Effect of Oral Androstenedione on Serum Testosterone and Adaptations
to Resistance Training in Young Men
A Randomized Controlled Trial
Douglas S. King, PhD; Rick L. Sharp, PhD; Matthew D. Vukovich, PhD; Gregory A. Brown, MS; Tracy A. Reifenrath, MS; Nathaniel L. Uhl; Kerry A. Parsons, MS
Context Androstenedione, a precursor to testosterone, is
marketed to increase blood testosterone concentrations as a natural
alternative to anabolic steroid use. However, whether androstenedione
actually increases blood testosterone levels or produces anabolic
androgenic effects is not known.
Objectives To determine if short- and long-term oral
androstenedione supplementation in men increases serum testosterone
levels and skeletal muscle fiber size and strength and to examine its
effect on blood lipids and markers of liver function.
Design and Setting Eight-week randomized controlled trial
conducted between February and June 1998.
Participants Thirty healthy, normotestosterogenic men (aged 19-29
years) not taking any nutritional supplements or androgenic-anabolic
steroids or engaged in resistance training.
Interventions Twenty subjects performed 8 weeks of
whole-body resistance training. During weeks 1, 2, 4, 5, 7, and 8, the
men were randomized to either androstenedione, 300 mg/d
(n=10), or placebo (n=10). The effect
of a single 100-mg androstenedione dose on serum testosterone and
estrogen concentrations was determined in 10 men.
Main Outcome Measures Changes in serum testosterone and estrogen
concentrations, muscle strength, muscle fiber cross-sectional area,
body composition, blood lipids, and liver transaminase activities based
on assessments before and after short- and long-term androstenedione
administration.
Results Serum free and total testosterone concentrations were not
affected by short- or long-term androstenedione administration. Serum
estradiol concentration (mean [SEM]) was higher (P<.05) in
the androstenedione group after 2 (310 [20] pmol/L), 5 (300 [30]
pmol/L), and 8 (280 [20] pmol/L) weeks compared with
presupplementation values (220 [20] pmol/L). The serum estrone
concentration was significantly higher (P<.05) after 2 (153
[12] pmol/L) and 5 (142 [15] pmol/L) weeks of androstenedione
supplementation compared with baseline (106 [11] pmol/L). Knee
extension strength increased significantly (P<.05) and
similarly in the placebo (770 [55] N vs 1095 [52] N) and
androstenedione (717 [46] N vs 1024 [57] N) groups. The increase of
the mean cross-sectional area of type 2 muscle fibers was also similar
in androstenedione (4703 [471] vs 5307 [604] mm2;
P<.05) and placebo (5271 [485] vs 5728 [451]
mm2; P<.05) groups. The significant
(P<.05) increases in lean body mass and decreases in fat
mass were also not different in the androstenedione and placebo groups.
In the androstenedione group, the serum high-density lipoprotein
cholesterol concentration was reduced after 2 weeks (1.09 [0.08]
mmol/L [42 (3) mg/dL] vs 0.96 [0.08] mmol/L [37 (3) mg/dL];
P<.05) and remained low after 5 and 8 weeks of training and
supplementation.
Conclusions Androstenedione supplementation does not increase
serum testosterone concentrations or enhance skeletal muscle
adaptations to resistance training in normotestosterogenic young men
and may result in adverse health consequences.
JAMA. 1999;281:2020-2028
Androgenic-anabolic
steroids have been shown to enhance the gains in muscle size and
strength associated with resistance training.1-4
Androstenedione, a precursor to testosterone, is normally produced by
the adrenal gland and gonads and is converted to testosterone through
the action of 17
-hydroxysteroid dehydrogenase, which is found in
most body tissues.5-9 Androstenedione is also produced by
some plants and has recently been marketed as a product for increasing
blood testosterone concentrations to be used as a natural alternative
to anabolic steroid use.
However, the interconversions of androstenedione and testosterone to
other androgens, as well as to estrogens, are complex. In addition to
serving as a precursor to testosterone, androstenedione may be
converted into estrogens directly.10, 11 Since testosterone
is also aromatized to estradiol,11, 12 it is also possible
that increased production of testosterone following androstenedione
administration may also result in increased aromatization, which would
further attenuate any increase in the blood testosterone concentration.
These considerations raise the question of
whether androstenedione supplementation
increases the blood testosterone concentration and produces
anabolic-androgenic effects.
To date only one study has investigated the effect of oral
androstenedione administration on the blood testosterone
concentration.13 These authors observed 4- and 7-fold
increases in the blood testosterone concentration in 2 healthy women,
respectively, after the ingestion of a single dose of 100 mg of
androstenedione. The effect of androstenedione administration on blood
testosterone levels in healthy men is unknown. Therefore, one purpose
of this study was to determine whether short- and long-term
administration of oral androstenedione increases the blood
testosterone concentration and enhances gains in muscle size and
strength when combined with a resistance-training program.
Increased concentrations of testosterone in the blood have been
associated with an increased risk of cardiovascular disease, due both
to a lowering of the serum high-density lipoprotein cholesterol (HDL-C)
concentration and an increased serum concentration of low-density
lipoprotein (LDL) concentration.3, 14-19 Elevated blood
testosterone concentrations may also result in significant alterations
in liver function.20, 21 The effects on blood lipids and
liver function appear to be more pronounced in oral anabolic steroids,
compared with injectable agents. A second purpose of this study,
therefore, was to examine the effect of androstenedione administration
on blood lipids and on clinical markers of liver function.
METHODS
Subjects
A total of 30 healthy, normotestosterogenic young (aged 19-29
years) men were recruited for this experiment, approved by the Iowa
State University Human Subjects Committee. These participants were
screened to ensure that they were not consuming androstenedione or any
other nutritional supplement prior to enrollment in the study and were
not currently engaged in a resistance-training program. Subjects were
also not taking illicit drugs or abusing alcohol consumption. All
subjects were free of any cardiovascular or orthopedic condition that
would contraindicate exercise testing or training.
Short-term Administration
of Androstenedione
The effect of short-term administration of androstenedione on the serum
concentration of androstenedione, free and total testosterone,
luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was
studied in 10 of the men (mean age [SEM], 23 [4] years). On 2
separate days after an overnight fast, separated by 1 week, subjects
ingested 100 mg of androstenedione or placebo (250 mg of rice flour),
administered in a randomly assigned double-blind manner. This dose was
chosen based on the previous report that 100 mg of androstenedione
increases blood testosterone concentration by 4- to 7-fold in
women.13 Blood samples were obtained before and every 30
minutes after ingestion for 6 hours. Serum hormone concentrations were
determined as described below.
Androstenedione Supplementation During Resistance Training
After screening, 20 of the men were randomly assigned in a
double-blind manner to groups that consumed either androstenedione or
placebo during weeks 1-2, 4-5, and 7-8, during the 8 weeks of
resistance training. One subject in each group reported prior
resistance-training experience, although none had performed resistance
training during the preceding year. Supplementation was administered in
a cyclic fashion as recommended by the manufacturer to simulate the
supplementation regimen followed by many athletes. This cycle is
believed by athletes to allow for a "washout" period and reduce the
likelihood of adverse effects due to anabolic steroid administration.
Subjects consumed 300 mg of androstenedione or a placebo (250 mg of
rice flour) in capsule form each day. The 300-mg/d dosage was chosen to
exceed the maximal dosage typically recommended by manufacturers
(100-300 mg/d), as well as the dosage shown to increase blood
testosterone concentrations in women.13 Supplements were
taken in unmarked white capsules in 3 equal doses before 9
AM, at 3 PM, and at bedtime. The androstenedione
was derived from wild yams and was provided by Experimental and Applied
Sciences Inc (Golden, Colo). Purity of the androstenedione contained in
the capsules was assessed with high-performance liquid chromatography
by 2 independent laboratories (Biomedical Laboratories Inc, Petaluma,
Calif, and Integrated Biomolecule Corp, Tucson, Ariz). These analyses
produced values for purity of 99% and 100%, respectively. To
encourage compliance, subjects maintained a record of supplement
ingestion and were required to return unused supplements at the
completion of the study. At the conclusion of the study, when subjects
were asked to identify which supplement they were taking, 2 subjects in
the placebo group correctly identified the supplement they were taking.
Resistance Training
During the 8-week resistance-training program, subjects performed
resistance training 3 days per week on nonconsecutive days. Subjects
were instructed on proper lifting technique and supervised by 1 of the
investigators (G.A.B., T.A.R., N.L.U., or K.A.P.)during all lifting
sessions. The resistance-training program was designed to increase the
strength of all major muscle groups. Subjects trained on bench press,
shoulder press, knee extension, right and left knee flexion, vertical
butterfly, leg press, calf press, biceps curl, triceps extension, and
lattisimus dorsi pull-down. Subjects performed 3 sets of 10 repetitions
for the first 2 weeks. For the final 6 weeks of training, subjects
performed 3 sets of 8 repetitions. Resistance was set at 80% to 85%
of 1 repetition maximum (1-RM). Following the determination of 1-RM
after 4 weeks of training, the training intensity was adjusted to 80%
to 85% of the
new 1-RM. All resistance training and 1-RM
testing was performed on multistation isotonic resistance equipment
(FTX; Paramount Fitness Equipment, Los Angeles, Calif).
Strength Testing
Muscle strength was assessed with the measurement of 1-RM before
and after 4 and 8 weeks of resistance training. After a brief warm-up,
subjects were encouraged to meet their 1-RM within 5 trials of
progressing resistance. One repetition maximum was assessed on bench
press, shoulder press, knee extension, right and left knee flexion,
biceps curl, triceps extension, lattisimus dorsi pull-down, and
vertical butterfly.
Body Composition
Body mass and circumference measures were obtained before training and
after 4 and 8 weeks of training. All circumference measurements were
performed by the same investigator (T.A.R) and were obtained for the
following sites: biceps, shoulder, chest, abdomen, waist, hips,
gluteal, thigh, and calf. Body density and percent body fat were
determined with hydrostatic weighing before and after 8 weeks of
training using a computer-interfaced load cell and custom computer
program. Body fat percent was calculated using the Siri
equation22 after estimation of the residual
volume.23
Dietary Analysis
To assess diet, subjects kept a food-intake record for 3 days prior to
beginning resistance training and supplementation. Subjects were
instructed to maintain their typical dietary intake during the course
of the study. Diet records were analyzed for composition using a
food analysis software package (Food Comp; Iowa State University,
Ames). Mean (SEM) daily energy intake was not different in placebo
(9983 [214] kJ/d) and androstenedione (9660 [198] kJ/d) groups
prior to supplementation and resistance training. Daily protein intake
was also not different in placebo (83 [5] g/d) and androstenedione
(98 [4] g/d) groups and exceeded the recommended daily allowance for
all subjects, suggesting adequate nitrogen balance. Although it was not
possible to directly assess diet compliance during the study, subjects
were queried at the end of training, and all indicated that their diet
did not change during the 8 weeks.
Clinical Blood Chemistry
and Hormonal Analyses
Blood samples were obtained after an overnight fast for a
standard blood chemistry and hormonal analyses before training and
after 2, 5, and 8 weeks of training. Blood samples were drawn without
stasis from a catheter inserted into an antecubital vein. Clinical
blood chemistry analyses were performed by a commercial laboratory
(Labcorp Inc, Kansas City, Mo). Another sample was centrifuged and
serum was frozen at -80°C until analysis. Serum concentrations of
free and total testosterone, androstenedione, LH, FSH, estradiol,
estrone, and estriol were measured with radioimmunoassay using
commercially available kits (Diagnostic Products, Los Angeles, Calif,
and Diagnostic Systems Laboratories Inc, Webster, Tex). All samples for
each subject were assayed in the same run. The intra-assay coefficients
of variation were 7.3%, 7.7%, 6.7%, 4.7%, 3.9%, 6.0%, 8.2%, and
7.3% for free testosterone, total testosterone, androstenedione, LH,
FSH, estradiol, estrone, and estriol, respectively.
Muscle Histochemistry
Muscle samples (about 100 mg) were obtained from the lateral aspect of
the vastus lateralis muscle using the needle
biopsy technique described by
Bergstrom.24 Muscle specimens were placed in mounting
medium and immediately frozen in isopentane cooled to the temperature
of liquid nitrogen for later sectioning and staining. Frozen transverse
sections (about 10 µm) were cut on a cryostat (Histostat Microtome;
AO Scientific Instruments, Buffalo, NY ) at -20°C and mounted on
cover glasses. Muscle sections were stained for adenosine
triphosphatase activity at pH 9.4 after a preincubation at pH 4.3.
Samples were then counterstained with eosin Y (Sigma-Aldrich, St Louis,
Mo) for color enhancement to aid in image analysis. Muscle-fiber type
distribution and muscle-fiber areas were determined using a
computer-operated image analysis system (Neosis Visilog Image Analysis
Software; SGI-Computer; Sony DXC-3000A-Camera). The system captures the
light microscope image, traces the muscle-fiber boundaries, counts the
light and dark muscle fibers, and measures the cross-sectional areas.
For muscle-fiber type-distribution, all type 1 and type 2 muscle
fibers were counted. When the data from the placebo and androstenedione
groups before and after training are combined, fiber-type distribution
was determined on 337 fibers.25 For determination of mean
cross-sectional area of type 1 and type 2 fibers, groupings of clearly
delineated fibers were highlighted, and 20 fibers of each type were
randomly selected by a technician blinded to the treatments.
Statistical Analyses
Data were analyzed using commercial software (SPSS Inc, Chicago,
Ill). Statistical analyses were performed using 2-factor (time and
treatment) analyses of variance (ANOVA) with repeated measures. When
ANOVA revealed a significant interaction (P<.05), specific
mean differences were assessed with t tests, using the
Bonferroni 
correction for multiple comparisons.
RESULTS
One subject assigned to the androstenedione group for the training
study had elevated fasting glucose levels, was referred to a physician,
and was diagnosed as having diabetes mellitus. This subject's data
were therefore excluded from the analysis.
Acute Hormonal Response to Androstenedione Administration
Ingestion of 100 mg of androstenedione increased the serum
androstenedione concentration by 175% during the first 60 minutes
following ingestion (Figure 1; P<.05). Between 90 and 270 minutes after ingestion, the
serum androstenedione concentration was increased by 325% to 350%
with androstenedione. Although the serum androstenedione concentration
tended to decrease from 270 to 360 minutes after ingestion, serum
levels remained elevated above baseline for androstenedione. Serum
concentrations of LH and FSH did not change during the 360 minutes
following ingestion of either androstenedione or placebo (Figure 1). Ingestion of 100 mg of androstenedione did not affect the serum
concentrations of either free or total testosterone (Figure 2).
Hormonal Response to Androstenedione Administration During
Resistance Training
The serum androstenedione concentration (Figure
3) increased 100% in the androstenedione
group after 2 and 5 weeks of training and supplementation
(P<.05) and tended to be elevated after 8 weeks
(P=.07). Serum concentrations of LH and FSH
were unaffected by supplementation and training in either
androstenedione or placebo groups (Figure 3).
The serum free testosterone concentration (Figure
4) was significantly higher in the
androstenedione group than in the placebo group before and following
supplementation (significant main effect,
P=.01). The serum free testosterone
concentration was not significantly altered by the 8-week period of
training and supplementation in either placebo or androstenedione
groups. The serum total testosterone concentration was not different in
placebo and androstenedione groups prior to supplementation and did not
change in either group during the period of training and
supplementation.
The calculated effect size for the comparison of the serum free
testosterone concentrations between week 0 and week 8 for
androstenedione was 0.28. Assuming a power of 80% and
P=.05, a sample size of 160 would have been
required to detect an effect of this size. These calculations highlight
the lack of effect of androstenedione supplementation on serum
testosterone concentrations.
The serum estradiol concentration was higher prior to supplementation
in
placebo, due to a very high initial value for 1
subject (460 pmol/L). Figure 1 shows the serum estradiol concentration,
after eliminating the data of this subject. The serum estradiol
concentration prior to supplementation was not different in placebo and
androstenedione groups. The serum estradiol concentration did not
change significantly during the 8-week experimental period for the
placebo group (Figure 5). The serum
estradiol concentration increased significantly (P<.05) in
the androstenedione group after 2 weeks (310 [20] pmol/L), 5 weeks
(300 [30] pmol/L), and 8 weeks (280 [20] pmol/L) of supplementation
compared with presupplementation values (220 [20] pmol/L). The
serum estradiol concentration was significantly higher for the
androstenedione group compared with the placebo group after 2 and 5
weeks of training and supplementation (P<.05). The serum
estriol concentration did not change during the 8 weeks of training and
supplementation in either placebo or androstenedione groups. In
contrast, the serum estrone concentration was significantly
(P<.05) elevated in the androstenedione group after 2 weeks
(153 [12] pmol/L) and 5 weeks (142 [15] pmol/L) of training and
supplementation compared with presupplement values (106 [11] pmol/L).
The serum estrone concentration did not change during the training and
supplementation period in the placebo group. The increases in serum
estradiol and estrone concentrations observed after 2 weeks of
supplementation were observed in all subjects ingesting
androstenedione.
The observed values for serum estradiol concentrations appear to
be somewhat (20%) higher than those typically reported in the
literature. However, there appears to be considerable variability
between laboratories, as well as between and within subjects. In
addition, these estradiol values obtained at the lower end of the
standard curve create more error in the calculation between defined and
calculated dose. Serum estriol concentrations were also somewhat higher
than those reported in the literature. However, the levels of estriol
found in the current study are below the minimal reportable range as
indicated by the manufacturer of the radioimmunoassay kits and,
therefore, are considered to be within normal limits for men.
Regardless of the explanation for these data, comparisons within these
subjects over time are valid, since all samples for each subject were
analyzed in the same assay.
Clinical Blood Chemistry
The 8-week period of training and supplementation did not affect serum
concentrations of total cholesterol, LDL cholesterol, very LDL
cholesterol, or triglycerides (Table
1). The serum HDL cholesterol concentration
was significantly reduced by 12% (P<.05) after 2 weeks and
remained reduced after 5 and 8 weeks of training and supplementation
with androstenedione. Serum concentrations of liver function enzymes
were within normal limits for all subjects throughout the study and
were unaffected by training or supplementation. Training or
supplementation did not significantly affect total iron,
hematocrit, and hemoglobin concentrations.
Resistance Training
There was no significant difference between placebo and
androstenedione groups in the number of repetitions per training
session, amount of force produced, or relative intensity expressed as a
percentage of maximal force
production (1-RM). When the data from all exercises
are combined, the total amount of force production (SE) during the
resistance-training program was 343.2 (16.9) kN and 317.8 (30.3) kN for
the placebo group and the androstenedione group, respectively. During
the first 4 weeks of training, the mean exercise intensity (SEM) for
all exercises was 85% (1%) and 86% (1%) of 1-RM for placebo and
androstenedione groups, respectively. During the final 4 weeks of
training, the mean exercise intensity for all exercises was 82% (1%)
and 84% (1%) of 1-RM for placebo and androstenedione groups,
respectively.
Muscle Strength
Muscle strength (Table 2) did not differ between placebo and androstenedione groups before
training or after 4 and 8 weeks of resistance training and
supplementation. The resistance training resulted in significant
increases in strength for each exercise after 4 weeks of resistance
training (P<.05). The final 4 weeks of training further
increased muscle strength for each of these exercises. When the data
from placebo and androstenedione groups are combined, gains in strength
ranged from 14% (3%) for the biceps curl to 47% (4%) for the left
leg curl. Knee extension strength increased (P<.05) by 43%
and 42% in androstenedione and placebo groups, respectively.
Muscle Histochemistry
Due to an accidental thawing of 1 sample from the placebo group
and 2 samples from the androstenedione group due to freezer failure,
muscle-fiber-type distribution and cross-sectional areas were
determined in 9 placebo and 7 androstenedione subjects. The percentage
of type 1 fibers prior to resistance training and supplementation was
similar in placebo (44% [4%]) and androstenedione (48% [2%])
groups. Muscle fiber-type distribution did not change as a consequence
of resistance training and supplementation in either androstenedione
(44% [3%]) or placebo (44% [4%]) groups. The mean (SEM)
cross-sectional area of type 1 fibers was not altered with resistance
training and supplementation in placebo (3980 [411] vs 4102 [604]
µm2) or androstenedione (3310 [308] vs 3812 [398]
µm2). The mean cross-sectional area of type 2 fibers
increased similarly (significant main effect; P<.05) in
placebo (5271 [485] vs 5728 [451] µm2) and
androstenedione (4703 [471] vs 5307 [604] µm2)
subjects.
Body Composition
Although the resistance-training program (Table
3) significantly affected body composition,
there were no significant differences between androstenedione and
placebo subjects. When the data for both groups are combined, the
resistance-training
program significantly (P<.05) increased
mean body mass (SEM) (80.9 [3.2] vs 82.3 [3.1] kg), mean lean body
mass (SEM) (62.2 [1.7 ] vs 65.1 [1.6] kg), and mean reduced fat
mass (SEM) (18.6 [1.9] vs 17.2 [2.1] kg). Significant increases in
circumferences occurred for the biceps, shoulder, and chest sites
(P<.05), while the abdominal, waist, hip, and gluteal
circumferences decreased during resistance training in both
androstenedione and placebo subjects (P<.05).
COMMENT
A major finding of this study is that short- and long-term
androstenedione supplementation did not increase the serum testosterone
concentration in young men with normal serum testosterone levels. The
only prior report on androstenedione administration in humans
demonstrated substantial elevations in the blood testosterone
concentration in 2 healthy women.13 In these women, 100 mg
of androstenedione produced increases in the blood androstenedione
concentration from 0 to 5 nmol/L and increased the blood total
testosterone from 3 to 18 nmol/L. The results of the present study are
in striking contrast, since the 36-nmol/L increase in the serum
androstenedione concentration observed after short-term intake of
androstenedione was not accompanied by any increase in the serum
testosterone concentration. In the German patent26 for
androstenedione, it is claimed that ingestion of androstenedione
increases the serum testosterone concentration by as much as 237%
within 15 minutes, followed by a secondary increase of 48% to 97%
occurring 3 to 4 days later, and persisting for an additional 6 to 7
days. However, interpretation of this claim is impossible, since the
subject population was not described with respect to age, sex, or
hormonal status, and no data are presented.
The unchanged serum testosterone concentration with
androstenedione supplementation in the present study, coupled with
significant elevations in the serum estrone and estradiol
concentrations, suggests that a significant proportion of the ingested
androstenedione underwent aromatization to these
estrogens.10, 11 Anabolic steroid administration has
previously been shown to suppress endogenous testosterone production,
secondary to decreased serum levels of LH and FSH.27 In our
study, serum concentrations of LH and FSH were unaffected by
supplementation, suggesting that hypothalamic-pituitary function was
not modified by androstenedione supplementation. Therefore, the
unchanged serum testosterone concentration, in spite of the
approximately 2.5 times higher androstenedione concentration, appears
to be related to an increased formation of estrogens from the exogenous
androstenedione.
The quantitative contribution of different tissues to the
aromatization of androstenedione is unknown. However, aromatizing
activity has been reported in most body tissues, and it is clear that
there is ample capacity to support the increased estrone and estradiol
concentrations reported in the present study. For example, adipose
tissue has a maximal aromatizing activity of 0.072 pmol/g per hour with
a Michaelis constant of 25 nmol/L.28 Since serum
androstenedione concentrations were increased to approximately 24
nmol/L, aromatizing activity would have been at half the maximum rate (
Vmax or 0.036 pmol/g per hour). With a fat mass
of 19.3 kg, calculated total adipose tissue aromatizing activity is 695
pmol/h. If plasma volume is assumed to equal 20% of body weight, or
about 4.0 L, the 47-pmol/L increase in the serum estrone concentration
observed from week 0 to week 2 would reflect an increase of 188 pmol in
the total increase in circulating estrone concentration. Thus, the
aromatizing activity of adipose tissue alone could theoretically
account for the increased serum estrone concentration observed with
androstenedione supplementation. It has also been reported that muscle
converts tritiated androstenedione to estrone at a rate almost as great
as adipose tissue.29 Because of its large mass, muscle is
also, therefore, a quantitatively significant source of estrogens.
Since it has been estimated that muscle and adipose tissue combined
account for only 35% to 45% of total extragonadal aromatization to
estrogens,30 it is clear that whole-body aromatizing
activity is sufficient to account for the observed increase in the
serum estrone concentration.
Since many androstenedione users undoubtedly ingest amounts in excess
of the 300 mg/d taken in our study, it could be
argued that the dose of androstenedione was insufficient to raise serum
testosterone levels. This dose exceeds the 100- to 200-mg/d intake
recommended by most manufacturers and the dose (100 mg) observed to
increase the blood testosterone concentration in women.13
The lack of any significant increase in the serum testosterone
concentration, despite the 175% and 100% increases in the serum
androstenedione concentration observed with short- and long-term
administration of androstenedione, however, suggests than any
putative increase in serum testosterone with higher doses would be
associated with additional elevations in the serum estrogen
concentration and lowering of the serum HDL concentration.
The significantly higher serum free testosterone concentrations
observed in androstenedione both before and during resistance training
and supplementation were unexpected, and difficult to explain, given
the random assignment of subjects to each treatment group. However,
values for all subjects were in the normal range, and it is unlikely
that the initial differences influenced the response to the
supplementation period.
Although androstenedione supplementation did not enhance the serum
testosterone concentration in these young normotestosterogenic men, the
reported increase in serum testosterone levels in women13
may suggest that androstenedione supplementation increases the serum
testosterone concentration in hypotestosterogenic populations, such as
women and older men.31, 32
The resistance-training program used in this investigation was
effective in enhancing lean body mass, the cross-sectional area of type
2 muscle fibers, and muscle strength. Gains in muscle size and strength
are markedly enhanced when androgenic-anabolic steroids are taken in
conjunction with a resistance-training program.1-4 In our
study, the increases in lean body mass, muscle fiber cross-sectional
area, and muscle strength were not enhanced with androstenedione
supplementation. These results are not surprising, since serum
testosterone concentrations were not affected by androstenedione
supplementation, and since androstenedione has only weak
anabolic-androgenic activity in comparison with
testosterone.33 The large increases in strength observed in
both experimental groups suggest that the lack of any improvement in
strength with androstenedione supplementation is not due to an
inadequate training stimulus but instead is due to lack of efficacy of
androstenedione as an anabolic-androgenic supplement.
A significant lowering of the serum HDL-C concentration was
observed with androstenedione administration, a finding in agreement
with prior work demonstrating a lowering of the HDL-C concentration
with anabolic steroid use.3, 15-19 The reduction in HDL-C
appears to be due primarily to a reduction in the HDL2
subfraction, secondary to an induction of hepatic triacylglycerol
lipase activity.21, 34 The serum HDL-C concentration did not
reach a level (<0.91 mmol/L [<35 mg/dL]) typically considered to
constitute a risk factor for cardiovascular disease.35
However, the finding that cardiovascular disease risk increases 2% to
3% with every 0.03-mmol/L (1-mg/dL) decrease in HDL-C suggests that
the significant reduction in HDL-C observed with androstenedione
supplementation is clinically relevant.36 Since serum
testosterone concentrations were unaffected by androstenedione
supplementation, the decrease in HDL-C may be due to the approximately
2.5 times higher serum androstenedione concentration. Previous research
has reported that anabolic steroid administration lowers the HDL-C
concentration by as much as 27% to 70%.3, 15-19 One
possible explanation for the significant, but smaller (12%), decrease
in the HDL-C concentration in our study is the lower metabolic potency
of androstenedione compared with testosterone.33 In
addition, subjects in prior studies typically consumed high doses of
more metabolically active anabolic steroids for more prolonged periods.
Elevated serum liver transaminase concentrations are frequently
observed during clinical steroid therapy using 17-alkylated or other
oral compounds.37, 38 Although the serum concentration of
liver transaminases has been reported to be significantly elevated with
anabolic steroid administration in athletes,20, 21 this is
not a universal finding.3, 25, 39 In our study, serum liver
enzyme levels were unaffected by the 8-week period of androstenedione
administration. However, significant impairment of liver function
following more prolonged androstenedione supplementation or with higher
dosages cannot be ruled out.
The hormonal milieu induced by androstenedione supplementation may
predispose the user to adverse consequences in addition to those
documented in this study. Increased serum estrogen levels have been
known for some time to be associated with the development of
gynecomastia.40 Increased concentrations of estrogens may
also increase the risk of cardiovascular disease.41
Elevated estradiol concentrations have been related to increased risk
of breast cancer in women42 and pancreatic cancer in
men.43 Furthermore, elevated serum androstenedione
concentrations have been observed to increase the risk for prostate
cancer in some44 but not all45 previous
studies, and increased serum androstenedione concentrations may also be
associated with pancreatic cancer.46 Taken together, these
previous findings suggest that androstenedione supplementation may
predispose the user to additional health risks.
In summary, androstenedione administration during resistance
training did not significantly alter the serum testosterone
concentration in normotestosterogenic young men. The increased muscle
size and strength observed with resistance training were also not
augmented with androstenedione administration. The use of
androstenedione increased the serum concentrations of estradiol and
estrone, suggesting an increased aromatization of the ingested
androstenedione and/or
testosterone derived from the exogenous
androstenedione. The use of androstenedione was associated with
decreased levels of HDL-C. These data provide evidence that
androstenedione does not enhance adaptations to resistance training and
may result in potentially serious adverse health consequences in young
men.
Author/Article Information
Author Affiliations: Exercise Biochemistry
Laboratory, Department of Health and Human Performance, Iowa State
University, Ames (Drs King, Sharp, and Vukovich, Messrs Brown and Uhl,
and Mss Reifenrath and Parsons); and Experimental and Applied
Sciences, Golden, Colo (Dr Vukovich).
Corresponding Author and Reprints: Douglas S. King, PhD,
Department of Health and Human Performance, 248 Forker Bldg, Iowa State
University, Ames, IA 50011 (e-mail: dsking@iastate.edu).
Funding/Support: This research was supported
by Experimental and Applied Sciences Inc, Golden, Colo, a manufacturer
of oral androstenedione.
Acknowledgment: We appreciate the technical
assistance of Emily Martini, Trina Radske, and Vicki Strissel, without
whom the project would not have been accomplished. We also thank Murray
Kaplan, PhD, for the use of the gamma counter in his laboratory, Roger
A. Fielding, PhD, for his insightful comments, and Jerry Thomas, PhD,
and Kathi Thomas, PhD, for their help with the statistical analyses.
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