ArticlePDF Available

The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men

Authors:
  • University of Texas Medical Branch / NASA Johnson Space Center

Abstract and Figures

Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity.
Content may be subject to copyright.
87
Journal of Gerontology: MEDICAL SCIENCES
Cite journal as: J Gerontol A Biol Sci Med Sci. 2013 January;68(1):87–95
doi:10.1093/gerona/gls078
© The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Advance Access publication March 28, 2012
Journal of Gerontology: MEDICAL SCIENCES © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America.
Cite journal as: J Gerontol A Biol Sci Med Sci All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
doi:10.1093/gerona/gls078
1
AS men and women grow old, they lose muscle mass,
muscle strength , and leg power ( 1 , 2 , 3 , 4 , 5 , 6 ), mostly
due to the preferential loss of type II muscle fi bers ( 5 ).
Sarcopenia, the age-associated loss of muscle mass and
strength, increases the risk of falls, fractures, physical dis-
ability, and poor quality of life ( 1 , 3 , 6 , 7 ). Similarly, the
course of many illnesses, such as chronic obstructive lung
disease, end - stage renal disease, and some types of cancer,
is punctuated by the loss of muscle mass and physical func-
tion, which contributes to mobility limitation and disability
( 7 , 8 ). Thus, there is an unmet need for anabolic therapies
that improve physical function and reduce the burden of
disability in persons experiencing functional limitations
due to aging or illness. Among the various candidate function -
promoting anabolic therapies that are in development,
androgens are the farthest along in development.
Testosterone administration increases muscle mass and
strength ( 9 , 10 , 11 , 12 , 13 , 14 , 15 ), but concerns regarding its
potential adverse effects on the prostate have restrained
enthusiasm for its use as an anabolic therapy and have
motivated efforts to develop selective androgen receptor
modulators (SARMs), a new class of androgen receptor
The Safety, Pharmacokinetics, and Effects of
LGD-4033, a Novel Nonsteroidal Oral, Selective
Androgen Receptor Modulator, in Healthy Young Men
Shehzad Basaria , 1 Lauren Collins , 1 , * E. Lichar Dillon , 2 , * Katie Orwoll , 1 Thomas W. Storer , 1
Renee Miciek , 1 Jagadish Ulloor , 1 Anqi Zhang , 1 Richard Eder , 1 Heather Zientek , 3 Gilad Gordon , 3
Syed Kazmi , 3 Melinda Sheffi eld-Moore , 2 , * and Shalender Bhasin 1
1 Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Massachusetts .
2 Department of Medicine, University of Texas Medical Branch, Galveston .
3 Ligand Pharmaceuticals , San Diego, California .
* These authors contributed equally and are joint second authors.
Address correspondence to Shalender Bhasin, MD, Section of Endocrinology, Boston University School of Medicine, Boston, MA 02118.
Email: Bhasin@bu.edu
Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of
selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a
novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affi nity and selectivity.
Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 admin-
istered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones.
Methods. In this placebo-controlled study, 76 healthy men (21 50 years) were randomized to placebo or 0.1, 0.3, or
1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specifi c antigen, electrocardiogram,
hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.
Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was
similar between active and placebo groups. Hemoglobin, prostate-specifi c antigen, aspartate aminotransferase, alanine
aminotransferase, or QT intervals did not change signifi cantly at any dose. LGD-4033 had a long elimination half-life and
dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent
suppression of total testosterone, sex hormone binding globulin, high density lipoprotein cholesterol, and triglyceride
levels. Follicle-stimulating hormone and free testosterone showed signifi cant suppression at 1.0-mg dose only. Lean body
mass increased dose dependently, but fat mass did not change signifi cantly. Hormone levels and lipids returned to baseline
after treatment discontinuation.
Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profi le, and increased lean body mass even during
this short period without change in prostate-specifi c antigen. Longer randomized trials should evaluate its effi cacy
in improving physical function and health outcomes in select populations.
Key Words: Selective androgen receptor modulators — SARMs — Sarcopenia — Function promoting anabolic therapies —
Cachexia .
Received December 8 , 2011 ; Accepted February 2 , 2012
Decision Editor: Luigi Ferrucci, MD, PhD
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
88 BASARIA ET AL.
BASARIA ET AL.
2
ligands that are tissue selective ( 8 , 16 , 17 , 18 , 19 ). The last
decade has witnessed substantial pharmaceutical efforts to
develop nonsteroidal SARMs to treat muscle wasting and
functional limitations associated with acute and chronic ill-
ness and aging ( 8 , 16 , 17 , 18 , 19 ). LGD-4033 is a novel non-
steroidal, oral SARM that binds to androgen receptor with
high affi nity (Ki of ~ 1 nM) and selectivity. In animal models,
LGD-4033 has demonstrated anabolic activity in the mus-
cle, anti-resorptive and anabolic activity in bone, and robust
selectivity for muscle versus prostate.
Here we report the results of a randomized, double-blind,
placebo-controlled, ascending-dose study, which evaluated
the safety, tolerability, and pharmacokinetics (PK) of LGD-
4033 in healthy men. We also evaluated the effects of graded
doses of LGD-4033 on lean body mass (LBM), muscle
strength , and physical function. LGD-4033 doses of 0.1,
0.3, and 1.0 mg were selected for multiple dosing over 21
days because a previous phase I single ascending-dose study
had established the safety of up to 22 mg LGD-4033. We also
tested the hypothesis that the LGD-4033 increases muscle
mass by stimulating fractional synthetic rate (FSR) of mixed -
muscle proteins, measured using continuous steady state
infusion of labeled phenylalanine in men randomized to either
placebo or 0.3-mg daily dose of LGD-4033. This dose was
selected for FSR study because preclinical data suggested
that this dose was the most likely to increase LBM.
Study Design
This was a double-blind, placebo-controlled, multiple
once-daily dose escalation study of LGD-4033 in healthy
men, approved by Boston University s Institutional Review
Board. All subjects provided written, informed consent.
Subjects
Nonsmoking, healthy men, 21 50 years, with body mass
index between 18 and 32 kg/m
2 , who were capable of
providing informed consent, were eligible. We excluded
subjects who had an active disease, prostate-specifi c antigen
>3 ng/mL, aspartate aminotransferase or ALT >1.5 times the
upper limit of normal, hematocrit <37% or >48%, creatinine
>2.0 mg/dL, and (HDL) cholesterol <40 mg/dL ; had used
anabolic steroids, recombinant human growth hormone,
dehydroepiandrosterone , and androstenedione during the
past year ; or were using any recreational drug.
Study Intervention
Three dose levels — 0.1, 0.3 , and 1.0 mg — were evalu-
ated against placebo. Each dose of LGD-4033 or placebo
was administered daily orally with 8 ounces of water
after an overnight fast. A total of 20 doses were adminis-
tered over 21 days; no dose was given on day 2 to allow
PK sampling for 48 hours after the fi rst dose. The 21-day
treatment period was followed by a 5-week observation
period.
Randomization
The subjects were randomized to the active drug or
placebo group based on protocol-defi ned randomization
schema: six active and two placebo in 0.1-mg cohort; 10 12
active and 10 12 placebo in 0.3-mg and 1.0-mg cohorts.
A protocol amendment after the completion of 1.0-mg
cohort added 12 active and six placebo subjects in the
0.1-mg cohort. Randomization lists, generated by the
biostatistician, were sent directly to Investigational Drug
Service.
The subjects were initially assigned to either placebo or
0.1 mg LGD-4033 daily. At the completion of each dose
level, the safety data were reviewed by a Safety Panel and
separately by a Data and Safety Monitoring Board, which
determined whether the dose could be escalated to a higher
level, based on prespecifi ed safety criteria. Dose escalation
proceeded only if an acceptable safety profi le with no clini-
cally signifi cant and/or unexpected toxicity was observed at
the lower dose.
Blinding
The study was a double-blind trial with concealed ran-
domization. The subjects and study personnel were unaware
of the intervention. Only the biostatistician and Investi-
gational Drug Service were aware of the subject s group
allocation. The Investigational Drug Service maintained the
randomization code and dispensed the study medication
based on the randomization list.
Outcomes
The primary aim was to assess the safety and tolerability
of escalating doses of LGD-4033 following repeated once-
daily oral administration for 21 days. Secondary aims included
the determination of the PK and pharmacodynamics of
LGD-4033 and its effects on mixed - muscle FSR. Addition-
ally, we investigated the effects of 21 days of treatment with
LGD-4033 on LBM measured by dual - energy x-ray absorp-
tiometry, maximal voluntary strength measured by one rep-
etition maximum method, and physical function, assessed
by the stair-climbing power, recognizing that a 21-day dura-
tion may not be suffi ciently long to fully elucidate the
anabolic effects of the SARM on LBM, muscle strength,
and physical function.
Schedule of Events
LGD-4033 concentrations were measured using a vali-
dated liquid chromatographic – tandem mass spectrometry
method in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6, 8,
10, 12, 24, 28, 32, and 48 hours after the fi rst dose. Once-
daily dosing recommenced on day 3 for 20 days , and on day
21, venous blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10,
12, 24, 28, 32, 48, 72, 96, 120 , and 168 hours after day 21
dosing.
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 3
Luteinizing hormone, follicle-stimulating hormone,
adrenocorticotropic hormone, cortisol, total and free testos-
terone, sex hormone – binding globulin levels, and plasma
lipids were measured periodically throughout the 21-day
intervention period and 7 and 35 days after drug cessation.
LBM and fat mass were measured at baseline and on days
20 and 28. Leg press strength and stair-climbing power and
speed were assessed at baseline and between days 23 and 25.
M ethods
Body composition was assessed using dual-energy x-ray
absorptiometry (Hologic 4500) scanner, calibrated using a
soft tissue phantom before each scan. To measure the leg
press strength ( 15 , 20 , 21 ), subjects underwent whole-body
warm up, followed by one set of 5 10 repetitions using
40 % 60% of the estimated maximum. Following appropriate
rest periods between attempts, subjects lifted progressively
heavier weights until the subject could not complete the lift.
The last successfully completed lift was recorded as the one
repetition maximum .
The 12-step stair-climb test required subjects to ascend a
staircase with step rise of 17 cm as fast as possible with time
recorded by activation of switchmats on the 8th and 12th
stair ( 15 , 20 , 21 ). The test – retest reliability is 0.85 and coef-
cients of variation 2%. After familiarization, two trials
were given with the best time taken as the stair-climb score.
Power was calculated from the time elapsed, body weight,
and vertical distance.
Fractional Protein Synthesis Rates
On days 1 and 20, at 7 am , an 18-gauge catheter was
inserted into the forearm vein of each arm, one for blood
sampling and one for tracer infusion. Baseline blood sam-
ples were drawn for analysis of amino acid enrichments from
one arm, heated with a heating pad. At 8 am , a primed
(2.0 μ mol / kg) constant infusion (0.06 μ mol / kg / min utes ) of
l -[ring- 13 C 6 ] phenylalanine was started and maintained for
6 hours. Venous blood was obtained at 0, 60, 120, 150, 165,
180, 195, 210, 240, 300, 330, 345, and 360 min utes during
the infusion. Two muscle biopsies (100 300 mg) were taken
at 180 and 360 min utes from vastus lateralis, ~ 10 to 15 cm
above the knee, using a 5-mm Bergstrom biopsy needle, and
snap frozen in liquid nitrogen for storage in a 80 ° C freezer
until analysis.
Phenylalanine enrichments in arterialized venous blood
was determined after deproteinization with sulfosalicylic acid,
extraction with cation exchange chromatography (Dowex AG
50W-8X, 100 200 mesh H+ form; BioRad Laboratories,
Richmond, CA), derivatization using tert -butyldimethylsilyl,
followed by gas chromatography – mass spectrometry in
electron impact mode (GC HP 5890, MSD HP 5989, Hewlett
Packard, Palo Alto, CA ; 22 ).
Muscle samples were weighed and the proteins precipi-
tated with 800 μ l of 10% sulfosalicylic acid. Intracellular
phenylalanine enrichment was determined by extraction
with cation exchange chromatography (Dowex AG 50W-8X,
200 400 mesh H+ form; BioRad Laboratories, Inc.), tert -
butyldimethylsilyl derivatization, and gas chromatography
mass spectrometry in electron impact mode ( 22 ). The
remaining pellet containing bound mixed-muscle proteins
was repeatedly washed, dried at 50°C overnight , and hydro-
lyzed in 3 mL of 6 N HCL at 110 ° C for 24 hours. Amino
acids in the hydrolysate were extracted and derivatized and
analyzed by monitoring the ions 238 and 240 ( 22 ).
Mixed - muscle FSR was calculated by measuring the
incorporation of l -[ring- 13 C 6 ]-phenylalanine into protein
using the precursor – product model:
= − ××
P2 P1 M
FSR [( ) /( )]60 100,E E Et
where E P1 and E P2 are enrichments of bound l -[ring- 13 C 6 ]-
phenylalanine in the fi rst and second muscle biopsies, t is the
time between biopsies, and E M is the mean l -[ring- 13 C 6 ]-
phenylalanine enrichment in muscle intracellular pool ( 22 ).
Hormone Assays
Total testosterone was measured using liquid chroma-
tography – tandem mass spectrometry ( 23 ) , and free testos-
terone was calculated using a published law-of-mass-action
equation ( 24 ). Serum luteinizing hormone , follicle-stimulating
hormone , and sex hormone – binding globulin were mea-
sured using two site - directed immunofl uorometric assays
( 9 , 21 ).
Statistical Analyses
Safety parameters were listed and summarized by study
intervention, dose, and time point. Adverse events were
tabulated by System Organ Class and Preferred Term based
on MedDRA dictionary version 12.
Plasma drug concentration time data were analyzed using
noncompartmental methods. PK parameters were summa-
rized by dose group , and selected PK parameters were
analyzed using comparative statistics. Dose proportionality
of PK parameters was assessed by linear regression.
Pharmacodynamic assessments were summarized for each
dose and time point. Changes from baseline in hormone levels,
lipids, and FSR were analyzed using repeated measures
analyses of variance, with a dose factor and time-in-treatment
factor and baseline value as covariate. A similar approach
was used to analyze change from baseline in LBM, one rep-
etition maximum strength , and stair-climbing power.
For dual-energy x-ray absorptiometry , muscle strength,
and stair-climbing power, a trend analysis of change from
baseline was applied using a mixed-model analysis of re-
peated measures and adjusted for baseline value. Two post-
baseline measures up to day 28 were utilized in repeated
measure model. This analysis was performed on evaluable
subjects who had baseline measures and at least one
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 89
BASARIA ET AL.
2
ligands that are tissue selective ( 8 , 16 , 17 , 18 , 19 ). The last
decade has witnessed substantial pharmaceutical efforts to
develop nonsteroidal SARMs to treat muscle wasting and
functional limitations associated with acute and chronic ill-
ness and aging ( 8 , 16 , 17 , 18 , 19 ). LGD-4033 is a novel non-
steroidal, oral SARM that binds to androgen receptor with
high affi nity (Ki of ~ 1 nM) and selectivity. In animal models,
LGD-4033 has demonstrated anabolic activity in the mus-
cle, anti-resorptive and anabolic activity in bone, and robust
selectivity for muscle versus prostate.
Here we report the results of a randomized, double-blind,
placebo-controlled, ascending-dose study, which evaluated
the safety, tolerability, and pharmacokinetics (PK) of LGD-
4033 in healthy men. We also evaluated the effects of graded
doses of LGD-4033 on lean body mass (LBM), muscle
strength , and physical function. LGD-4033 doses of 0.1,
0.3, and 1.0 mg were selected for multiple dosing over 21
days because a previous phase I single ascending-dose study
had established the safety of up to 22 mg LGD-4033. We also
tested the hypothesis that the LGD-4033 increases muscle
mass by stimulating fractional synthetic rate (FSR) of mixed -
muscle proteins, measured using continuous steady state
infusion of labeled phenylalanine in men randomized to either
placebo or 0.3-mg daily dose of LGD-4033. This dose was
selected for FSR study because preclinical data suggested
that this dose was the most likely to increase LBM.
Study Design
This was a double-blind, placebo-controlled, multiple
once-daily dose escalation study of LGD-4033 in healthy
men, approved by Boston University s Institutional Review
Board. All subjects provided written, informed consent.
Subjects
Nonsmoking, healthy men, 21 50 years, with body mass
index between 18 and 32 kg/m
2 , who were capable of
providing informed consent, were eligible. We excluded
subjects who had an active disease, prostate-specifi c antigen
>3 ng/mL, aspartate aminotransferase or ALT >1.5 times the
upper limit of normal, hematocrit <37% or >48%, creatinine
>2.0 mg/dL, and (HDL) cholesterol <40 mg/dL ; had used
anabolic steroids, recombinant human growth hormone,
dehydroepiandrosterone , and androstenedione during the
past year ; or were using any recreational drug.
Study Intervention
Three dose levels — 0.1, 0.3 , and 1.0 mg — were evalu-
ated against placebo. Each dose of LGD-4033 or placebo
was administered daily orally with 8 ounces of water
after an overnight fast. A total of 20 doses were adminis-
tered over 21 days; no dose was given on day 2 to allow
PK sampling for 48 hours after the fi rst dose. The 21-day
treatment period was followed by a 5-week observation
period.
Randomization
The subjects were randomized to the active drug or
placebo group based on protocol-defi ned randomization
schema: six active and two placebo in 0.1-mg cohort; 10 12
active and 10 12 placebo in 0.3-mg and 1.0-mg cohorts.
A protocol amendment after the completion of 1.0-mg
cohort added 12 active and six placebo subjects in the
0.1-mg cohort. Randomization lists, generated by the
biostatistician, were sent directly to Investigational Drug
Service.
The subjects were initially assigned to either placebo or
0.1 mg LGD-4033 daily. At the completion of each dose
level, the safety data were reviewed by a Safety Panel and
separately by a Data and Safety Monitoring Board, which
determined whether the dose could be escalated to a higher
level, based on prespecifi ed safety criteria. Dose escalation
proceeded only if an acceptable safety profi le with no clini-
cally signifi cant and/or unexpected toxicity was observed at
the lower dose.
Blinding
The study was a double-blind trial with concealed ran-
domization. The subjects and study personnel were unaware
of the intervention. Only the biostatistician and Investi-
gational Drug Service were aware of the subject s group
allocation. The Investigational Drug Service maintained the
randomization code and dispensed the study medication
based on the randomization list.
Outcomes
The primary aim was to assess the safety and tolerability
of escalating doses of LGD-4033 following repeated once-
daily oral administration for 21 days. Secondary aims included
the determination of the PK and pharmacodynamics of
LGD-4033 and its effects on mixed - muscle FSR. Addition-
ally, we investigated the effects of 21 days of treatment with
LGD-4033 on LBM measured by dual - energy x-ray absorp-
tiometry, maximal voluntary strength measured by one rep-
etition maximum method, and physical function, assessed
by the stair-climbing power, recognizing that a 21-day dura-
tion may not be suffi ciently long to fully elucidate the
anabolic effects of the SARM on LBM, muscle strength,
and physical function.
Schedule of Events
LGD-4033 concentrations were measured using a vali-
dated liquid chromatographic – tandem mass spectrometry
method in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6, 8,
10, 12, 24, 28, 32, and 48 hours after the fi rst dose. Once-
daily dosing recommenced on day 3 for 20 days , and on day
21, venous blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10,
12, 24, 28, 32, 48, 72, 96, 120 , and 168 hours after day 21
dosing.
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 3
Luteinizing hormone, follicle-stimulating hormone,
adrenocorticotropic hormone, cortisol, total and free testos-
terone, sex hormone – binding globulin levels, and plasma
lipids were measured periodically throughout the 21-day
intervention period and 7 and 35 days after drug cessation.
LBM and fat mass were measured at baseline and on days
20 and 28. Leg press strength and stair-climbing power and
speed were assessed at baseline and between days 23 and 25.
M ethods
Body composition was assessed using dual-energy x-ray
absorptiometry (Hologic 4500) scanner, calibrated using a
soft tissue phantom before each scan. To measure the leg
press strength ( 15 , 20 , 21 ), subjects underwent whole-body
warm up, followed by one set of 5 10 repetitions using
40 % 60% of the estimated maximum. Following appropriate
rest periods between attempts, subjects lifted progressively
heavier weights until the subject could not complete the lift.
The last successfully completed lift was recorded as the one
repetition maximum .
The 12-step stair-climb test required subjects to ascend a
staircase with step rise of 17 cm as fast as possible with time
recorded by activation of switchmats on the 8th and 12th
stair ( 15 , 20 , 21 ). The test – retest reliability is 0.85 and coef-
cients of variation 2%. After familiarization, two trials
were given with the best time taken as the stair-climb score.
Power was calculated from the time elapsed, body weight,
and vertical distance.
Fractional Protein Synthesis Rates
On days 1 and 20, at 7 am , an 18-gauge catheter was
inserted into the forearm vein of each arm, one for blood
sampling and one for tracer infusion. Baseline blood sam-
ples were drawn for analysis of amino acid enrichments from
one arm, heated with a heating pad. At 8 am , a primed
(2.0 μ mol / kg) constant infusion (0.06 μ mol / kg / min utes ) of
l -[ring- 13 C 6 ] phenylalanine was started and maintained for
6 hours. Venous blood was obtained at 0, 60, 120, 150, 165,
180, 195, 210, 240, 300, 330, 345, and 360 min utes during
the infusion. Two muscle biopsies (100 300 mg) were taken
at 180 and 360 min utes from vastus lateralis, ~ 10 to 15 cm
above the knee, using a 5-mm Bergstrom biopsy needle, and
snap frozen in liquid nitrogen for storage in a 80 ° C freezer
until analysis.
Phenylalanine enrichments in arterialized venous blood
was determined after deproteinization with sulfosalicylic acid,
extraction with cation exchange chromatography (Dowex AG
50W-8X, 100 200 mesh H+ form; BioRad Laboratories,
Richmond, CA), derivatization using tert -butyldimethylsilyl,
followed by gas chromatography – mass spectrometry in
electron impact mode (GC HP 5890, MSD HP 5989, Hewlett
Packard, Palo Alto, CA ; 22 ).
Muscle samples were weighed and the proteins precipi-
tated with 800 μ l of 10% sulfosalicylic acid. Intracellular
phenylalanine enrichment was determined by extraction
with cation exchange chromatography (Dowex AG 50W-8X,
200 400 mesh H+ form; BioRad Laboratories, Inc.), tert -
butyldimethylsilyl derivatization, and gas chromatography
mass spectrometry in electron impact mode ( 22 ). The
remaining pellet containing bound mixed-muscle proteins
was repeatedly washed, dried at 50°C overnight , and hydro-
lyzed in 3 mL of 6 N HCL at 110 ° C for 24 hours. Amino
acids in the hydrolysate were extracted and derivatized and
analyzed by monitoring the ions 238 and 240 ( 22 ).
Mixed - muscle FSR was calculated by measuring the
incorporation of l -[ring- 13 C 6 ]-phenylalanine into protein
using the precursor – product model:
= − ××
P2 P1 M
FSR [( ) /( )]60 100,E E Et
where E P1 and E P2 are enrichments of bound l -[ring- 13 C 6 ]-
phenylalanine in the fi rst and second muscle biopsies, t is the
time between biopsies, and E M is the mean l -[ring- 13 C 6 ]-
phenylalanine enrichment in muscle intracellular pool ( 22 ).
Hormone Assays
Total testosterone was measured using liquid chroma-
tography – tandem mass spectrometry ( 23 ) , and free testos-
terone was calculated using a published law-of-mass-action
equation ( 24 ). Serum luteinizing hormone , follicle-stimulating
hormone , and sex hormone – binding globulin were mea-
sured using two site - directed immunofl uorometric assays
( 9 , 21 ).
Statistical Analyses
Safety parameters were listed and summarized by study
intervention, dose, and time point. Adverse events were
tabulated by System Organ Class and Preferred Term based
on MedDRA dictionary version 12.
Plasma drug concentration time data were analyzed using
noncompartmental methods. PK parameters were summa-
rized by dose group , and selected PK parameters were
analyzed using comparative statistics. Dose proportionality
of PK parameters was assessed by linear regression.
Pharmacodynamic assessments were summarized for each
dose and time point. Changes from baseline in hormone levels,
lipids, and FSR were analyzed using repeated measures
analyses of variance, with a dose factor and time-in-treatment
factor and baseline value as covariate. A similar approach
was used to analyze change from baseline in LBM, one rep-
etition maximum strength , and stair-climbing power.
For dual-energy x-ray absorptiometry , muscle strength,
and stair-climbing power, a trend analysis of change from
baseline was applied using a mixed-model analysis of re-
peated measures and adjusted for baseline value. Two post-
baseline measures up to day 28 were utilized in repeated
measure model. This analysis was performed on evaluable
subjects who had baseline measures and at least one
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
90 BASARIA ET AL.
BASARIA ET AL.
4
post-baseline measure. Placebo subjects from the three co-
horts were pooled for analysis. This resulted in sample sizes
of 30 men for dual-energy x-ray absorptiometry analysis
and 29 men for muscle strength analysis in the placebo
group, 17 in the 0.1-mg, 10 in the 0.3-mg, and 11 in the 1.0-mg
dose groups.
R esults
Flow of Subjects
A total of 389 subjects were screened in person, 131 were
eligible , and 76 were randomized (CONSORT diagram,
Supplementary Appendix Figure 1 ). Eight subjects were
either lost to follow-up or discontinued and 68 subjects
completed the trial.
Subjects
The participants were young (mean age 37 years), lean
( body mass index 25.8 kg/m
2 ) , and had normal testosterone,
luteinizing hormone , and follicle-stimulating hormone
levels ( Table 1 ). The groups were similar in their baseline
characteristics.
Compliance
The compliance, assessed by drug logs and by counting
the unused tablets, was 100%, among men who were included
in the effi cacy analysis.
Safety Data
LGD-4033 was safe and well tolerated at all doses. The
frequency of adverse events was similar between the pla-
cebo and any dose group. Headache, pain related to muscle
biopsy, and dry mouth were the most common events and
did not show dose relationship ( Supplementary Appendix
Table 1 ). More upper respiratory tract infections were
observed in LGD-4033 1.0 - mg group , but these events were
not considered drug related. No drug-related severe or serious
adverse events occurred. One cellulitis (in placebo group)
and one gastroenteritis (0.3 mg group) were severe but were
not considered study drug related. There was no study dis-
continuation due to adverse events. There were no clinically
signifi cant changes in liver enzymes, hematocrit, prostate-
specifi c antigen , or electrocardiogram at any dose.
Pharmacokinetics
LGD-4033 displayed a prolonged elimination half-life
(24 36 hours) and linear PK ( Figure 1 ). There was a dose -
proportional increase in LGD-4033 concentrations on
days 1 and 21. Serum LGD-4033 concentrations were nearly
threefold higher on day 21 than on day 1, refl ecting accu-
mulation upon multiple dosing. The mean areas under the
drug concentration curve on day 21 were 19, 85 , and 238 ng
24 hour/mL, respectively, in men receiving 0.1, 0.3, and 1.0 mg
LGD-4033 daily.
Hormone Levels
There was a dose-dependent suppression of total testos-
terone and sex hormone binding globulin levels from
baseline to day 21 ( Figure 2 ). Free testosterone suppres-
sion was noted at the 1.0-mg dose only. The suppression of
total testosterone was greater than that of free testoster-
one. Serum luteinizing hormone levels did not show any
meaningful changes from baseline, whereas the follicle-
stimulating hormone levels were suppressed only in the
1.0-mg dose group ( Figure 2D and E ). Upon discontinua-
tion of LGD-4033, the hormone levels returned to baseline
by day 56.
Table 1. Baseline Characteristics of the Subjects
Placebo/LGD Dose Group Placebo
LGD-4033 Doses
All Subjects 0.1 mg 0.3 mg 1 mg
N 33 18 11 14 76
Age (years) 36.0 (9.4) 37.0 (10.4) 35.6 (8.4) 40.9 (8.7) 37.1 (9.4)
Body weight (kg) 81.5 (13.6) 78.2 (13.9) 80.5 (13.5) 84.6 (10.2) 81.2 (13.0)
Height (cm) 176.8 (6.4) 178.0 (9.6) 175.3 (7.3) 176.8 (6.9) 176.9 (7.4)
Body mass index (kg/m
2 ) 25.9 (3.4) 24.6 (3.0) 26.2 (3.5) 27.0 (2.7) 25.8 (3.3)
TESTO (ng/dL) 549 (136) 564 (153) 543 (111) 551 (144) 552 (136)
FT (ng/dL) 11.39 (3.11) 11.4 (3.1) 11.4 (3.4) 11.36 (3.3) 11.2 (3.1)
Sex hormone binding globulin (nmol/L) 34.1 (11.7) 37.5 (21.6) 34.0 (8.6) 36.4 (11.1) 35.3 (14.1)
Luteinizing hormone (U/L) 3.9 (1.9) 3.6 (1.5) 3.0 (0.7) 3.7 (1.1) 3.7 (1.5)
Follicle-stimulating hormone (U/L) 4.0 (3.4) 3.1 (2.1) 4.1 (2.0) 4.1 (2.2) 3.8 (2.7)
prostate-specifi c antigen (ng/mL) 0.8 (0.5) 1.3 (1.6) 0.7 (0.2) 0.8 (0.5) 0.9 (0.9)
Lean body mass (kg) 60.6 (9.1) 58.9 (7.6) 60.6 (8.7) 63.9 (4.7) 60.7 (8.1)
Fat mass (kg) 16.4 (7.5) 13.3 (7.5) 15.7 (5.5) 17.2 (6.5) 15.7 (7.0)
Leg press strength (N) 1440.6 (381.0) 1364.8 (298.8) 1535.0 (287.1) 1476.1 (247.6) 1441.3 (326.8)
Stair-climbing power (W) 659.3 (123.1) 614.2 (125.3) 678.7 (98.4) 665.9 (136.8) 651.8 (122.2)
Notes : The subjects assigned to the placebo group in each of the three cohorts were pooled for the purpose of analyses. Data are mean ± ( SD ). The number of
subjects in each group is shown in row 2. FT= free testosterone; TESTO = testosterone.
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 5
Plasma Lipids
Total and low density lipoprotein (LDL) cholesterol did
not change signifi cantly from baseline at any dose ( Table 2 ).
HDL cholesterol decreased from baseline at doses 0.3 mg;
HDL cholesterol returned to baseline after treatment discon-
tinuation ( Table 2 ). Triglyceride levels decreased from
baseline across all doses.
Body Composition
LBM increased dose dependently ( p for trend = .04 ;
Figure 3A ). The increase in LBM averaged 1.21 kg at the
1.0 - mg dose ( p = .047 vs placebo). The increase in LBM
was correlated with the dose. Fat mass ( Figure 3B ) did not
change signifi cantly. The increase in appendicular skeletal
muscle mass in the 0.3 - and 1.0 - mg groups was not signifi -
cantly differently from that in the placebo group (change
from baseline 0.2, 0.04, 0.47 , and 0.37 kg for the placebo,
0.1, 0.3, and 1.0-mg groups, p for trend = .078).
L4033-2: Day 1 PK
0.1
1
10
100
0
10 20 30 40 50
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=6)
Cohort 2- 0.3 mg (n=11)
Cohort 3- 1 mg (n=14)
L4033-2: Day 21 PK
0.1
1
10
100
0
30 60 90 120 150 180
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=5)
Cohort 2- 0.3 mg (n=10)
Cohort 3- 1 mg (n=11)
Figure 1 . Pharmacokinetics of LGD-4033 in Healthy Men. Legend.LGD-4033
concentrations were measured in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6,
8, 10, 12, 24, 28, 32, and 48 hours after the fi rst dose (upper panel). Once-daily
dosing recommenced on day 3. On day 21, venous blood was collected at 0, 0.5,
1, 2, 3, 4, 6, 8, 10, 12, 24, 28, 32, 48, 72, 96, 120, and 168 hours after day 21
dosing (lower panel).
Muscle Performance and Physical Function
The increase in strength averaged 68.3 N at the 1.0-mg
dose, but this change was not signifi cantly different from
that in the placebo group ( Figure 3C ). Stair - climbing speed
and power revealed a trend toward dose-related improvement,
but these changes did not achieve statistical signifi cance.
Fractional Mixed - Muscle Protein Synthesis Rates
Plasma phenylalanine concentrations did not change sig-
nifi cantly from 180 to 360 min utes indicating achievement
of a steady state. Baseline FSR averaged ~ 6% / h , consistent
with published literature. The change in FSR from baseline,
measured in the fasted state, did not differ signifi cantly
between 0.3-mg dose and the placebo groups (0.033 ± 0.016
vs 0.031 ± 0.011, p = .99 ; Supplementary Appendix Table 2 ).
D iscussion
LGD-4033 was safe and well tolerated over the range of
doses that were evaluated over a 3-week period. Even dur-
ing this short treatment period, there was clear evidence of
the compound s androgenic activity, as refl ected in the
increase in LBM, and signifi cant suppression of testosterone,
sex hormone – binding globulin , and HDL cholesterol levels.
In spite of demonstrable androgenic activity, serum prostate-
specifi c antigen did not change signifi cantly. The study also
revealed other attractive PK attributes of the drug including
a prolonged circulating half-life, dose - proportional systemic
exposure, and robust relationships between the dose and
outcomes. The gains in LBM were similar to those reported
with another SARM ( 17 ), although the treatment duration
in the latter trial was substantially longer (12 weeks).
The study had many features of a good trial design; sub-
ject allocation by randomization, concealed randomization,
blinding, and independent appraisal of safety data by a Data
and Safety Monitoring Board . By virtue of being an ascending-
dose study, the study also had some inherent constraints.
The doses of study medication were administered sequen-
tially in ascending order rather than in random order. The
sample size, although substantially larger than in most
phase I ascending - dose studies, was not based on consider-
ations of effect sizes, as the study s primary aim was to
establish safety and tolerability rather than effi cacy. Similarly,
the 3 -week study duration was not designed to demonstrate
maximal effects on skeletal muscle mass and muscle strength
which were not the primary outcomes of the trial. In light of
these inherent constraints, it is particularly remarkable that
signifi cant dose-dependent gains in LBM were evident in
this short duration, indicating this SARM s substantial
androgenic anabolic activity on the skeletal muscle.
Several attractive PK features of this SARM are notewor-
thy. Its prolonged elimination half - life renders it amenable
to once daily or even a less frequent dosing regimen.
Daily administration of the drug was associated with dose-
proportional increase in systemic exposure resulting in
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 91
BASARIA ET AL.
4
post-baseline measure. Placebo subjects from the three co-
horts were pooled for analysis. This resulted in sample sizes
of 30 men for dual-energy x-ray absorptiometry analysis
and 29 men for muscle strength analysis in the placebo
group, 17 in the 0.1-mg, 10 in the 0.3-mg, and 11 in the 1.0-mg
dose groups.
R esults
Flow of Subjects
A total of 389 subjects were screened in person, 131 were
eligible , and 76 were randomized (CONSORT diagram,
Supplementary Appendix Figure 1 ). Eight subjects were
either lost to follow-up or discontinued and 68 subjects
completed the trial.
Subjects
The participants were young (mean age 37 years), lean
( body mass index 25.8 kg/m
2 ) , and had normal testosterone,
luteinizing hormone , and follicle-stimulating hormone
levels ( Table 1 ). The groups were similar in their baseline
characteristics.
Compliance
The compliance, assessed by drug logs and by counting
the unused tablets, was 100%, among men who were included
in the effi cacy analysis.
Safety Data
LGD-4033 was safe and well tolerated at all doses. The
frequency of adverse events was similar between the pla-
cebo and any dose group. Headache, pain related to muscle
biopsy, and dry mouth were the most common events and
did not show dose relationship ( Supplementary Appendix
Table 1 ). More upper respiratory tract infections were
observed in LGD-4033 1.0 - mg group , but these events were
not considered drug related. No drug-related severe or serious
adverse events occurred. One cellulitis (in placebo group)
and one gastroenteritis (0.3 mg group) were severe but were
not considered study drug related. There was no study dis-
continuation due to adverse events. There were no clinically
signifi cant changes in liver enzymes, hematocrit, prostate-
specifi c antigen , or electrocardiogram at any dose.
Pharmacokinetics
LGD-4033 displayed a prolonged elimination half-life
(24 36 hours) and linear PK ( Figure 1 ). There was a dose -
proportional increase in LGD-4033 concentrations on
days 1 and 21. Serum LGD-4033 concentrations were nearly
threefold higher on day 21 than on day 1, refl ecting accu-
mulation upon multiple dosing. The mean areas under the
drug concentration curve on day 21 were 19, 85 , and 238 ng
24 hour/mL, respectively, in men receiving 0.1, 0.3, and 1.0 mg
LGD-4033 daily.
Hormone Levels
There was a dose-dependent suppression of total testos-
terone and sex hormone binding globulin levels from
baseline to day 21 ( Figure 2 ). Free testosterone suppres-
sion was noted at the 1.0-mg dose only. The suppression of
total testosterone was greater than that of free testoster-
one. Serum luteinizing hormone levels did not show any
meaningful changes from baseline, whereas the follicle-
stimulating hormone levels were suppressed only in the
1.0-mg dose group ( Figure 2D and E ). Upon discontinua-
tion of LGD-4033, the hormone levels returned to baseline
by day 56.
Table 1. Baseline Characteristics of the Subjects
Placebo/LGD Dose Group Placebo
LGD-4033 Doses
All Subjects 0.1 mg 0.3 mg 1 mg
N 33 18 11 14 76
Age (years) 36.0 (9.4) 37.0 (10.4) 35.6 (8.4) 40.9 (8.7) 37.1 (9.4)
Body weight (kg) 81.5 (13.6) 78.2 (13.9) 80.5 (13.5) 84.6 (10.2) 81.2 (13.0)
Height (cm) 176.8 (6.4) 178.0 (9.6) 175.3 (7.3) 176.8 (6.9) 176.9 (7.4)
Body mass index (kg/m
2 ) 25.9 (3.4) 24.6 (3.0) 26.2 (3.5) 27.0 (2.7) 25.8 (3.3)
TESTO (ng/dL) 549 (136) 564 (153) 543 (111) 551 (144) 552 (136)
FT (ng/dL) 11.39 (3.11) 11.4 (3.1) 11.4 (3.4) 11.36 (3.3) 11.2 (3.1)
Sex hormone binding globulin (nmol/L) 34.1 (11.7) 37.5 (21.6) 34.0 (8.6) 36.4 (11.1) 35.3 (14.1)
Luteinizing hormone (U/L) 3.9 (1.9) 3.6 (1.5) 3.0 (0.7) 3.7 (1.1) 3.7 (1.5)
Follicle-stimulating hormone (U/L) 4.0 (3.4) 3.1 (2.1) 4.1 (2.0) 4.1 (2.2) 3.8 (2.7)
prostate-specifi c antigen (ng/mL) 0.8 (0.5) 1.3 (1.6) 0.7 (0.2) 0.8 (0.5) 0.9 (0.9)
Lean body mass (kg) 60.6 (9.1) 58.9 (7.6) 60.6 (8.7) 63.9 (4.7) 60.7 (8.1)
Fat mass (kg) 16.4 (7.5) 13.3 (7.5) 15.7 (5.5) 17.2 (6.5) 15.7 (7.0)
Leg press strength (N) 1440.6 (381.0) 1364.8 (298.8) 1535.0 (287.1) 1476.1 (247.6) 1441.3 (326.8)
Stair-climbing power (W) 659.3 (123.1) 614.2 (125.3) 678.7 (98.4) 665.9 (136.8) 651.8 (122.2)
Notes : The subjects assigned to the placebo group in each of the three cohorts were pooled for the purpose of analyses. Data are mean ± ( SD ). The number of
subjects in each group is shown in row 2. FT= free testosterone; TESTO = testosterone.
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 5
Plasma Lipids
Total and low density lipoprotein (LDL) cholesterol did
not change signifi cantly from baseline at any dose ( Table 2 ).
HDL cholesterol decreased from baseline at doses 0.3 mg;
HDL cholesterol returned to baseline after treatment discon-
tinuation ( Table 2 ). Triglyceride levels decreased from
baseline across all doses.
Body Composition
LBM increased dose dependently ( p for trend = .04 ;
Figure 3A ). The increase in LBM averaged 1.21 kg at the
1.0 - mg dose ( p = .047 vs placebo). The increase in LBM
was correlated with the dose. Fat mass ( Figure 3B ) did not
change signifi cantly. The increase in appendicular skeletal
muscle mass in the 0.3 - and 1.0 - mg groups was not signifi -
cantly differently from that in the placebo group (change
from baseline 0.2, 0.04, 0.47 , and 0.37 kg for the placebo,
0.1, 0.3, and 1.0-mg groups, p for trend = .078).
L4033-2: Day 1 PK
0.1
1
10
100
0
10 20 30 40 50
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=6)
Cohort 2- 0.3 mg (n=11)
Cohort 3- 1 mg (n=14)
L4033-2: Day 21 PK
0.1
1
10
100
0
30 60 90 120 150 180
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=5)
Cohort 2- 0.3 mg (n=10)
Cohort 3- 1 mg (n=11)
Figure 1 . Pharmacokinetics of LGD-4033 in Healthy Men. Legend.LGD-4033
concentrations were measured in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6,
8, 10, 12, 24, 28, 32, and 48 hours after the fi rst dose (upper panel). Once-daily
dosing recommenced on day 3. On day 21, venous blood was collected at 0, 0.5,
1, 2, 3, 4, 6, 8, 10, 12, 24, 28, 32, 48, 72, 96, 120, and 168 hours after day 21
dosing (lower panel).
Muscle Performance and Physical Function
The increase in strength averaged 68.3 N at the 1.0-mg
dose, but this change was not signifi cantly different from
that in the placebo group ( Figure 3C ). Stair - climbing speed
and power revealed a trend toward dose-related improvement,
but these changes did not achieve statistical signifi cance.
Fractional Mixed - Muscle Protein Synthesis Rates
Plasma phenylalanine concentrations did not change sig-
nifi cantly from 180 to 360 min utes indicating achievement
of a steady state. Baseline FSR averaged ~ 6% / h , consistent
with published literature. The change in FSR from baseline,
measured in the fasted state, did not differ signifi cantly
between 0.3-mg dose and the placebo groups (0.033 ± 0.016
vs 0.031 ± 0.011, p = .99 ; Supplementary Appendix Table 2 ).
D iscussion
LGD-4033 was safe and well tolerated over the range of
doses that were evaluated over a 3-week period. Even dur-
ing this short treatment period, there was clear evidence of
the compound s androgenic activity, as refl ected in the
increase in LBM, and signifi cant suppression of testosterone,
sex hormone – binding globulin , and HDL cholesterol levels.
In spite of demonstrable androgenic activity, serum prostate-
specifi c antigen did not change signifi cantly. The study also
revealed other attractive PK attributes of the drug including
a prolonged circulating half-life, dose - proportional systemic
exposure, and robust relationships between the dose and
outcomes. The gains in LBM were similar to those reported
with another SARM ( 17 ), although the treatment duration
in the latter trial was substantially longer (12 weeks).
The study had many features of a good trial design; sub-
ject allocation by randomization, concealed randomization,
blinding, and independent appraisal of safety data by a Data
and Safety Monitoring Board . By virtue of being an ascending-
dose study, the study also had some inherent constraints.
The doses of study medication were administered sequen-
tially in ascending order rather than in random order. The
sample size, although substantially larger than in most
phase I ascending - dose studies, was not based on consider-
ations of effect sizes, as the study s primary aim was to
establish safety and tolerability rather than effi cacy. Similarly,
the 3 -week study duration was not designed to demonstrate
maximal effects on skeletal muscle mass and muscle strength
which were not the primary outcomes of the trial. In light of
these inherent constraints, it is particularly remarkable that
signifi cant dose-dependent gains in LBM were evident in
this short duration, indicating this SARM s substantial
androgenic anabolic activity on the skeletal muscle.
Several attractive PK features of this SARM are notewor-
thy. Its prolonged elimination half - life renders it amenable
to once daily or even a less frequent dosing regimen.
Daily administration of the drug was associated with dose-
proportional increase in systemic exposure resulting in
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 5
Plasma Lipids
Total and low density lipoprotein (LDL) cholesterol did
not change signifi cantly from baseline at any dose ( Table 2 ).
HDL cholesterol decreased from baseline at doses 0.3 mg;
HDL cholesterol returned to baseline after treatment discon-
tinuation ( Table 2 ). Triglyceride levels decreased from
baseline across all doses.
Body Composition
LBM increased dose dependently ( p
for trend = .04 ;
Figure 3A ). The increase in LBM averaged 1.21 kg at the
1.0 - mg dose ( p
= .047 vs placebo). The increase in LBM
was correlated with the dose. Fat mass ( Figure 3B ) did not
change signifi cantly. The increase in appendicular skeletal
muscle mass in the 0.3 - and 1.0 - mg groups was not signifi -
cantly differently from that in the placebo group (change
from baseline 0.2, 0.04, 0.47 , and 0.37 kg for the placebo,
0.1, 0.3, and 1.0-mg groups, p for trend = .078).
L4033-2: Day 1 PK
0.1
1
10
100
0
10 20 30 40 50
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=6)
Cohort 2- 0.3 mg (n=11)
Cohort 3- 1 mg (n=14)
L4033-2: Day 21 PK
0.1
1
10
100
0
30 60 90 120 150 180
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=5)
Cohort 2- 0.3 mg (n=10)
Cohort 3- 1 mg (n=11)
Figure 1 . Pharmacokinetics of LGD-4033 in Healthy Men. Legend.LGD-4033
concentrations were measured in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6,
8, 10, 12, 24, 28, 32, and 48 hours after the fi rst dose (upper panel). Once-daily
dosing recommenced on day 3. On day 21, venous blood was collected at 0, 0.5,
1, 2, 3, 4, 6, 8, 10, 12, 24, 28, 32, 48, 72, 96, 120, and 168 hours after day 21
dosing (lower panel).
Muscle Performance and Physical Function
The increase in strength averaged 68.3 N at the 1.0-mg
dose, but this change was not signifi cantly different from
that in the placebo group ( Figure 3C ). Stair - climbing speed
and power revealed a trend toward dose-related improvement,
but these changes did not achieve statistical signifi cance.
Fractional Mixed - Muscle Protein Synthesis Rates
Plasma phenylalanine concentrations did not change sig-
nifi cantly from 180 to 360 min utes indicating achievement
of a steady state. Baseline FSR averaged ~ 6% / h , consistent
with published literature. The change in FSR from baseline,
measured in the fasted state, did not differ signifi cantly
between 0.3-mg dose and the placebo groups (0.033 ± 0.016
vs 0.031 ± 0.011, p = .99 ; Supplementary Appendix Table 2 ).
D iscussion
LGD-4033 was safe and well tolerated over the range of
doses that were evaluated over a 3-week period. Even dur-
ing this short treatment period, there was clear evidence of
the compound s androgenic activity, as refl ected in the
increase in LBM, and signifi cant suppression of testosterone,
sex hormone – binding globulin , and HDL cholesterol levels.
In spite of demonstrable androgenic activity, serum prostate-
specifi c antigen did not change signifi cantly. The study also
revealed other attractive PK attributes of the drug including
a prolonged circulating half-life, dose - proportional systemic
exposure, and robust relationships between the dose and
outcomes. The gains in LBM were similar to those reported
with another SARM ( 17 ), although the treatment duration
in the latter trial was substantially longer (12 weeks).
The study had many features of a good trial design; sub-
ject allocation by randomization, concealed randomization,
blinding, and independent appraisal of safety data by a Data
and Safety Monitoring Board . By virtue of being an ascending-
dose study, the study also had some inherent constraints.
The doses of study medication were administered sequen-
tially in ascending order rather than in random order. The
sample size, although substantially larger than in most
phase I ascending - dose studies, was not based on consider-
ations of effect sizes, as the study s primary aim was to
establish safety and tolerability rather than effi cacy. Similarly,
the 3 -week study duration was not designed to demonstrate
maximal effects on skeletal muscle mass and muscle strength
which were not the primary outcomes of the trial. In light of
these inherent constraints, it is particularly remarkable that
signifi cant dose-dependent gains in LBM were evident in
this short duration, indicating this SARM s substantial
androgenic anabolic activity on the skeletal muscle.
Several attractive PK features of this SARM are notewor-
thy. Its prolonged elimination half - life renders it amenable
to once daily or even a less frequent dosing regimen.
Daily administration of the drug was associated with dose-
proportional increase in systemic exposure resulting in
L4033-2: Day 1 PK
0.1
1
10
100
0
10 20 30 40 50
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=6)
Cohort 2- 0.3 mg (n=11)
Cohort 3- 1 mg (n=14)
L4033-2: Day 21 PK
0.1
1
10
100
0
30 60 90 120150 180
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=5)
Cohort 2- 0.3 mg (n=10)
Cohort 3- 1 mg (n=11)
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
92 BASARIA ET AL.
BASARIA ET AL.
6
AB
CD
EF
Figure 2. (A) The effects of LGD-4033 selective androgen receptor modulator on serum total testosterone levels. Change from baseline in serum total testosterone
levels are shown. The data are mean ± standard error of the mean ( SEM ) , n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in
the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( B ) Change in the free testosterone levels from baseline. Change from
baseline in serum free testosterone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and
14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( C ) Change in sex hormone binding globulin levels from baseline.
Change from baseline in serum sex hormone binding globulin levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose,
11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( D ) Change in luteinizing hormone
(U/L) levels from baseline. Change from baseline in serum luteinizing hormone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the
0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( E ) Change in follicle -
stimulating hormone (U/L) levels from baseline. Change from baseline in serum follicle-stimulating hormone levels is shown. The data are mean ± SEM, n = 33
in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment
period. ( F ) Change in prostate - specifi c antigen (ng/mL) levels from baseline. Change from baseline in prostate-specifi c antigen levels is shown. The data are mean ±
SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the
21-day treatment period.
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 7
predictable accumulation upon multiple dosing. There was
a robust relationship between the dose and the plasma con-
centrations. The mean area-under-the-curves (AUC) in men
receiving the 0.3 - and 1.0 - mg dose were above the drug
AUC estimated to be effi cacious in monkeys, and all three
doses produced AUCs that exceeded the AUC estimated to
be effi cacious in orchidectomized rats.
In a manner typical of all oral androgens ( 25 , 26 , 27 ), the
oral administration of LGD-4033 was associated with sig-
nifi cant suppression of HDL cholesterol at the 1.0-mg dose.
Triglyceride levels also decreased, but LDL cholesterol did
not change. Neither the mechanism nor the clinical signifi -
cance of the HDL suppression with orally administered
androgens is well understood ( 25 ). HDL cholesterol has
been negatively associated with the risk of coronary artery
disease in epidemiological studies ( 25 , 28 ); however, phar-
macologically induced changes in HDL cholesterol have
not been necessarily associated with changes in cardio-
vascular risk. In animal models, the degree of anti-atherogenic
effect of HDL cholesterol is determined more by the mech-
anism of HDL modifi cation than by the changes in HDL
levels ( 28 , 29 ). Thus, the increases in HDL cholesterol due
to overproduction of apoA1, but not due to inhibition of
HDL catabolism, have been found to be atheroprotective
( 28 , 29 , 30 , 31 , 32 ). The HDL lowering effect of oral androgens
has been attributed to the upregulation of scavenger receptor
B1 and the hepatic lipase, both of which are involved in HDL
catabolism ( 32 , 33 ). Neither the hyperexpression of scavenger
receptor B1 nor that of hepatic lipase has been associated
with acceleration of atherogenesis, even though increased
Table 2. The Effects of LGD-4033 Selective Androgen Receptor
Modulator on Plasma Lipids
Treatment Group *
Mean ( SD )
Baseline
Mean ( SE ) Change From
Baseline
Day 21 Day 56
Total cholesterol (mg/dL)
Placebo 163.4 (28.1) − 1.6 (2.9) 5.2 (4.2)
0.1 mg 163.3 (33.5) − 10.8 (3.6) 0.4 (5.5)
0.3 mg 168.6 (16.6) − 18.0 (4.8) 6.4 (5.0)
1 mg 175.1 (33.5) − 14.3 (8.1) 0.3 (4.4)
HDL cholesterol (mg/dL)
Placebo 52.5 (11.8) − 1.7 (1.2) 0.4 (1.8)
0.1 mg 56.1 (17.3) − 1.0 (2.6) 3.5 (2.3)
0.3 mg 50.3 (8.0) − 10.4 (1.4) 0.6 (1.7)
1 mg 49.2 (11.7) − 19.4 (2.1) − 1.1 (3.2)
LDL cholesterol (mg/dL)
Placebo 92.4 (26.2) 0.9 (2.6) 4.4 (3.7)
0.1 mg 91.0 (29.6) − 5.5 (3.3) − 4.5 (4.9)
0.3 mg 101.5 (15.9) − 2.8 (4.5) 1.7 (3.7)
1 mg 106.8 (31.6) 7.1 (7.1) 4.42 (4.0)
Triglycerides (mg/dL)
Placebo 92.6 (36.8) − 4.3 (4.7) 1.9 (7.5)
0.1 mg 80.0 (31.0 ) − 21.4 (8.1) 7.2 (9.1)
0.3 mg 84.4 (26.1) − 24.0 (4.3) 20.8 (8.0)
1 mg 95.4 (39.1) − 10.1 (6.7) − 15.6 (8.0)
Notes : * Number of subjects with at least one post - baseline test: placebo =
30, 0.1 mg = 17, 0.3 mg = 10 , and 1 mg = 14. LDL = Low density lipoprotein.
Total Body
PBO 0.1 mg 0.3 mg 1 mg
-0.5
0.0
0.5
1.0
1.5
2.0
*
*p =0.047 vs. Placebo
A
Total Body
PBO 0.1 mg 0.3 mg 1 mg
-1.0
-0.5
0.0
0.5
1.0
B
C
PBO 0.1 mg 0.3 mg 1 mg
-50
0
50
100
150
Change from Baseline (kg)
Change from Baseline (kg)
Change from Baseline (Newton)
Figure 3. (A) Mean ( SE ) lean mass (kg) change from baseline up to day 28.
Change from baseline in lean body mass is shown. The data are mean ± standard
error of the mean , n = 30 in the placebo group pooled from the three cohorts,
17 in the 0.1 - mg dose, 10 in the 0.3 - mg group, and 11 in the 1.0 - mg group. BL =
baseline. * p < .05 vs placebo. PBO = placebo; p for trend = .04. ( B ) Mean ( SE )
fat mass (kg) change from baseline up to day 28. Change from baseline in fat
mass is shown. The data are mean ± standard error of the mean , n = 30 in the
placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the
0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo. p for trend = .261.
( C ) Change in leg press strength (Newton) from baseline. Change from baseline
in fat mass is shown. The data are mean ± standard error of the mean , n = 30 in
the placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the
0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo; p for trend = .203.
expression of each is associated with reduced HDL cholesterol
( 28 , 29 , 30 , 31 ). Thus, clinical signifi cance of the HDL decrease
associated with oral androgens remains unclear. Long - term
studies are needed to clarify the effects of long-term SARM
administration on cardiovascular risk. In the interim, the
initial trials are likely to be conducted for acute or subacute
AB
CD
EF
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 93
BASARIA ET AL.
6
AB
CD
EF
Figure 2. (A) The effects of LGD-4033 selective androgen receptor modulator on serum total testosterone levels. Change from baseline in serum total testosterone
levels are shown. The data are mean ± standard error of the mean ( SEM ) , n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in
the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( B ) Change in the free testosterone levels from baseline. Change from
baseline in serum free testosterone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and
14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( C ) Change in sex hormone binding globulin levels from baseline.
Change from baseline in serum sex hormone binding globulin levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose,
11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( D ) Change in luteinizing hormone
(U/L) levels from baseline. Change from baseline in serum luteinizing hormone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the
0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( E ) Change in follicle -
stimulating hormone (U/L) levels from baseline. Change from baseline in serum follicle-stimulating hormone levels is shown. The data are mean ± SEM, n = 33
in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment
period. ( F ) Change in prostate - specifi c antigen (ng/mL) levels from baseline. Change from baseline in prostate-specifi c antigen levels is shown. The data are mean ±
SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the
21-day treatment period.
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 7
predictable accumulation upon multiple dosing. There was
a robust relationship between the dose and the plasma con-
centrations. The mean area-under-the-curves (AUC) in men
receiving the 0.3 - and 1.0 - mg dose were above the drug
AUC estimated to be effi cacious in monkeys, and all three
doses produced AUCs that exceeded the AUC estimated to
be effi cacious in orchidectomized rats.
In a manner typical of all oral androgens ( 25 , 26 , 27 ), the
oral administration of LGD-4033 was associated with sig-
nifi cant suppression of HDL cholesterol at the 1.0-mg dose.
Triglyceride levels also decreased, but LDL cholesterol did
not change. Neither the mechanism nor the clinical signifi -
cance of the HDL suppression with orally administered
androgens is well understood ( 25 ). HDL cholesterol has
been negatively associated with the risk of coronary artery
disease in epidemiological studies ( 25 , 28 ); however, phar-
macologically induced changes in HDL cholesterol have
not been necessarily associated with changes in cardio-
vascular risk. In animal models, the degree of anti-atherogenic
effect of HDL cholesterol is determined more by the mech-
anism of HDL modifi cation than by the changes in HDL
levels ( 28 , 29 ). Thus, the increases in HDL cholesterol due
to overproduction of apoA1, but not due to inhibition of
HDL catabolism, have been found to be atheroprotective
( 28 , 29 , 30 , 31 , 32 ). The HDL lowering effect of oral androgens
has been attributed to the upregulation of scavenger receptor
B1 and the hepatic lipase, both of which are involved in HDL
catabolism ( 32 , 33 ). Neither the hyperexpression of scavenger
receptor B1 nor that of hepatic lipase has been associated
with acceleration of atherogenesis, even though increased
Table 2. The Effects of LGD-4033 Selective Androgen Receptor
Modulator on Plasma Lipids
Treatment Group *
Mean ( SD )
Baseline
Mean ( SE ) Change From
Baseline
Day 21 Day 56
Total cholesterol (mg/dL)
Placebo 163.4 (28.1) − 1.6 (2.9) 5.2 (4.2)
0.1 mg 163.3 (33.5) − 10.8 (3.6) 0.4 (5.5)
0.3 mg 168.6 (16.6) − 18.0 (4.8) 6.4 (5.0)
1 mg 175.1 (33.5) − 14.3 (8.1) 0.3 (4.4)
HDL cholesterol (mg/dL)
Placebo 52.5 (11.8) − 1.7 (1.2) 0.4 (1.8)
0.1 mg 56.1 (17.3) − 1.0 (2.6) 3.5 (2.3)
0.3 mg 50.3 (8.0) − 10.4 (1.4) 0.6 (1.7)
1 mg 49.2 (11.7) − 19.4 (2.1) − 1.1 (3.2)
LDL cholesterol (mg/dL)
Placebo 92.4 (26.2) 0.9 (2.6) 4.4 (3.7)
0.1 mg 91.0 (29.6) − 5.5 (3.3) − 4.5 (4.9)
0.3 mg 101.5 (15.9) − 2.8 (4.5) 1.7 (3.7)
1 mg 106.8 (31.6) 7.1 (7.1) 4.42 (4.0)
Triglycerides (mg/dL)
Placebo 92.6 (36.8) − 4.3 (4.7) 1.9 (7.5)
0.1 mg 80.0 (31.0 ) − 21.4 (8.1) 7.2 (9.1)
0.3 mg 84.4 (26.1) − 24.0 (4.3) 20.8 (8.0)
1 mg 95.4 (39.1) − 10.1 (6.7) − 15.6 (8.0)
Notes : * Number of subjects with at least one post - baseline test: placebo =
30, 0.1 mg = 17, 0.3 mg = 10 , and 1 mg = 14. LDL = Low density lipoprotein.
Total Body
PBO 0.1 mg 0.3 mg 1 mg
-0.5
0.0
0.5
1.0
1.5
2.0
*
*p =0.047 vs. Placebo
A
Total Body
PBO 0.1 mg 0.3 mg 1 mg
-1.0
-0.5
0.0
0.5
1.0
B
C
PBO 0.1 mg 0.3 mg 1 mg
-50
0
50
100
150
Change from Baseline (kg)
Change from Baseline (kg)
Change from Baseline (Newton)
Figure 3. (A) Mean ( SE ) lean mass (kg) change from baseline up to day 28.
Change from baseline in lean body mass is shown. The data are mean ± standard
error of the mean , n = 30 in the placebo group pooled from the three cohorts,
17 in the 0.1 - mg dose, 10 in the 0.3 - mg group, and 11 in the 1.0 - mg group. BL =
baseline. * p < .05 vs placebo. PBO = placebo; p for trend = .04. ( B ) Mean ( SE )
fat mass (kg) change from baseline up to day 28. Change from baseline in fat
mass is shown. The data are mean ± standard error of the mean , n = 30 in the
placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the
0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo. p for trend = .261.
( C ) Change in leg press strength (Newton) from baseline. Change from baseline
in fat mass is shown. The data are mean ± standard error of the mean , n = 30 in
the placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the
0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo; p for trend = .203.
expression of each is associated with reduced HDL cholesterol
( 28 , 29 , 30 , 31 ). Thus, clinical signifi cance of the HDL decrease
associated with oral androgens remains unclear. Long - term
studies are needed to clarify the effects of long-term SARM
administration on cardiovascular risk. In the interim, the
initial trials are likely to be conducted for acute or subacute
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
94 BASARIA ET AL.
BASARIA ET AL.
8
indications, such as cancer cachexia and functional limita-
tions associated with acute illness or hip fracture, where
the short-term changes in HDL cholesterol may not be
clinically important.
Exogenous androgens would be expected to lower
endogenous testosterone levels. However, LGD-4033 has
been shown to increase bone mineral density, periosteal
bone formation, and femur bending strength in preclinical
models. Other SARMs have also been shown to maintain
measures of sexual function in the orchiectomized rodent
model ( 18 ).
The mechanisms by which androgens increase muscle
mass remain incompletely understood. Testosterone admin-
istration induces hypertrophy of both type I and type II
muscle fi bers ( 34 ). Muscle fi ber hypertrophy can result
from either increased muscle protein synthesis or decreased
muscle protein degradation. Our studies did not reveal a sig-
nifi cant difference in fractional muscle protein synthesis
between the placebo and the active drug groups at the 0.3-mg
dose. These studies were conducted in the fasted state when
the fractional muscle protein synthesis is low; however, tes-
tosterone trials that have reported an increase in FSR have
also been conducted in the fasted state as have trials that
failed to show improvements in FSR ( 35 ). Previous human
and animal studies have shown inhibition of muscle prote-
olysis and muscle protein degradation pathways during
testosterone administration, as potential mechanisms for
increased muscle mass ( 36 , 37 ). Testosterone also increases
the number of satellite cells ( 38 ) by promoting the prolifera-
tion of satellite cells and the differentiation of muscle progen-
itor cells ( 39 , 40 ). Those mechanisms were not investigated
in this study.
The past decade has witnessed the emergence of a num-
ber of nonsteroidal SARMs from several pharmaceutical
companies. Currently, SARMs are being developed as a
new class of function - promoting anabolic therapies to treat
the loss of muscle mass and function associated with aging
and illness, cancer cachexia, osteoporosis, and other condi-
tions associated with muscle loss. This 3-week phase I study,
by demonstrating the safety and tolerability of LGD-4033
and signifi cant gains in muscle mass and strength, paves
the way for longer term effi cacy trials in one or more
populations of older individuals for which SARMs may
be indicated. Short-term indications for grievous condi-
tions, such as cancer cachexia or functional limitations
following an acute illness or hip fracture, might provide
a more attractive risk:benefi t profi le for initial trials of
SARMs than long-term indications such as aging-associated
sarcopenia.
F unding
This trial was supported by Ligand Pharmaceuticals.
S upplementary M aterial
Supplementary material can be found at: http://biomedgerontology.
oxfordjournals.org/
Acknowledgment
The authors thank the Data and Safety Monitoring Board: Glenn
Cunningham, MD, and Ronal S. Swerdloff, MD.
References
1. Baumgartner RN , Waters DL , Gallagher D , Morley JE , Garry PJ .
Predictors of skeletal muscle mass in elderly men and women . Mech
Ageing Dev . 1999 ; 107 : 123 – 136 .
2. Roy TA , Blackman MR , Harman SM , Tobin JD , Schrager M , Metter EJ .
Interrelationships of serum testosterone and free testosterone index
with FFM and strength in aging men . Am J Physiol Endocrinol Metab .
2002 ; 283 : E284 – E294 .
3. Melton LJ III , Khosla S , Crowson CS , O’Connor MK , O’Fallon WM ,
Riggs BL . Epidemiology of sarcopenia . J Am Geriatr Soc . 2000 ; 48 :
625 – 630 .
4. Bassey EJ , Fiatarone MA , O’Neill EF , Kelly M , Evans WJ , Lipsitz
LA . Leg extensor power and functional performance in very old men
and women . Clin Sci (Lond) . 1992 ; 82 : 321 – 327 .
5. Lexell J , Downham D , Sjostrom M . Distribution of different bre
types in human skeletal muscles. A statistical and computational study
of the fi bre type arrangement in m. vastus lateralis of young, healthy
males . J Neurol Sci . 1984 ; 65 : 353 – 365 .
6. Orwoll E , Lambert LC , Marshall LM , et al . Endogenous testosterone
levels, physical performance, and fall risk in older men . Arch Intern
Med . 2006 ; 166 : 2124 – 2131 .
7. Morely JE , Thomas DR . Cachexia: new advances in the management
of wasting diseases . J Am Med Dir Assoc . 2006 ; 9 ( 4 ): 205 – 210 .
8. Bhasin S , Calof OM , Storer TW , et al . Drug insight: testosterone and
selective androgen receptor modulators as anabolic therapies for
chronic illness and aging . Nat Clin Practice Endocrinol Metab . 2006 ;
2 : 146 – 159 .
9. Bhasin S , Storer TW , Berman N , et al . The effects of supraphysiologic
doses of testosterone on muscle size and strength in normal men .
N Engl J Med . 1996 ; 335 : 1 – 7 .
10. Srinivas-Shankar U , Roberts SA , Connolly MJ , et al . Effects of testos-
terone on muscle strength, physical function, body composition, and
quality of life in intermediate-frail and frail elderly men: a randomized,
double-blind, placebo-controlled study . J Clin Endocrinol Metab .
2010 ; 95 : 639 – 650 .
11. Page ST , Amory JK , Bowman FD , et al . Exogenous testosterone (T)
alone or with fi nasteride increases physical performance, grip strength,
and lean body mass in older men with low serum T . J Clin Endocrinol
Metab . 2005 ; 90 : 1502 – 1510 .
12. Snyder PJ , Peachey H , Berlin JA , et al . Effects of testosterone re-
placement in hypogonadal men . J Clin Endocrinol Metab . 2000 ; 85 :
2670 – 2677 .
13. Bhasin S , Woodhouse L , Casaburi R , et al . Older men are as respon-
sive as young men to the anabolic effects of graded doses of testoster-
one on the skeletal muscle . J Clin Endocrinol Metab . 2005 ; 90 : 678 – 688 .
14. Storer TW , Magliano L , Woodhouse L , et al . Testosterone dose-
dependently increases maximal voluntary strength and leg power, but
does not affect fatigability or specifi c tension . J Clin Endocrinol Metab .
2003 ; 88 : 1478 – 1485 .
15. Travison TG , Basaria S , Storer TW , et al . Clinical meaningfulness of
the changes in muscle performance and physical function associated
with testosterone administration in older men with mobility limitation .
J Gerontol A Biol Sci Med Sci . 2011 ; 66 : 1090 – 1099 .
16. Narayanan R , Mohler ML , Bohl CE , Miller DD , Dalton JT . Selective
androgen receptor modulators in preclinical and clinical development .
Nucl Recept Signal . 2008 ; 6 e010 .
17. Dalton JT , Barnette KG , Bohl CE , et al . The selective androgen recep-
tor modulator GTx-024 (enobosarm) improves lean body mass and
physical function in healthy elderly men and postmenopausal women:
results of a double-blind, placebo-controlled phase II trial . J Cachexia
Sarcopenia Muscle . 2011 ; 2 : 153 – 161 .
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 95
BASARIA ET AL.
8
indications, such as cancer cachexia and functional limita-
tions associated with acute illness or hip fracture, where
the short-term changes in HDL cholesterol may not be
clinically important.
Exogenous androgens would be expected to lower
endogenous testosterone levels. However, LGD-4033 has
been shown to increase bone mineral density, periosteal
bone formation, and femur bending strength in preclinical
models. Other SARMs have also been shown to maintain
measures of sexual function in the orchiectomized rodent
model ( 18 ).
The mechanisms by which androgens increase muscle
mass remain incompletely understood. Testosterone admin-
istration induces hypertrophy of both type I and type II
muscle fi bers ( 34 ). Muscle fi ber hypertrophy can result
from either increased muscle protein synthesis or decreased
muscle protein degradation. Our studies did not reveal a sig-
nifi cant difference in fractional muscle protein synthesis
between the placebo and the active drug groups at the 0.3-mg
dose. These studies were conducted in the fasted state when
the fractional muscle protein synthesis is low; however, tes-
tosterone trials that have reported an increase in FSR have
also been conducted in the fasted state as have trials that
failed to show improvements in FSR ( 35 ). Previous human
and animal studies have shown inhibition of muscle prote-
olysis and muscle protein degradation pathways during
testosterone administration, as potential mechanisms for
increased muscle mass ( 36 , 37 ). Testosterone also increases
the number of satellite cells ( 38 ) by promoting the prolifera-
tion of satellite cells and the differentiation of muscle progen-
itor cells ( 39 , 40 ). Those mechanisms were not investigated
in this study.
The past decade has witnessed the emergence of a num-
ber of nonsteroidal SARMs from several pharmaceutical
companies. Currently, SARMs are being developed as a
new class of function - promoting anabolic therapies to treat
the loss of muscle mass and function associated with aging
and illness, cancer cachexia, osteoporosis, and other condi-
tions associated with muscle loss. This 3-week phase I study,
by demonstrating the safety and tolerability of LGD-4033
and signifi cant gains in muscle mass and strength, paves
the way for longer term effi cacy trials in one or more
populations of older individuals for which SARMs may
be indicated. Short-term indications for grievous condi-
tions, such as cancer cachexia or functional limitations
following an acute illness or hip fracture, might provide
a more attractive risk:benefi t profi le for initial trials of
SARMs than long-term indications such as aging-associated
sarcopenia.
F unding
This trial was supported by Ligand Pharmaceuticals.
S upplementary M aterial
Supplementary material can be found at: http://biomedgerontology.
oxfordjournals.org/
Acknowledgment
The authors thank the Data and Safety Monitoring Board: Glenn
Cunningham, MD, and Ronal S. Swerdloff, MD.
References
1. Baumgartner RN , Waters DL , Gallagher D , Morley JE , Garry PJ .
Predictors of skeletal muscle mass in elderly men and women . Mech
Ageing Dev . 1999 ; 107 : 123 – 136 .
2. Roy TA , Blackman MR , Harman SM , Tobin JD , Schrager M , Metter EJ .
Interrelationships of serum testosterone and free testosterone index
with FFM and strength in aging men . Am J Physiol Endocrinol Metab .
2002 ; 283 : E284 – E294 .
3. Melton LJ III , Khosla S , Crowson CS , O’Connor MK , O’Fallon WM ,
Riggs BL . Epidemiology of sarcopenia . J Am Geriatr Soc . 2000 ; 48 :
625 – 630 .
4. Bassey EJ , Fiatarone MA , O’Neill EF , Kelly M , Evans WJ , Lipsitz
LA . Leg extensor power and functional performance in very old men
and women . Clin Sci (Lond) . 1992 ; 82 : 321 – 327 .
5. Lexell J , Downham D , Sjostrom M . Distribution of different bre
types in human skeletal muscles. A statistical and computational study
of the fi bre type arrangement in m. vastus lateralis of young, healthy
males . J Neurol Sci . 1984 ; 65 : 353 – 365 .
6. Orwoll E , Lambert LC , Marshall LM , et al . Endogenous testosterone
levels, physical performance, and fall risk in older men . Arch Intern
Med . 2006 ; 166 : 2124 – 2131 .
7. Morely JE , Thomas DR . Cachexia: new advances in the management
of wasting diseases . J Am Med Dir Assoc . 2006 ; 9 ( 4 ): 205 – 210 .
8. Bhasin S , Calof OM , Storer TW , et al . Drug insight: testosterone and
selective androgen receptor modulators as anabolic therapies for
chronic illness and aging . Nat Clin Practice Endocrinol Metab . 2006 ;
2 : 146 – 159 .
9. Bhasin S , Storer TW , Berman N , et al . The effects of supraphysiologic
doses of testosterone on muscle size and strength in normal men .
N Engl J Med . 1996 ; 335 : 1 – 7 .
10. Srinivas-Shankar U , Roberts SA , Connolly MJ , et al . Effects of testos-
terone on muscle strength, physical function, body composition, and
quality of life in intermediate-frail and frail elderly men: a randomized,
double-blind, placebo-controlled study . J Clin Endocrinol Metab .
2010 ; 95 : 639 – 650 .
11. Page ST , Amory JK , Bowman FD , et al . Exogenous testosterone (T)
alone or with fi nasteride increases physical performance, grip strength,
and lean body mass in older men with low serum T . J Clin Endocrinol
Metab . 2005 ; 90 : 1502 – 1510 .
12. Snyder PJ , Peachey H , Berlin JA , et al . Effects of testosterone re-
placement in hypogonadal men . J Clin Endocrinol Metab . 2000 ; 85 :
2670 – 2677 .
13. Bhasin S , Woodhouse L , Casaburi R , et al . Older men are as respon-
sive as young men to the anabolic effects of graded doses of testoster-
one on the skeletal muscle . J Clin Endocrinol Metab . 2005 ; 90 : 678 – 688 .
14. Storer TW , Magliano L , Woodhouse L , et al . Testosterone dose-
dependently increases maximal voluntary strength and leg power, but
does not affect fatigability or specifi c tension . J Clin Endocrinol Metab .
2003 ; 88 : 1478 – 1485 .
15. Travison TG , Basaria S , Storer TW , et al . Clinical meaningfulness of
the changes in muscle performance and physical function associated
with testosterone administration in older men with mobility limitation .
J Gerontol A Biol Sci Med Sci . 2011 ; 66 : 1090 – 1099 .
16. Narayanan R , Mohler ML , Bohl CE , Miller DD , Dalton JT . Selective
androgen receptor modulators in preclinical and clinical development .
Nucl Recept Signal . 2008 ; 6 e010 .
17. Dalton JT , Barnette KG , Bohl CE , et al . The selective androgen recep-
tor modulator GTx-024 (enobosarm) improves lean body mass and
physical function in healthy elderly men and postmenopausal women:
results of a double-blind, placebo-controlled phase II trial . J Cachexia
Sarcopenia Muscle . 2011 ; 2 : 153 – 161 .
THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 9
18. Miner JN , Chang W , Chapman MS , et al . An orally active selective
androgen receptor modulator is effi cacious on bone, muscle, and sex
function with reduced impact on prostate . Endocrinology . 2007 ; 148 :
363 – 373 .
19. Schmidt A , Kimmel DB , Bai C , et al . Discovery of the selective androgen
receptor modulator MK-0773 using a rational development strategy based
on differential transcriptional requirements for androgenic anabolism
versus reproductive physiology . J Biol Chem . 2010 ; 285 : 17054 – 17064 .
20. LeBrasseur NK , Bhasin S , Miciek R , Storer TW . Tests of muscle
strength and physical function: reliability and discrimination of
performance in younger and older men and older men with mobility
limitations . J Am Geriatr Soc . 2008 ; 56 : 2118 – 2123 .
21. Basaria S , Coviello AD , Travison TG , et al . Adverse events associated
with testosterone administration . N Engl J Med . 2010 ; 363 : 109 – 122 .
22. Wolfe RR . Radioactive and Stable Isotope Tracers in Biomedicine.
Principles and Practice of Kinetic Analysis . New York, NY : Wiley-
Liss ; 1992 .
23. Bhasin S , Pencina M , Jasuja GK , et al . Reference ranges for testosterone
in men generated using liquid chromatography tandem mass spec-
trometry in a community-based sample of healthy nonobese young
men in the framingham heart study and applied to three geographi-
cally distinct cohorts . J Clin Endocrinol Metab . 2011 ; 96 : 2430 – 2439 .
24. Mazer NA . A novel spreadsheet method for calculating the free serum
concentrations of testosterone, dihydrotestosterone, estradiol, estrone
and cortisol: with illustrative examples from male and female popula-
tions . Steroids . 2009 ; 74 : 512 – 519 .
25. Wu FC , von Eckardstein A . Androgens and coronary artery disease .
Endocr Rev . 2003 ; 24 : 183 – 217 .
26. Schroeder ET , Singh A , Bhasin S , et al . Effects of an oral androgen on
muscle and metabolism in older, community-dwelling men . Am J Physiol
Endocrinol Metab . 2003 ; 284 : E120 – E128 .
27. Thompson PD , Cullinane EM , Sady SP , Chenevery C , Saritelli AL ,
Sady MA . Contrasting effects of testosterone and stanozolol on serum
lipoprotein levels . JAMA . 1989 ; 261 : 1165 – 1168 .
28. von Eckardstein A , Nofer JR , Assmann G . HDL and coronary heart
disease: role of cholesterol effl ux and reverse cholesterol transport .
Arterioscler Thromb Vasc Biol . 2001 ; 20 : 13 .
29. von Eckardstein A , Assmann G . Prevention of coronary heart disease
by raising of HDL cholesterol? Curr Opin Lipidol . 2000 ; 11 : 627 – 663 .
30. Tang J , Srivastava RAK , Krul E S , et al . In vivo regulation of apolipo-
protein A-I gene expression by estradiol and testosterone occurs by
different mechanisms in inbred strains of mice . J Lipid Res . 1991 ; 32 :
1571 – 1585 .
31. Krieger M . Charting the fate of the “ good cholesterol ” : identifi cation
and characterization of the high-density lipoprotein receptor SR-BI .
Annu Rev Biochem . 1999 ; 68 : 523 – 555 .
32. Langer C , Gansz B , Goepfert C , et al . Testosterone up-regulates scav-
enger receptor BI and stimulates cholesterol effl ux from macrophages .
Biochem Biophys Res Commun . 2002 ; 296 : 1051 – 1057 .
33. Glueck CJ , Gartside P , Fallat RW , Mendoza S . Effect of sex hormones
on protamine inactivated and resistant postheparin plasma lipase .
Metabolism . 1976 ; 25 : 625 – 630 .
34. Sinha-Hikim I , Artaza J , Woodhouse L , et al . Testosterone-induced
increase in muscle size in healthy young men is associated with
muscle fi ber hypertrophy . Am J Physiol Endocrinol Metab . 2002 ; 283 :
E154 – E164 .
35. Ibebunjo C , Eash JK , Li C , Ma Q , Glass DJ . Voluntary running, skeletal
muscle gene expression, and signaling inversely regulated by orchi-
dectomy and testosterone replacement . Am J Physiol Endocrinol Metab .
2011 ; 300 : E327 – E340 .
36. Urban RJ , Bodenburg YH , Gilkison C , et al . Testosterone administra-
tion to elderly men increases skeletal muscle strength and protein
synthesis . Am J Physiol . 1995 ; 269 ( 5 Pt 1 ): E820 – E826 .
37. Ferrando AA , Sheffi eld-Moore M , Yeckel CW , et al . Testosterone
administration to older men improves muscle function: molecular and
physiological mechanisms . Am J Physiol Endocrinol Metab . 2002 ; 282 :
E601 – E607 .
38. Sinha-Hikim I , Roth SM , Lee MI , Bhasin S . Testosterone-induced
muscle hypertrophy is associated with an increase in satellite cell
number in healthy, young men . Am J Physiol Endocrinol Metab .
2003 ; 285 : E197 – E205 .
39. Singh R , Artaza JN , Taylor WE , Gonzalez-Cadavid NF , Bhasin S .
Androgens stimulate myogenic differentiation and inhibit adipogenesis
in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated
pathway . Endocrinology . 2003 ; 144 : 5081 – 5088 .
40. Serra C , Bhasin S , Tangherlini F , et al . The role of GH and IGF-I
in mediating anabolic effects of testosterone on androgen-responsive
muscle . Endocrinology . 2011 ; 152 : 193 – 206 .
OR
by guest on July 20, 2015http://biomedgerontology.oxfordjournals.org/Downloaded from
... One SARM, RAD-140, has been reported to have an A/A ratio of around 90:1 as it acts as a partial antagonist in prostate tissue but as a full agonist in skeletal muscle tissue 67 . The exact mechanism by which SARMs exert their tissue-selective effects has yet to be determined, although it is likely related to their unique AR binding and coregulator/transcription factor recruitment as well as their lack of aromatization/5AR-reduction 53 70 . No significant changes in hemoglobin, PSA, liver enzymes, or QT interval were noted, but a dose-dependent decrease in high-density lipoprotein and endogenous testosterone production was observed. ...
Article
Full-text available
In the clinical setting, anabolic agents serve to ameliorate muscle- and bone-wasting diseases. However, many of these anabolic agents are also used by bodybuilders to surpass natural limits of body composition as performance-enhancing drugs (PEDs). The first generation of PEDs comprises testosterone-derived anabolic-androgenic steroids (AAS) which have demonstrated significant myotropic effects. However, AAS lack optimal tissue-selectively and thus, are prone to numerous adverse health consequences. Hence, a newer generation of PEDs, selective androgen receptor modulators (SARMs), was developed with the goal of achieving superior tissue-selectivity (i.e., exerting anabolic effects only in muscle and bone tissue, while minimally affecting other body systems). In general, AAS and SARMs enhance muscle growth primarily through androgen receptor (AR) agonism in target tissues. Despite multiple attempts, no single AAS nor SARM to date is completely risk free. As such, a significant portion of research efforts has been dedicated to manipulating anabolic pathways beyond the AR. Another class of PEDs, myostatin inhibitors, have shown to cause drastic muscle anabolism across multiple species by inhibiting myostatin, the primary deterrent to continuous muscle growth. The myostatin inhibitor, YK-11, blocks myostatin by upregulating its antagonist, follistatin. This effect appears to be mediated through the AR, suggesting a novel and promising gene-selective approach to engineering AR ligands that isolate benefits from risks. At any rate, the exact mechanisms by which these PEDs function is not well understood. Further pioneering regarding these topics is encouraged as it appears that the innovation of a truly tissue-selective anabolic agent is within reach.
... What do we know about the side effects of SARMs in healthy individuals and in experimental models with animals or humans up to now? For example, after an intake of LGD 4033 for 21 days by healthy men the following adverse side effects were reported: a decrease of plasma levels of the sex hormone binding globulin (SHBG), triglycerides, HDL and FSH (Basaria et al. 2013). The changes found were manageable, with lipid and hormone concentrations returning to normal after discontinuation of the intake of LGD-4033. ...
Article
Full-text available
The current issue is the third of the eighth volume of the Athens Journal of Sports, published by the Sport, Exercise, & Kinesiology Unit of the ATINER under the aegis of the Panhellenic Association of Sports Economists and Managers (PASEM).
Article
Objectives: Selective Androgen Receptor Modulators (SARMs) social media interest is at an all-time high. The aim of this study is to analyze the: (1) quality; (2) educational content; and (3) reliability of the most relevant YouTube videos on SARMs to explain growing SARMs abuse by recreational and professional athletes. Methods: 'SARMs' was queried (November 28, 2021) through the YouTube video library. The top 100 videos filtered by relevance were categorized by source, type of content, educational quality by Global Quality Score (GQS), reliability by Journal of American Medicine Association (JAMA) criteria, YouTube tags, attitude towards SARMs use, and whether the video provided specific support on how to use SARMs. For all outcome variables, descriptive statistics and comparison among source types and category types were performed. Results: Mean JAMA score was 1.6 ± 0.7 out of 4. Mean GQS score was 2.5 ± 1.1 out of 5. Patient videos were of lower educational quality than athletic trainer videos (GQS: 2.11 ± 0.95 vs. 2.95 ± 1.00, p < 0.01), and videos categorized as user experience were of lower educational quality than videos categorized as general SARMs information (GQS: 1.92 ± 0.90 vs. 2.72 ± 1.07, p < 0.05). User experience and dosing recommendation videos were statistically significantly more positive in attitude than both general SARMs information and SARMS vs. other PEDs. Conclusion: Quality, content, and reliability of SARMs YouTube videos was low. Social media likely causes SARMs abuse through disseminating biased SARMs misinformation. These results serve to educate public health oversight bodies, healthcare providers, and sports team members to better identify signs of SARMs abuse, and promote discussion to discourage SARMs abuse.
Article
The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.
Article
Background Selective androgen receptor modulators (SARMs), because of their preferential muscle versus prostate selectivity, are being developed for muscle wasting conditions. Oral SARMs suppress high-density lipoprotein cholesterol (HDL-C) but their effects on functional capacity and atherogenic potential of HDL particles are unknown. Methods We measured cholesterol efflux capacity (CEC); HDL particle number and size; APOB; APOA1; and protein-defined HDL subspecies associated with coronary heart disease (CHD) risk in men, who had undergone prostatectomy for low-grade prostate cancer during 12-week treatment with placebo or 1, 5 or 15-mg of an oral SARM (OPK-88004). Results SARM significantly suppressed HDL-C (p<0.001) but HDL particle size did not change significantly. SARM had minimal effect on CEC of HDL particles (change +0.016, -0.036, +0.070, and -0.048%/µmol-HDL*L -1 at 0, 1, 5, and 15-mg SARM, p=0.045). SARM treatment suppressed APOAI (p<0.001) but not APOB (p=0.077), and reduced APOA1 in HDL subspecies associated with increased (subspecies containing α2-macroglobulin, complement-C3,or plasminogen) as well as decreased (subspecies containing APOC1 or APOE) CHD risk; relative proportions of APOA1 in these HDL subspecies did not change. SARM increased hepatic triacylglycerol lipase (HTGL) (P<0.001). Conclusions SARM treatment suppressed HDL-C but had minimal effect on their size or cholesterol efflux function. SARM reduced APOA1 in HDL subspecies associated with increased as well as decreased CHD risk. SARM-induced increase in HTGL could contribute to HDL-C suppression. These data do not support the simplistic notion that SARM-associated suppression of HDL-C is necessarily pro-atherogenic; randomized trials are needed to determine SARM's effects on cardiovascular events.
Article
Full-text available
Selective Androgen Receptor Modulators (SARMs) abuse and social media prevalence is rapidly growing. Despite the paucity of literature on the clinical effects and safety profile of SARMs, abuse by recreational and professional athletes increases annually. SARMs, a World Anti-Doping Agency (WADA) prohibited performance enhancing drug (PED), display stronger tissue-selective activation of androgen signaling as compared to anabolic steroids. Published case reports and anecdotal evidence suggest liver toxicity, cardiac injury, and other adverse effects are associated with SARMs consumption. However, social media misinformation may lead individuals to believe that SARMs are safe. With no established evidence-based guidelines, we propose that treatment for SARMs abuse should mimic treatment for anabolic-steroid abuse. Health care providers and sports team members must educate themselves on the SARMs literature and social media trends to promote open dialogue and prevent SARMs abuse.
Article
Rationale: Dietary supplements advertised to strengthen muscles have earned fame among athletes. However, several products containing unauthorized compounds are often detected, which can cause a public health risk. Particularly, steroids and selective androgen receptor modulators (SARM) can cause serious side effects as hormone modulators. In this study, we analyzed 15 steroids and 20 SARMs by LC-QTOF-MS to provide fundamental information about fragmentation pathways and fragment ion structures. Method: The optimal conditions of LC-QTOF-MS were explored to obtain fragmentation patterns for each compound. The optimal conditions were established by comparing the area and height of the precursor ion peak at 125 or 175 V as a fragmentor energy. Furthermore, the optimized spectra were acquired by applying collision energy ranging from 1 to 50 eV. The energy value was selected under the condition that the mass error of precursor ions was less than 10 ppm. Results: The 35 compounds are classified on the basis of their chemical core structures: arylpropionamide (3), quinolinone (2), pyrrolidinyl-benzonitrile (1), indole (2), tropanol (2), phenyl-axadaizole (1), hydantoin (2), phenylthiazole (1), nitrothiophene (1), and steroidal derivate (20). Fragmentation pathways and each chemical structure of each product ion were predicted and identified. Furthermore, the obtained structural information was applied to screen seized samples. As a result, 10 seized samples were confirmed to contain one or more SARMs by comparing each precursor ion and fragmentation pattern. Conclusions: The application to the real samples for accurate screening figured out that the same fragmentation patterns and product ions as one or more SARMs standards were detected and identified in the seized samples advertised as muscle building. Therefore, this study can be contributed to ensuring the safety of public health through providing fundamental information about the risk of illegal adulteration.
Article
Samenvatting In het Nederlandse fitness- en sportschoolmilieu wint een nieuwe groep dopingmiddelen snel aan populariteit. In het jargon van de sporters in dit circuit heten ze SARMs, een afkorting voor Selective Androgen Receptor Modulators. SARMs zijn experimentele middelen die spiergroei en vetverlies moeten bewerkstelligen, die nog in de ontwikkelingsfase zijn, nog niet zijn goedgekeurd voor gebruik door artsen, maar al wel vrijelijk verkrijgbaar zijn via webwinkels. SARMs zijn verboden in de sport en staan op de dopinglijst. De farmabedrijven die deze stoffen hebben ontwikkeld, hebben in een aantal gevallen hun trials stopgezet nadat er zorgwekkende bijwerkingen aan het licht kwamen. Desondanks bieden wereldwijd honderden webwinkels deze experimentele middelen aan, en vertellen diverse ‘experts’ op sociale media dat SARMs volstrekt veilig zijn. De verkrijgbaarheid van deze middelen geeft aanleiding tot zorg.
Article
Context Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol. The relative contributions of each hormone to the observed effects of testosterone remain incompletely understood. Methods Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and DHT levels over 12-months of testosterone treatment with hemoglobin, HDL cholesterol (HDLC), volumetric bone mineral density (vBMD) of lumbar spine, sexual desire, and prostate-specific antigen (PSA). We used random forests to model the associations of predicted mean changes in outcomes with change in each hormone at low, mean, or high change in the other two hormones. Stepwise regression models were run to confirm the findings of random forests. Results Predicted increases in hemoglobin and sexual desire were greater with larger increases in estradiol and were larger with high change in DHT compared to low change in DHT. Greater increases in estradiol were associated with larger decreases in HDLC; this association did not vary according to changes in DHT or testosterone. Change in vBMD was most robustly associated with change in estradiol and was greater with high change in testosterone and DHT. There was no consistent relation between change in PSA and change in any hormone. Conclusions Change in estradiol level was the best predictor not only of the change in vBMD and sexual desire but also of the changes in hemoglobin and HDLC. Consideration of testosterone, E2, and DHT together offers a superior prediction of treatment response in older hypogonadal men than testosterone alone.
Article
Osteoporosis is a common disease in which the risk of fracture increases due to decreased bone mass and qualitative skeletal changes. Selective androgen receptor modulators (SARMs) are agonists with tissue selectivity, which act as partial or weak androgen receptor (AR) agonists in androgenic tissues, but mainly as complete AR agonists in synthetic metabolic tissues. In the recent 20 years, many scaffolds of SARMs have been reported, among which several molecules are promising and are undergoing clinical trial evaluation. However, it is still a challenge to discover SARMs with high activity and reduced side effects. In this review, not only are structure of SARMs reported in the literatures systematically collected and classified but also the structure-activity relationships (SAR) are systematically summarized. Furthermore, the advances in SARMs as potential treatment for osteoporosis are also updated.
Article
Full-text available
Background Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation. Methods A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety. Results GTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (P = 0.013, 3 mg vs. placebo) and insulin resistance (P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups. Conclusion GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.
Article
Full-text available
Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial's Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant's perception of change. Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared. Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change. Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.
Article
Full-text available
Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)
Article
Full-text available
Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40–80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.
Article
Full-text available
Context: Physical frailty is associated with reduced muscle strength, impaired physical function, and quality of life. Testosterone (T) increases muscle mass and strength in hypogonadal patients. It is unclear whether T has similar effects in intermediate-frail and frail elderly men with low to borderline-low T. Objective: Our objective was to determine the effects of 6 months T treatment in intermediate-frail and frail elderly men, on muscle mass and strength, physical function, and quality of life. Design and setting: We conducted a randomized, double-blind, placebo-controlled, parallel-group, single-center study. Participants: PARTICIPANTS were community-dwelling intermediate-frail and frail elderly men at least 65 yr of age with a total T at or below 12 nmol/liter or free T at or below 250 pmol/liter. Methods: Two hundred seventy-four participants were randomized to transdermal T (50 mg/d) or placebo gel for 6 months. Outcome measures included muscle strength, lean and fat mass, physical function, and self-reported quality of life. Results: Isometric knee extension peak torque improved in the T group (vs. placebo at 6 months), adjusted difference was 8.6 (95% confidence interval, 1.3-16.0; P = 0.02) Newton-meters. Lean body mass increased and fat mass decreased significantly in the T group by 1.08 +/- 1.8 and 0.9 +/- 1.6 kg, respectively. Physical function improved among older and frailer men. Somatic and sexual symptom scores decreased with T treatment; adjusted difference was -1.2 (-2.4 to -0.04) and -1.3 (-2.5 to -0.2), respectively. Conclusions: T treatment in intermediate-frail and frail elderly men with low to borderline-low T for 6 months may prevent age-associated loss of lower limb muscle strength and improve body composition, quality of life, and physical function. Further investigations are warranted to extend these results.
Article
Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men. TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study. In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes. Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.
Article
Testosterone (T) supplementation increases skeletal muscle mass, circulating GH, IGF-I, and im IGF-I expression, but the role of GH and IGF-I in mediating T's effects on the skeletal muscle remains poorly understood. Here, we show that T administration increased body weight and the mass of the androgen-dependent levator ani muscle in hypophysectomized as well as castrated plus hypophysectomized adult male rats. T stimulated the proliferation of primary human skeletal muscle cells (hSKMCs) in vitro, an effect blocked by transfecting hSKMCs with small interference RNA targeting human IGF-I receptor (IGF-IR). In differentiation conditions, T promoted the fusion of hSKMCs into larger myotubes, an effect attenuated by small interference RNA targeting human IGF-IR. Notably, MKR mice, which express a dominant negative form of the IGF-IR in skeletal muscle fibers, treated with a GnRH antagonist (acyline) to suppress endogenous T, responded to T administration by an attenuated increase in the levator ani muscle mass. In conclusion, circulating GH and IGF-I are not essential for mediating T's effects on an androgen-responsive skeletal muscle. IGF-I signaling plays an important role in mediating T's effects on skeletal muscle progenitor cell growth and differentiation in vitro. However, IGF-IR signaling in skeletal muscle fibers does not appear to be obligatory for mediating the anabolic effects of T on the mass of androgen-responsive skeletal muscles in mice.
Article
Declines in skeletal muscle size and strength, often seen with chronic wasting diseases, prolonged or high-dose glucocorticoid therapy, and the natural aging process in mammals, are usually associated with reduced physical activity and testosterone levels. However, it is not clear whether the decline in testosterone and activity are causally related. Using a mouse model, we found that removal of endogenous testosterone by orchidectomy results in an almost complete cessation in voluntary wheel running but only a small decline in muscle mass. Testosterone replacement restored running behavior and muscle mass to normal levels. Orchidectomy also suppressed the IGF-I/Akt pathway, activated the atrophy-inducing E3 ligases MuRF1 and MAFBx, and suppressed several energy metabolism pathways, and all of these effects were reversed by testosterone replacement. The study also delineated a distinct, previously unidentified set of genes that is inversely regulated by orchidectomy and testosterone treatment. These data demonstrate the necessity of testosterone for both speed and endurance of voluntary wheel running in mice and suggest a potential mechanism for declined activity in humans where androgens are deficient.
Article
In humans, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), estrone (E1) and cortisol (C) bind to the serum proteins sex hormone-binding globulin (SHBG), albumin (Alb) and corticosteroid-binding globulin (CBG). Equilibrium dialysis is considered to be the "gold standard" for measuring the free concentrations of these steroids but is technically difficult and not widely available. Based on a mathematical model of the 5-ligand/3-protein binding equilibria, we developed a novel spreadsheet method for calculating the free and bioavailable (free+Alb-bound) concentrations of each steroid in terms of the total steroid and protein concentrations. The model uses 15 association constants K(SHBG-X), K(Alb-X), and K(CBG-X) (X=T, DHT, E2, E1 and C) that have been estimated from a systematic review of published binding studies. The computation of the free and bioavailable concentrations uses an iterative numerical method that can be readily programmed on a spreadsheet. The method is illustrated with six examples corresponding to young men (YM), old men (OM), obese men (Ob M), young women (YM), pregnant women in the 3rd trimester (Preg T3) and oophorectomized women on oral conjugated equine estrogens (CEE). The resulting free hormone concentrations for YM and YW fall within the normal references ranges obtained by equilibrium dialysis for all five hormones. The model also accounts for the competitive binding effects of high estrogen levels on the free T levels in Preg T3. This novel spreadsheet method provides a "user-friendly" approach for estimating the free concentrations of circulating sex hormones and cortisol in men and women.