone and oxymetholone) is almost illogical despite the assumed threshold for skeletal muscle gains. The same is true for clinical populations (female-to-male transgender persons, patients with HIV/AIDS, sarcopenia, etc.), whose muscle anabolism is the expected effect induced by AAS regimens, seemingly reaching a plat-eau with the maintenance of a therapeutic dosage [80][81][82][83][84]. In these cases, the muscle-building plateau must not be considered an AR-disrupting factor, as if the chronic use of T and general AASs promoted the downregulation of ARs, muscle mass gains would not be sustainable irrespective of the population. ...
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Researchers and health practitioners seek to understand the upper limit of muscle hypertrophy under different conditions. Although there are models to estimate the muscle-building threshold in drug-free resistance training practitioners, little is known about the population using anabolic-androgenic steroids (AASs) in this regard. Because of a plateau effect of muscle hypertrophy upon AAS regimens, there is a hypothesis among clinicians and enthusiasts that AASs down-regulate skeletal muscle androgen receptors (ARs). Conversely, in this narrative review, we show that seminal and recent evidence-primarily using testosterone and oxandrolone administration as human experimental models-support that AASs upregulate ARs, eliciting greater anabolic effects on skeletal muscle receptors through a dose-dependent relationship. Thus, to date, there is no scientific basis for claiming that myocyte AR downregulation is the cause of the AAS-induced plateau in muscle gains. This phenomenon is likely driven by the neutral nitrogen balance, but further research is imperative to clarify the intrinsic mechanisms related to this landscape.
... [162] Treatment of elderly men with the synthetic anabolic androgen, oxandrolone, was associated with improvements in lean body mass, fat mass, and muscle strength. [163] , but significant reductions in high-density lipoprotein (HDL) cholesterol were also observed. [164] Other treatments currently in development include inhibitors of transcription factor nuclear factor kappa B (NF-κB) for protection against cancer-related cachexia. ...
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Purpose of review: Sarcopenic obesity is a chronic condition, which is due to progressively aging populations, the increasing incidence of obesity, and lifestyle changes. The increasing prevalence of sarcopenic obesity in elderly has augmented interest in identifying the most effective treatment. This article aims at highlighting potential pathways to muscle impairment in obese individuals, the consequences that joint obesity and muscle impairment may have on health and disability, recent progress in management with attention on lifestyle management and pharmacologic therapy involved in reversing sarcopenic obesity. Recent findings: It has been suggested that a number of disorders affecting metabolism, physical capacity, and quality of life may be attributed to sarcopenic obesity. Excess dietary intake, physical inactivity, low-grade inflammation, insulin resistance and hormonal changes may lead to the development of sarcopenic obesity. Weight loss and exercise independently reverse sarcopenic obesity. Optimum protein intake appears to have beneficial effects on net muscle protein accretion in older adults. Myostatin inhibition causes favourable changes in body composition. Testosterone and growth hormone offer improvements in body composition but the benefits must be weighed against potential risks of therapy. GHRH-analog therapy is effective but further studies are needed in older adults. Summary: Lifestyle changes involving both diet-induced weight loss and regular exercise appear to be the optimal treatment for sarcopenic obesity. It is also advisable to maintain adequate protein intake. Ongoing studies will determine whether pharmacologic therapy such as myostatin inhibitors or GHRH-analogs have a role in the treatment of sarcopenic obesity.
... To date, few studies have investigated the effects of TRT withdrawal in androgen-deficient patients and conflicting data exist in the literature. Early investigations bySchroeder et al.demonstrated that while the effects of TRT on bone mineral density and muscle mass returned to baseline, reduction in central and peripheral fat were largely maintained after 3-months treatment withdrawal in overweight older men with low testosterone[12,13]. In a small retrospective intervention study, TRT withdrawal was also shown not to increase proinflammatory cytokine production by antigen-presenting cells in men with T2D and partial androgen deficiency over 3-months[14]. ...
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Whether testosterone replacement therapy (TRT) is a lifelong treatment for men with hypogonadism remains unknown. We investigated long-term TRT and TRT withdrawal on obesity and prostate-related parameters. Two hundred and sixty-two hypogonadal patients (mean age 59.5) received testosterone undecanoate in 12-week intervals for a maximum of 11 years. One hundred and forty-seven men had TRT interrupted for a mean of 16.9 months and resumed thereafter (Group A). The remaining 115 patients were treated continuously (Group B). Prostate volume, prostate-specific antigen (PSA), residual voiding volume, bladder wall thickness, C-reactive protein (CRP), aging male symptoms (AMS), International Index of erectile function - erectile function (IIEF-EF) and International Prostate Symptoms Scores (IPSS) were measured over the study period with anthropometric parameters of obesity, including weight, body mass index (BMI) and waist circumference. Prior to interruption, TRT resulted in improvements in residual voiding volume, bladder wall thickness, CRP, AMS, IIEF-EF, IPSS and obesity parameters while PSA and prostate volume increased. TRT interruption reduced total testosterone to hypogonadal levels in Group A and resulted in worsening of obesity parameters, AMS, IPSS, residual voiding volume and bladder wall thickness, IIEF-EF and PSA while CRP and prostate volume were unchanged until treatment resumed whereby these effects were reversed. TRT interruption results in worsening of symptoms. Hypogonadism may require lifelong TRT.
Objective: It remains unknown whether myonuclei remain elevated post anabolic-androgenic steroid (AAS) usage in humans. Limited data exist on AAS-induced changes in gene expression. Design: Cross-sectional/longitudinal. Setting: University. Participants: Fifty-six men aged 20 to 42 years. Independent variables: Non-resistance-trained (C) or resistance-trained (RT), RT currently using AAS (RT-AS), of which if AAS usage ceased for ≥18 weeks resampled as Returning Participants (RP) or RT previously using AAS (PREV). Main outcome measures: Myonuclei per fiber and cross-sectional area (CSA) of trapezius muscle fibers. Results: There were no significant differences between C (n = 5), RT (n = 15), RT-AS (n = 17), and PREV (n = 6) for myonuclei per fiber. Three of 5 returning participants (RP1-3) were biopsied twice. Before visit 1, RP1 ceased AAS usage 34 weeks before, RP2 and RP3 ceased AAS usage ≤2 weeks before, and all had 28 weeks between visits. Fiber CSA decreased for RP1 and RP2 between visits (7566 vs 6629 μm2; 7854 vs 5677 μm2) while myonuclei per fiber remained similar (3.5 vs 3.4; 2.5 vs 2.6). Respectively, these values increased for RP3 between visits (7167 vs 7889 μm2; 2.6 vs 3.3). Conclusions: This cohort of past AAS users did not have elevated myonuclei per fiber values, unlike previous research, but reported AAS usage was much lower. Training and AAS usage history also varied widely among participants. Comparable myonuclei per fiber numbers despite decrements in fiber CSA postexposure adheres with the muscle memory mechanism, but there is variation in usage relative to sampling date and low numbers of returning participants.
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Background: Several of young people and adults make use of anabolic-androgenic steroid (ASS), during resistance training. The purposes of this study were to compare blood and salivary parameters in male resistance training practitioners using oxandrolone with reference values, compare these with a control group in triplicate, and correlate salivary and blood parameters. Methods: In this prospective analytical observational study, blood, saliva, and urine were collected from 22 individuals (oxandrolone group, OG, n = 11 and control group, CG, n = 11), and these samples were analyzed at three time points: before oxandrolone consumption, at cessation of oxandrolone use, and three months after cessation of oxandrolone use. Complete blood count, lipid profile, metabolites, and enzymes were analyzed from blood samples. Salivary flow, pH, triglycerides, urea, aspartate transaminase, alanine aminotransferase, phosphorus, and calcium were analyzed from saliva. Urinalysis was used for toxicological screening. Mann-Whitney U tests, chi-square analysis, Friedman's ANOVA, and Spearman’s correlation tests were performed, with significance p<0.05. Results: We found a lower blood HDL level for the oxandrolone group (24 mg/dL) compared with the reference value (>40 mg/dL), as soon as its use ceased, and a return to normal HDL levels three months later (49 mg/dL, >40 mg/dL). We also found higher triglyceride level (177 mg/dL) in this group compared with the reference value (<175 mg/dL), three months after use. Conclusions: Although there were distinct differences between the groups and timepoints, these did not show clinical relevance, as they were within typical values. There was no correlation between blood and salivary parameters, but it is clear that oxandrolone causes changes in the lipid profile of users.
Muscle atrophy may occur under different circumstances throughout a person’s life. These conditions include periods of immobilization of a limb or of the whole body and aging accompanied by the onset of sarcopenia. Muscle mass is reduced as a result of decreased protein synthesis or increased protein degradation. Most studies aim to prevent the degradation of muscle proteins, but the way in which protein synthesis can be stimulated is often neglected. This study will provide an up-to-date review regarding nutritional considerations and resistance exercise countermeasures in the prevention of muscle mass loss and recovery of muscle mass in muscle atrophy secondary to immobilization or in sarcopenic obesity. We do not address muscle atrophy in disease states associated with inflammation (rheumatoid arthritis, COPD, cancer cachexia, AIDS, burns, sepsis, and uremia) which are governed by particular mechanisms of muscle loss.
Acquired hypogonadism is being increasingly recognized in adult men. However, the effects of long term testosterone replacement on bone density and body composition are largely unknown. We investigated 36 adult men with acquired hypogonadism (age, 22-69 yr; median, 58 yr), including 29 men with central hypogonadism and 7 men with primary hypogonadism, and 44 age-matched eugonadal controls. Baseline evaluation included body composition analysis by bioimpedance, determination of site-specific adipose area by dual energy quantitative computed tomography scan (QCT) of the lumbar spine, and measurements of spinal bone mineral density (BMD) using dual energy x-ray absortiometry, spinal trabecular BMD with QCT, and radial BMD with single photon absorptiometry. Percent body fat was significantly greater in the hypogonadal men compared to eugonadal men (mean +/- SEM, 26.4 +/- 1.1% vs. 19.2 +/- 0.8%; P < 0.01). The mean trabecular BMD determined by QCT for the hypogonadal men was 115 +/- 6 mg K2HPO4/cc. Spinal BMD was significantly lower than that in eugonadal controls (1.006 +/- 0.024 vs. 1.109 +/- 0.028 g/cm2; P = 0.02, respectively). Radial BMD was similar in both groups. Testosterone enanthate therapy was initiated in 29 hypogonadal men at a dose of 100 mg/week, and the subjects were evaluated at 6-month intervals for 18 months. During testosterone therapy, the percent body fat decreased 14 +/- 4% (P < 0.001). There was a 13 +/- 4% decrease in subcutaneous fat (P < 0.01) and a 7 +/- 2% increase in lean muscle mass (P = 0.01) during testosterone therapy. Spinal BMD and trabecular BMD increased by 5 +/- 1% (P < 0.001) and 14 +/- 3% (P < 0.001), respectively. Radial BMD did not change. Serum bone-specific alkaline phosphatase and urinary deoxypyridinoline excretion, markers of bone formation and resorption, respectively, decreased significantly over the 18 months (P = 0.003 and P = 0.04, respectively). We conclude that testosterone therapy given to adult men with acquired hypogonadism decreases sc fat and increases lean muscle mass. In addition, testosterone therapy reduces bone remodeling and increases trabecular bone density. The beneficial effects of androgen administration on body composition and bone density may provide additional indications for testosterone therapy in hypogonadal men.
In order to obtain joint-specific baseline strength characteristics in older adults, clinicians and researchers must have knowledge regarding the relative stability of the various strength tests (the strength difference between repeated measures) and the number of prebaseline practice sessions required to obtain consistent data. To address these needs, the relative multiple-test stability and reliability associated with lower extremity isokinetic and 1-repetition-maximum (1RM) strength measures were assessed in a sample of older adults (N = 30, 65.2 ± 6.3 years), over 4 weeks (T1-T4). Isokinetic ankle plantar-flexion (30°/s) strength and 1RM ankle plantar-flexion, leg-press, and knee-flexion strength exhibited poor stability between Weeks T1 and T2 but stabilized between Weeks T2 and T3 and Weeks T3 and T4. The measures exhibited low incidence of injury and induced low levels of residual muscle soreness. Findings suggest that the 1RM measures require at least 1 prebaseline training session in order to establish consistent baseline performance and are more reliable than isokinetic ankle plantar-flexion tests.
Context Hormone administration to elderly individuals can increase lean body mass (LBM) and decrease fat, but interactive effects of growth hormone (GH) and sex steroids and their influence on strength and endurance are unknown. Objective To evaluate the effects of recombinant human GH and/or sex steroids on body composition, strength, endurance, and adverse outcomes in aged persons. Design, Setting, and Participants A 26-week randomized, double-blind, placebo-controlled parallel-group trial in healthy, ambulatory, community-dwelling US women (n = 57) and men (n = 74) aged 65 to 88 years recruited between June 1992 and July 1998. Interventions Participants were randomized to receive GH (starting dose, 30 µg/kg, reduced to 20 µg/kg, subcutaneously 3 times/wk) + sex steroids (women: transdermal estradiol, 100 µg/d, plus oral medroxyprogesterone acetate, 10 mg/d, during the last 10 days of each 28-day cycle [HRT]; men: testosterone enanthate, biweekly intramuscular injections of 100 mg) (n = 35); GH + placebo sex steroid (n = 30); sex steroid + placebo GH (n = 35); or placebo GH + placebo sex steroid (n = 31) in a 2 × 2 factorial design. Main Outcome Measures Lean body mass, fat mass, muscle strength, maximum oxygen uptake (O2max) during treadmill test, and adverse effects. Results In women, LBM increased by 0.4 kg with placebo, 1.2 kg with HRT (P = .09), 1.0 kg with GH (P = .001), and 2.1 kg with GH + HRT (P<.001). Fat mass decreased significantly in the GH and GH + HRT groups. In men, LBM increased by 0.1 kg with placebo, 1.4 kg with testosterone (P = .06), 3.1 kg with GH (P<.001), and 4.3 kg with GH + testosterone (P<.001). Fat mass decreased significantly with GH and GH + testosterone. Women's strength decreased in the placebo group and increased nonsignificantly with HRT (P = .09), GH (P = .29), and GH + HRT (P = .14). Men's strength also did not increase significantly except for a marginally significant increase of 13.5 kg with GH + testosterone (P = .05). Women's O2max declined by 0.4 mL/min/kg in the placebo and HRT groups but increased with GH (P = .07) and GH + HRT (P = .06). Men's O2max declined by 1.2 mL/min/kg with placebo and by 0.4 mL/min/kg with testosterone (P = .49) but increased with GH (P = .11) and with GH + testosterone (P<.001). Changes in strength (r = 0.355; P<.001) and in O2max (r = 0.320; P = .002) were directly related to changes in LBM. Edema was significantly more common in women taking GH (39% vs 0%) and GH + HRT (38% vs 0%). Carpal tunnel symptoms were more common in men taking GH + testosterone (32% vs 0%) and arthralgias were more common in men taking GH (41% vs 0%). Diabetes or glucose intolerance occurred in 18 GH-treated men vs 7 not receiving GH (P = .006). Conclusions In this study, GH with or without sex steroids in healthy, aged women and men increased LBM and decreased fat mass. Sex steroid + GH increased muscle strength marginally and O2max in men, but women had no significant change in strength or cardiovascular endurance. Because adverse effects were frequent (importantly, diabetes and glucose intolerance), GH interventions in the elderly should be confined to controlled studies.
Context Several novel risk factors for atherosclerosis have recently been proposed, but few comparative data exist to guide clinical use of these emerging biomarkers.Objective To compare the predictive value of 11 lipid and nonlipid biomarkers as risk factors for development of symptomatic peripheral arterial disease (PAD).Design, Setting, and Participants Nested case-control study using plasma samples collected at baseline from a prospective cohort of 14 916 initially healthy US male physicians aged 40 to 84 years, of whom 140 subsequently developed symptomatic PAD (cases); 140 age- and smoking status–matched men who remained free of vascular disease during an average 9-year follow-up period were randomly selected as controls.Main Outcome Measure Incident PAD, as determined by baseline total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol–HDL-C ratio, triglycerides, homocysteine, C-reactive protein (CRP), lipoprotein(a), fibrinogen, and apolipoproteins (apo) A-I and B-100.Results In univariate analyses, plasma levels of total cholesterol (P<.001), LDL-C (P = .001), triglycerides (P = .001), apo B-100 (P = .001), fibrinogen (P = .02), CRP (P = .006), and the total cholesterol–HDL-C ratio (P<.001) were all significantly higher at baseline among men who subsequently developed PAD compared with those who did not, while levels of HDL-C (P = .009) and apo A-I (P = .05) were lower. Nonsignificant baseline elevations of lipoprotein(a) (P = .40) and homocysteine (P = .90) were observed. In multivariable analyses, the total cholesterol–HDL-C ratio was the strongest lipid predictor of risk (relative risk [RR] for those in the highest vs lowest quartile, 3.9; 95% confidence interval [CI], 1.7-8.6), while CRP was the strongest nonlipid predictor (RR for the highest vs lowest quartile, 2.8; 95% CI, 1.3-5.9). In assessing joint effects, addition of CRP to standard lipid screening significantly improved risk prediction models based on lipid screening alone (P<.001).Conclusions Of 11 atherothrombotic biomarkers assessed at baseline, the total cholesterol–HDL-C ratio and CRP were the strongest independent predictors of development of peripheral arterial disease. C-reactive protein provided additive prognostic information over standard lipid measures.