Leder BZ, Longcope C, Catlin DH, Ahrens B, Schoenfeld DA, Finkelstein JS. Oral Androstenedione Administration and Serum Testosterone Concentrations in Young Men. JAMA. 2000;283(6):779-782. doi:10.1001/jama.283.6.779
Author Affiliations: Endocrine Unit, Department of Medicine (Drs Leder and Finkelstein), and Department of Biostatistics (Dr Schoenfeld), Massachusetts General Hospital, Boston; Departments of Medicine and Obstetrics and Gynecology, University of Massachusetts Medical School, Worcester (Dr Longcope); and Olympic Analytical Laboratory, Departments of Medicine (Dr Catlin) and Molecular and Medical Pharmacology (Dr Catlin and Mr Ahrens), University of California, Los Angeles.
Context Androstenedione, a steroid hormone and the major precursor to testosterone,
is available without prescription and is purported to increase strength and
athletic performance. The hormonal effects of androstenedione, however, are
Objective To determine if oral administration of androstenedione increases serum
testosterone levels in healthy men.
Design Open-label randomized controlled trial conducted between October 1998
and April 1999.
Setting General clinical research center of a tertiary-care, university-affiliated
Participants Forty-two healthy men aged 20 to 40 years.
Intervention Subjects were randomized to receive oral androstenedione (either 100
mg/d [n = 15] or 300 mg/d [n = 14]) or no androstenedione (n = 13) for 7 days.
Main Outcome Measures Changes in serum testosterone, androstenedione, estrone, and estradiol
levels, measured by frequent blood sampling, compared among the 3 treatment
Results Mean (SE) changes in the area under the curve (AUC) for serum testosterone
concentrations were −2% (7%), −4% (4%), and 34% (14%) in the groups
receiving 0, 100, and 300 mg/d of androstenedione, respectively. When compared
with the control group, the change in testosterone AUC was significant for
the 300-mg/d group (P<.001) but not for the 100-mg/d
group (P = .48). Baseline testosterone levels, drawn
24 hours after androstenedione administration, did not change. Mean (SE) changes
in the AUC for serum estradiol concentrations were 4% (6%), 42% (12%), and
128% (24%) in the groups receiving 0, 100, and 300 mg/d of androstenedione,
respectively. When compared with the control group, the change in the estradiol
AUC was significant for both the 300-mg/d (P<.001)
and 100-mg/d (P = .002) groups. There was marked
variability in individual responses for all measured sex steroids.
Conclusions Our data suggest that oral androstenedione, when given in dosages of
300 mg/d, increases serum testosterone and estradiol concentrations in some
Androstenedione is a steroid hormone produced in the gonads and adrenal
glands of both sexes. It is synthesized from dehydroepiandrosterone and then
converted to testosterone by the enzyme 17β-hydroxysteroid dehydrogenase
or to estrone by the aromatase enzyme complex.1- 3
It is currently available without a prescription and marketed primarily to
athletes and bodybuilders. The number of people regularly using androstenedione
is not known. It has been estimated that 4.9% of male and 2.4% of female adolescents
in the United States have used illegal androgenic/anabolic steroids.4 Because androstenedione is readily available as a
dietary supplement, its use may be even greater.
Unsubstantiated claims have been made that orally administered androstenedione
increases testosterone levels and has anabolic effects in men. To determine
whether androstenedione increases serum testosterone concentrations, we administered
100 or 300 mg/d of androstenedione for 7 days (vs controls) to young, healthy
men and made detailed measurements of serum sex-steroid hormone concentrations.
We studied 42 healthy paid male volunteers (aged 20-40 years). No subjects
reported prior use of androstenedione, androgenic/anabolic steroids, medications
known to affect steroid hormone or binding protein levels, or participation
in competitive bodybuilding. All subjects had normal liver function, renal
function, and serum testosterone concentrations. The study was approved by
the human studies committee at Massachusetts General Hospital. All subjects
gave written informed consent.
Subjects were randomly assigned to 1 of 3 groups: no androstenedione
(n = 13) or 100 (n = 15) or 300 mg/d (n = 14) of androstenedione (Sports One,
Klein Laboratories, Wallingford, Conn) for 7 days. Androstenedione capsules
were dispensed at the general clinical research center at the same time each
day. Subjects were instructed to ingest nothing by mouth except water for
1 hour after androstenedione administration.
Serum androstenedione, testosterone, estrone, and estradiol concentrations
were measured at 0, 15, 30, 45, 60, 90, 120, 180, 240, 360, and 480 minutes
after administration on days 1 and 7. On days 2 to 6, hormone concentrations
were measured just prior to administration. Baseline serum luteinizing hormone,
follicle-stimulating hormone, liver function, creatinine, and total cholesterol
concentrations were measured each day. Hematocrit and serum sex hormone–binding
globulin concentrations were measured on days 1 and 7.
The amount of androstenedione in 13 different capsules, each of which
was purported to contain 100 mg of androstenedione, was determined by comparison
to a 100-mg reference standard of Δ4-androstene-3,17-dione
(Lot 18-C0226; Sigma Chemical Co, St Louis, Mo) by means of high-performance
liquid chromatography equipped with a diode array detector. The mean amount
of androstenedione was 99.8 mg (range, 83.9-113.9 mg; coefficient of variation,
8.7%). All capsules contained androstenedione as determined by high-performance
liquid chromatography and by liquid chromatography–tandem mass spectrometry.
The mass spectrum of the androstenedione peak was identical to that of the
reference standard. All other peaks were less than 1% of the androstenedione
peak and none were testosterone, 19-norandrostenedione, dehydroepiandrosterone,
Serum testosterone, estradiol, estrone, and androstenedione concentrations
were measured by radioimmunoassay. Serum luteinizing hormone, follicle-stimulating
hormone, and sex hormone–binding globulin concentrations were measured
using chemiluminescent immunometric assays. The cross-reactivity of androstenedione
in the testosterone assay was 0.5%. All samples for an individual subject
were analyzed in the same assay.
The primary end point was area under the curve (AUC) on days 1 and 7
for each steroid hormone, expressed in units of concentration-hours. The mean
values of AUC for each hormone were compared after log transformation by means
of repeated measures analysis of covariance, adjusting for baseline level
of the hormone and study day. Changes in serum luteinizing hormone, follicle-stimulating
hormone, cholesterol, and daily baseline sex-steroid hormone concentrations
were compared using a mixed-model analysis of covariance. Baseline clinical
characteristics were compared using the Kruskal-Wallis test.
There were no differences in most of the baseline clinical characteristics
between study groups, except for a statistically significant difference in
body mass index (Table 1).
In the control group, serum androstenedione, testosterone, estrone,
and estradiol levels were stable during frequent blood sampling (testosterone
and estradiol only shown in Figure 1).
The mean (SE) changes in AUC for serum testosterone concentrations during
the frequent blood sampling period were −2% (7%), −4 (4%), and
34% (14%) in the groups receiving 0, 100, and 300 mg/d of androstenedione,
respectively (Figure 2). For the
300-mg/d group, the change in testosterone AUC was significant when compared
with both the control (P<.001) and 100-mg/d (P<.001) groups. There was no difference between the
control and 100-mg/d groups (P = .48). In the 100-mg/d
group, the mean AUC for serum androstenedione, estrone, and estradiol concentrations
increased 72% (18%), 74% (20%), and 42% (12%), respectively (P<.001 for androstenedione and estrone, and P = .002 for estradiol vs control). In the 300-mg/d group, the mean
AUC for serum androstenedione, estrone, and estradiol concentrations increased
697% (136%), 196% (28%), and 128% (24%), respectively (P<.001 vs control for each comparison). Increases in mean serum
androstenedione (P<.001), estrone (P = .002), and estradiol (P = .001)concentrations
were greater in the subjects who received 300 mg/d of androstenedione vs the
Mean baseline and peak serum testosterone levels on days 1 and 7 are
shown in Table 2. There was considerable
individual variability in the changes in serum sex steroid levels (Figure 3). In the men who received 100 mg/d
of androstenedione, no subjects had serum testosterone concentrations that
exceeded the upper limit of normal (1000 ng/dL [34.7 nmol/L]), whereas 4 subjects
who received 300 mg/d of androstenedione had serum testosterone concentrations
above the normal range. Twelve of 15 subjects in the 100-mg/d group and 10
of 14 subjects in the 300-mg/d group had estradiol levels above the upper
limit of normal for men (50 pg/mL [184 pmol/L]).
Mean daily baseline serum androstenedione and estradiol concentrations
increased significantly during the 7-day period in the 300-mg/d group (P = .01 for androstenedione and P
= .003 for estradiol). Mean daily baseline serum testosterone, estrone, follicle-stimulating
hormone, and luteinizing hormone concentrations did not change. Serum sex-hormone–binding
globulin concentrations decreased in both treated groups (data not shown).
No subjects reported adverse effects. There were no changes in liver
function tests or serum creatinine, serum total cholesterol, or hematocrit
This study shows that oral androstenedione administration increases
serum testosterone, androstenedione, estradiol, and estrone concentrations
in healthy men. Few studies have examined the effects of oral androstenedione
administration on testosterone production in humans. A 100-mg dose of androstenedione
increased testosterone concentrations in 2 women.5
In a recent study, in which androstenedione was administered either as a single
100-mg dose or as 100 mg 3 times daily to healthy men, testosterone concentrations
did not increase, although estrogen levels did.6
Our data confirm that individual 100-mg doses of androstenedione are insufficient
to increase testosterone concentrations in healthy men. However, our data
also demonstrate that a higher dose does increase serum testosterone concentrations.
The enzyme that converts androstenedione to testosterone, 17β-hydroxysteroid
dehydrogenase, and aromatase, the enzyme complex that converts androstenedione
and testosterone to estrone and estradiol, are expressed in many human tissues
including skeletal muscle and fat.1,2,7- 12
Thus, it is possible that increases in local tissue levels of testosterone,
estrone, or estradiol are even greater than the increases in their circulating
That oral androstenedione administration increases serum testosterone
levels suggests that it could have androgenic or anabolic effects. High doses
of testosterone increase muscle size and strength in healthy men.13 It is unclear if smaller increases in serum testosterone
also have anabolic effects. Muscle size and strength did not change when 100
mg of androstenedione was administered 3 times daily to healthy men without
prior weight-lifting experience.6 As this dose
was not sufficient to raise testosterone levels, it remains unknown if doses
of androstenedione that increase testosterone levels would have significant
effects on muscle size and function. Finally, because androstenedione itself
is a weakly androgenic steroid,14 increases
in androstenedione itself could have anabolic effects.
While testosterone levels increased in the subjects receiving the 300-mg/d
dosage, levels returned to normal by the following day. This is expected given
that the half-life of testosterone in circulation is 60 to 80 minutes.15 Because many users probably take much higher and
more frequent dosages of androstenedione,16
it is likely that some individuals may experience sustained and larger increases
in testosterone levels compared with those observed in the present study.
Additionally, there was considerable variability in changes of circulating
sex steroid concentrations among the subjects. Because some individuals achieved
much higher circulating testosterone and estradiol concentrations than others
(often above the normal range), there may be subsets of men prone to develop
androgenic or estrogenic responses to androstenedione administration.
Oral administration of 17α-alkylated derivatives of testosterone
has been associated with liver abnormalities.17,18
Anabolic steroid use has also been associated with adverse effects on lipid
levels and cardiac events.19- 21
In women, androstenedione-induced increases in serum testosterone concentrations
could cause hirsutism or virilization. In men, increases in serum estrogen
concentrations might have feminizing effects, including gynecomastia. In children,
increases in sex steroid concentrations could cause precocious puberty or
premature closure of epiphyses, thereby compromising final adult height.22,23 Thus, even though no significant
adverse effects of androstenedione were observed in our short-term study,
long-term administration could be hazardous, particularly in women or children.
We conclude that orally administered androstenedione increases serum
testosterone and estrogen levels in healthy men, particularly at higher doses.
These increases could lead to anabolic or untoward effects in susceptible
populations. Long-term studies of androstenedione use are needed.