DHEA indicates dehydroepiandrosterone.
Villareal DT, Holloszy JO. Effect of DHEA on Abdominal Fat and Insulin Action in Elderly Women and MenA Randomized Controlled Trial. JAMA. 2004;292(18):2243-2248. doi:10.1001/jama.292.18.2243
Author Affiliations: Division of Geriatrics
and Nutritional Science, Department of Medicine, Washington University School
of Medicine, St Louis, Mo.
Context Dehydroepiandrosterone (DHEA) administration has been shown to reduce
accumulation of abdominal visceral fat and protect against insulin resistance
in laboratory animals, but it is not known whether DHEA decreases abdominal
obesity in humans. DHEA is widely available as a dietary supplement without
Objective To determine whether DHEA replacement therapy decreases abdominal fat
and improves insulin action in elderly persons.
Design and Setting Randomized, double-blind, placebo-controlled trial conducted in a US
university-based research center from June 2001 to February 2004.
Participants Fifty-six elderly persons (28 women and 28 men aged 71 [range, 65-78]
years) with age-related decrease in DHEA level.
Intervention Participants were randomly assigned to receive 50 mg/d of DHEA or matching
placebo for 6 months.
Main Outcome Measures The primary outcome measures were 6-month change in visceral and subcutaneous
abdominal fat measured by magnetic resonance imaging and glucose and insulin
responses to an oral glucose tolerance test (OGTT).
Results Of the 56 men and women enrolled, 52 underwent follow-up evaluations.
Compliance with the intervention was 97% in the DHEA group and 95% in the
placebo group. Based on intention-to-treat analyses, DHEA therapy compared
with placebo induced significant decreases in visceral fat area (–13
cm2 vs +3 cm2, respectively; P = .001)
and subcutaneous fat (–13 cm2 vs +2 cm2, P = .003). The insulin area under the curve (AUC)
during the OGTT was significantly reduced after 6 months of DHEA therapy compared
with placebo (–1119 μU/mL per 2 hours vs +818 μU/mL per 2 hours, P = .007). Despite the lower insulin levels,
the glucose AUC was unchanged, resulting in a significant increase in an insulin
sensitivity index in response to DHEA compared with placebo (+1.4 vs –0.7, P = .005).
Conclusion DHEA replacement could play a role in prevention and treatment of the
metabolic syndrome associated with abdominal obesity.
The accumulation of abdominal fat increases with advancing age, and
there is extensive evidence that abdominal obesity increases the risk for
development of insulin resistance, diabetes, and atherosclerosis.1- 4 In addition
to insufficient exercise and overeating, hormonal/metabolic changes that occur
with aging may contribute to the increase in abdominal fat that generally
occurs during middle and old age. One such change is the decline in production
of the adrenal hormone dehydroepiandrosterone (DHEA). The blood level of DHEA,
most of which is present in the sulfated form (DHEAS), peaks at approximately
20 years of age and declines rapidly and markedly after age 25 years.5
Administration of DHEA to rats and mice reduces visceral fat accumulation
in both genetic6,7 and diet-induced
obesity8,9 and results in a smaller
increase in body fat with advancing age.10 In
rats, DHEA also has a protective effect against both the insulin resistance
induced by a high-fat diet9 and the decrease
in insulin responsiveness that occurs with advancing age.10 A
possible explanation for these findings is that DHEA is an activator of peroxisome
proliferator-activated receptor α (PPARα), a transcription factor
that belongs to the steroid hormone nuclear receptor family.11,12 Activation
of PPARα induces transcriptional up-regulation of fatty acid transport
proteins that facilitate fatty acid entry into cells and the enzymes involved
in the β-oxidation of fatty acids.13- 15 Activation
of PPARα also results in decreased expression of fatty acid synthase
and acetyl-coenzyme A carboxylase.13 These
adaptations favor increased fat oxidation and reduced fat deposition. The
absence of PPARα in PPAR (−/−) mice results in late-onset
Dehydroepiandrosterone is widely available as a dietary supplement without
a prescription. However, it is not known whether DHEA decreases abdominal
obesity in humans as it does in rats and mice. In this context, the purpose
of this preliminary study was to test the hypothesis that DHEA replacement
therapy results in a decrease in abdominal fat and an improvement in insulin
action in elderly humans.
The study was conducted at Washington University School of Medicine
(WUSM) from June 2001 to February 2004. Men and women aged 65 to 78 years
were recruited from the community using direct mailing and mass media to participate
in a study of DHEA replacement therapy. Participants provided written informed
consent to participate in the study, which was approved by the WUSM institutional
We screened 128 volunteers (Figure).
The screening evaluation included a medical history, physical examination,
analyses of blood chemistry, and urinalysis. Of the 128 volunteers, 33 were
excluded because they did not meet our eligibility criteria. Exclusion criteria
included hormone therapy within the past year, a history of hormone-dependent
neoplasia, a prostate-specific antigen (PSA) level above 2.6 ng/mL, or active
serious illness. An additional 39 chose not to participate. The remaining
56 volunteers were randomly assigned to receive DHEA (15 men, 13 women) or
placebo (14 men, 14 women) using a computer-generated block random-permutation
procedure stratified for sex.17 None of the
participants smoked. They had received stable medications for at least 6 months,
and had maintained stable body weight (±2 kg) for the past year. None
exercised regularly. The participants were asked not to alter their diets
or physical activity during the study.
We conducted a randomized, double-blind, placebo-controlled study of
the effects of 6 months of DHEA replacement therapy. The dose was 50 mg of
DHEA per day taken at bedtime. The DHEA was synthesized by Schering-Plough
(Munich, Germany); we obtained the DHEA and placebo capsules from the Life
Extension Foundation (Fort Lauderdale, Fla). Placebo and active capsules were
identical in appearance. The randomization algorithm was generated by a member
of the WUSM Biostatistics Division and maintained by a member of the research
team who did not interact with the participants. The participants, the individual
performing the tests and measurements, the person dispensing the capsules,
and those assessing the outcomes were blinded to group assignment.
Compliance was checked by pill counts at monthly intervals. Adverse
effects were monitored by interview, physical examinations, and standard laboratory
tests, including serum PSA measurements in the men at 1, 3, and 6 months after
starting the study. Assessments of abdominal fat, oral glucose tolerance,
and hormone and lipid levels were performed at baseline and after 6 months
Proton magnetic resonance imaging of the abdominal region was obtained
to quantify abdominal fat. Axial images were acquired at the level of L3-4
using a 1.5-T superconducting magnet (Siemens, Iselin, NJ) and a T1-weighted
pulse sequence. Images were acquired with 134 phase-encoding steps to form
256 × 256 images that were stored in a 16-bit format. Consistent
slice localization was accomplished by performing coronal scouting images
to identify the starting point for image acquisition (L3-4 interspace). Eight
8-mm–thick axial images were acquired with no intersection gap. All
images were analyzed by the same experienced technician using the Image analysis
program (NIH, Bethesda, Md). Total abdominal area was expressed as the average
total cross-sectional area derived from the mean of the 8 slices. The area
of subcutaneous fat was calculated as the difference between the total abdominal
area and an area inside a continuous digitized line demarcating the subcutaneous
fat from the abdominal wall and paraspinal muscles. Abdominal visceral fat
was identified using the density slicing mode of the Image program, in which
the separation of fat from nonfat is performed using interactive level detection
with the thresholds set by an experienced technician blinded to the participant’s
identity and treatment status. The coefficients of variation for visceral
and subcutaneous fat areas from repeated blinded analysis of scans performed
on 11 individuals were 3.6% (SD, 2.5%) and 2.6% (SD, 2.9%), respectively.
A standard 75-g oral glucose tolerance test (OGTT) was performed after
an overnight fast. Venous blood samples were obtained in the fasted state
and 30, 60, 90, and 120 minutes after glucose ingestion for determination
of plasma glucose (glucose oxidase method) and insulin18 concentrations.
The glucose and insulin areas under the curve (AUC) were calculated using
the trapezoid method.19 An insulin sensitivity
index20 was calculated using the formula:
insulin sensitivity index = 10 000/square root of [(fasting
glucose × fasting insulin) × (mean glucose × mean
insulin during OGTT)]. This index correlates (r = 0.73)
with the rate of whole-body glucose disposal during a euglycemic insulin clamp.20
Serum levels of DHEAS were measured by enzyme-linked immunosorbent assay
(Diagnostic Systems Laboratory, Webster, Tex). Levels of testosterone, sex
hormones–binding globulin, and insulin-like growth factor–binding
protein 3 were measured by enzyme-linked immunosorbent assay; estradiol levels
were measured by ultrasensitive radioimmunoassay (Diagnostic Systems Laboratory).
Levels of insulin-like growth factor 1 (IGF-1) were measured by radioimmunoassay21 by the core laboratory of the Diabetes Research Training
Center at Washington University. The coefficients of variation of these assays
were all less than 10%. Levels of PSA were determined using a monoclonal antibody
assay (Hybritech Inc, San Diego, Calif).
The participants completed 3-day food records at the beginning and end
of the 6-month study period under the supervision of a dietitian. Records
were analyzed using Nutritionist IV (First Databank, San Bruno, Calif). Physical
activity was assessed using a physical activity questionnaire22 at
baseline and at the end of the study.
Based on a preliminary study of the effects of DHEA on abdominal visceral
fat in older women and men,23 the mean (SD)
difference between the placebo and DHEA groups was projected to be 10 (7)
cm2. Thus, for the projected sample sizes, the estimated power
to detect significant effects of DHEA was 98% for visceral fat.
Data analysis was carried out in an intention-to-treat fashion. When
follow-up data were not available (n = 4), the last observation
was carried forward. Data were analyzed using a 2 × 2 analysis
of variance to evaluate the effects of group (DHEA vs placebo) and sex on
the change between baseline and the results at 6 months. Paired t tests were performed to determine if there were significant changes
within a group. Data were analyzed using SPSS version 12.0 (SPSS Inc, Chicago,
Ill), and P<.05 was used to determine statistical
significance. All values are presented as mean (SD).
Of the 56 women and men enrolled, 52 underwent follow-up evaluations
(Figure). Two participants in the placebo
group (1 woman, 1 man) dropped out and refused final testing for personal
reasons; 2 participants in the DHEA group (1 woman, 1 man) dropped out for
medical reasons unrelated to the study. The percentage of prescribed doses
taken by those in the placebo group who completed the study averaged 95% (SD,
9%). Compliance in the DHEA group was 97% (SD, 10%).
There were no significant differences in baseline characteristics between
the placebo and the DHEA groups (Table 1).
On average, the participants were overweight. Compared with placebo, the 6
months of DHEA replacement resulted in a decrease in body weight (–0.9
[2.4] kg vs 0.6 [2.2] kg; P = .02), with
no difference in response between men and women (P = .74).
There were no significant changes in energy intake or physical activity
assessed using diet records and a physical activity questionnaire. Energy
intake averaged 2271 (338) kcal/d for the placebo group and 2219 (518) kcal/d
for the DHEA group at baseline, and 2191 (527) kcal/d for the placebo group
and 2156 (427) kcal/d for the DHEA group at the end of the study. Physical
activity scores averaged 50 (33) for the placebo group and 48 (37) for the
DHEA group at baseline, and 54 (34) for the placebo and 49 (42) for the DHEA
group at the end of the study.
The DHEA replacement therapy raised the participants’ serum DHEAS
concentrations into the young normal range (Table
2). In the women, DHEA replacement significantly increased testosterone
concentration, while in the men there was no effect of DHEA on testosterone
level. Estradiol concentration increased significantly in both men and women
in response to DHEA therapy. DHEA replacement also resulted in small but significant
increases in IGF-1 concentration. There were no significant changes in sex
hormones–binding protein or insulin-like growth factor–binding
protein 3 (data not shown).
Significant decreases in abdominal visceral fat occurred during the
6 months of DHEA replacement (Table 3).
These decreases were of similar magnitude in the men and women in absolute
terms. The decrease in visceral fat relative to initial values averaged 10.2%
in the women and 7.4% in the men. The DHEA therapy also resulted in a significant
decrease in abdominal subcutaneous fat, averaging approximately 6% in both
the men and women.
The insulin AUC during the OGTT was significantly reduced after 6 months
of DHEA replacement therapy (Table 4).
Despite the lower insulin levels, the glucose AUC was unchanged, providing
evidence for an improvement in insulin action. This improvement is reflected
in a significant increase in the insulin sensitivity index (Table 4). There was an inverse correlation between the changes in
insulin sensitivity index and visceral fat area (R = –0.50, P = .003).
There were no significant adverse effects of the DHEA replacement. Mean
PSA levels for the men in the DHEA group were 1.7 (0.9) ng/mL at baseline
and 1.6 (0.8) ng/mL after 6 months of DHEA replacement. For the men in the
placebo group, mean PSA values were 1.4 (0.6) ng/mL at baseline and 1.8 (1.3)
ng/mL at the end of the study.
In this randomized, double-blind, placebo-controlled study of 6 months
of DHEA replacement therapy, we found that DHEA induced significant decreases
in both visceral and subcutaneous fat in elderly men and women. The DHEA replacement
also resulted in a significant improvement in insulin action that correlated
with the reduction in visceral fat. These findings provide evidence that DHEA
replacement may partially reverse the aging-related accumulation of abdominal
fat in elderly people with low serum levels of DHEAS. They also raise the
possibility that long-term DHEA replacement therapy might reduce the accumulation
of abdominal fat and protect against development of the metabolic/insulin
An improvement in insulin action has also been reported by Kawano et
al24 in a study of the effect of DHEA therapy
in middle-aged men with hypercholesterolemia. To our knowledge, only 1 other
study has examined the effect of DHEA on abdominal fat in humans.25 In that study, DHEA was administered to women in
the form of skin cream and had no effect on abdominal fat measured by computed
tomography. A possible explanation for the lack of effect is that the cream
increased serum levels of DHEAS to only approximately 700 ng/mL, compared
with the value of approximately 3600 ng/mL in the present study. In a previous
study, 6 months of DHEA therapy in elderly men and women resulted in a 1.4-kg
decrease in total body fat mass and a 0.9-kg increase in fat-free mass, measured
by dual-energy x-ray absorptiometry (DXA).26 In
contrast, Jedrzejuk et al,27 in a crossover
study of 3 months of DHEA replacement in 12 men aged approximately 59 years,
found no effect on body composition measured by DXA or on fasting levels of
serum insulin and glucose. Flynn et al28 also
found no change in body composition measured using potassium K 40, or in fasting
glucose or insulin levels in a crossover study of 3 months of DHEA therapy
in older men. Similarly, Arlt et al29 found
no change in body composition measured using bioimpedence analysis and waist-hip
ratio in a crossover study of 4 months of DHEA treatment. Possible explanations
for the differences between the results of these 3 studies and the present
study include the relative insensitivity, compared with magnetic resonance
imaging, of potassium K 40, bioimpedence, and DXA in detecting small changes
in visceral fat; the shorter durations of DHEA treatment in these previous
studies; and the use of the insulin and glucose responses to an OGTT to evaluate
insulin action in the present study.
The results of epidemiologic studies of the relationship between DHEA
and abdominal fat have been conflicting. Haffner et al,30,31 in
studies on middle-aged men, found that DHEAS level was significantly inversely
related to abdominal obesity and insulin concentration. In contrast, in a
study by Barrett-Connor and Ferrara32 on postmenopausal
women, DHEAS levels were positively associated with waist-hip ratio, leading
the authors to conclude that DHEA does not protect against obesity. The seeming
discrepancy between this finding and the present results is probably explained
by the difference in DHEAS levels. In the study that led Barrett-Connor and
Ferrara to conclude that DHEA does not protect against obesity, the women
in the highest quartile of waist-hip ratio had a mean serum DHEAS level of
approximately 490 ng/mL, while those in the lowest quartile had a DHEAS level
of approximately 420 ng/mL, compared to a DHEAS level of approximately 3600
ng/mL in women receiving DHEA replacement in the present study.
With regard to its mechanism of action, DHEA is a PPARα agonist11,12 and serves as a precursor of testosterone
and estrogens. It also increases the concentration of circulating IGF-1.26,33 PPARα induces expression of
the mitochondrial enzymes involved in fatty acid oxidation and suppresses
expression of enzymes involved in fat synthesis.13- 15 Tenenbaum
et al34 showed that the PPARα receptor
ligand bezafibrate reduced the incidence and delayed the onset of type 2 diabetes
in patients with impaired fasting glucose levels. In laboratory rodent models,
PPARα agonists have been shown to reduce adiposity, decrease triglyceride
stores in liver and muscle, and improve insulin sensitivity.35- 37 In
rats or mice, DHEA administration reduces fat accumulation in both genetic6,7 and diet-induced obesity8,9 and
has a protective effect against the insulin resistance induced by a high-fat
diet9 as well as the decrease in insulin responsiveness
associated with aging.10 We think it likely
that this mechanism, ie, activation of PPARα, is also involved in the
decrease in abdominal fat and improvement in insulin action in response to
DHEA in this study.
As in previous studies,33,38,39 DHEA
replacement therapy increased serum testosterone concentration in women but
had no significant effect on testosterone level in men. Also in keeping with
earlier studies,39,40 DHEA replacement
resulted in increases in serum estradiol concentration. There was also an
increase in serum IGF-1 concentration in both men and women in response to
DHEA. The magnitude of this increase, approximately 12% in men and 18% in
women, was similar to that found in previous studies.33,41 There
is evidence suggesting that estrogen therapy protects postmenopausal women
against abdominal fat accumulation42 and that
increasing IGF-1 levels reduces abdominal fat.43,44 Thus,
it is possible that the increases in estradiol and IGF-1 levels could have
played a role in the decrease in abdominal fat induced by DHEA in our study.
Limitations of our study include the relatively small number of participants
and the short duration of DHEA replacement. Therefore, our findings should
be considered preliminary. Furthermore, the long-term effects of the small
but significant increases in IGF-1 and estradiol levels in both men and women,
and in levels of testosterone in women, caused by DHEA replacement are not
known. Larger-scale and longer-term studies are needed to determine whether
DHEA replacement has any adverse effects.
We found in this preliminary study that DHEA reduced abdominal fat and
improved insulin sensitivity index. Larger studies, however, will be needed
to verify our findings and should include patient groups that are fully representative
of the population at risk.
Corresponding Author: John O. Holloszy,
MD, Department of Medicine, Washington University School of Medicine, Campus
Box 8113, 4566 Scott Ave, St Louis, MO 63110 (firstname.lastname@example.org).
Author Contributions: Drs Villareal and Holloszy
had full access to all of the data in the study and take responsibility for
the integrity of the data and the accuracy of the data analyses.
Study concept and design; acquisition of data; analysis
and interpretation of data; drafting of the manuscript; critical revision
of the manuscript for important intellectual content; obtained funding; study
supervision: Villareal, Holloszy.
Statistical analysis: Villareal.
Administrative, technical, or material support:
Funding/Support: This study was supported by
National Institutes of Health grants AG13629 and AG20076, Patient-Oriented
Research Career Development Award K23RR16191 (Dr Villareal), General Clinical
Research Center Grant RR00036, Diabetes Research and Training Center Grant
DK20579, and Clinical Nutrition Research Unit Grant DK56341.
Role of the Sponsors: None of the organizations
funding this study had any role in the design and conduct of the study; the
collection, management, or interpretation of the data; the preparation of
the data; or the preparation, review, or approval of the manuscript.
Acknowledgment: We are grateful to the participants
for their cooperation, and to the staff of the Human Applied Physiology Laboratory
and the nurses of the General Clinical Research Center at Washington University
for their skilled assistance in the performance of this study.