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Original Studies |
Department of Endocrinology, Medical University Hospital Wuerzburg (F.C., M.F., J.C.v.V., I.K., W.A., B.A.), 97080 Wuerzburg; Jenapharm (D.H.), 07745 Jena; and Department of Internal Medicine I, University of Heidelberg (M.J.S.), 69 M5 Heidelberg, Germany
Address all correspondence and requests for reprints to: Dr. Frank Callies, Department of Endocrinology, Medical University Hospital, Josef Schneider Strasse 2, 97080 Wuerzburg, Germany.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Results in humans employing high doses of DHEA (1600 mg/day) have been conflicting (4, 5, 6). Using a physiological dose of DHEA (50 mg/day), no significant change in percent body fat or body mass index (BMI) were found after 3 months of treatment in elderly men and women (7). After 6 months of treatment with 100 mg DHEA, a decrease in fat mass and an increase in muscular strength were found in elderly men, but not in women (8, 9). Similarly, Diamond et al. (10) reported a significant decrease in skinfold thickness and an increase in midthigh muscular area in postmenopausal women receiving percutaneous DHEA for 12 months.
Replacement of DHEA in patients with adrenal insufficiency is ideally suited to elucidate the physiological role of DHEA in humans, as these patients suffer from a premature and nearly complete loss of DHEA secretion. In a double blind, placebo-controlled, randomized, cross-over trial we have recently shown that DHEA replacement in women with adrenal insufficiency increases circulating androgens and improves well-being and sexuality (11). Here we report the effects of DHEA replacement on metabolic parameters, body composition, and exercise capacity in these women.
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Subjects and Methods |
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A total of 24 women with adrenal insufficiency were enrolled in the study. The study sample has been described previously (11). Participants were aged 23–59 yr (mean ± SD age, 42 ± 9.3 yr) and had a disease duration of 9.2 ± 8.4 yr (range, 2–37 yr). Their mean BMI was 23.4 ± 4.0 kg/m2 (range, 17.8–31.4 kg/m2). Fourteen patients suffered from primary adrenal insufficiency (mean age, 46.6 ± 8.4 yr), and 10 from secondary adrenal insufficiency (mean age, 36.2 ± 7.0 yr); all had been on a stable hormone replacement regimen for at least 3 months. Seven patients with secondary hypogonadism, and three of the seven postmenopausal patients received estrogen/progestin replacement therapy.
Before inclusion in the study, medical history, physical examination, blood counts, and hepatic and renal function parameters excluded concomitant disease. Diabetes mellitus was considered an exclusion criterion. The ethics committee of the University of Wuerzburg approved the study protocol, and all patients gave written informed consent before enrollment.
Treatment
The study was performed in a double blind, placebo-controlled, cross-over design using a prearranged randomization schedule. Each patient received 4 months of DHEA and 4 months of placebo with a 1-month washout period between the two treatment periods. DHEA was administered in a daily dose of 50 mg taken orally in the morning. Jenapharm (Jena, Germany) provided both placebo and DHEA capsules. All patients were asked not to change their habits concerning diet and physical exercise during the course of the study. Patients were carefully instructed how to collect 24-h urine samples for each of the appointments.
All subjects were studied before administration of DHEA or placebo and after 1 and 4 months of both treatment periods. A final examination was performed 1 month after the end of the second treatment period. Bioimpedance analysis and a graded cycling exercise were performed on three occasions only: at baseline and after the end of each treatment period.
On each of the study days, patients reported to the ambulatory unit in the morning (0900–1100 h) after an overnight fast, having taken their regular morning replacement medication except for the DHEA/placebo capsule. Physical examination including bioimpedance analysis was carried out, followed by drawing of blood samples. Afterward the patients were served a standardized breakfast and allowed to take the DHEA/placebo capsule. After breakfast, the incremental cycling exercise test was carried out.
Measurements
Biochemical measurements on all study days included fasting serum glucose, insulin, leptin, and osteocalcin as well as urinary excretion of pyridinoline and desoxypyridinoline. Serum glucose was determined by an enzymatic colorimetric standard method, and insulin was measured using an established immunoassay (Immulite 227, Diagnostic Products, Bad Nanheim, Germany). The results of glucose and insulin measurements were used for calculation of the glucose/insulin ratio. We used established RIAs for measurement of serum leptin (BioMérieux, Nürfingen, Germany) and osteocalcin (Isotopen Diagnostik CIS, Dreieich, Germany). Urinary pyridinoline and deoxypyridinoline were determined by reverse phase ion-paired high pressure liquid chromatography as described previously (12). Measurements of serum steroid hormones, insulin-like growth factor I, lipids, and sex hormone-binding globulin were also performed and have been previously published (11).
On each of the 7 study days the BMI (weight in kilograms divided by height in square meters) and the waist to hip ratio (waist circumference in centimeters divided by hip circumference in centimeters) were determined. For determination of body composition parameters bioimpedance analysis was performed (Bioelectrical Impedance Analyzer, BIA 2000-M, Data Input, Hofheim, Germany), resulting in determination of resistance and reactance, which were used for further calculations (13, 14, 15).
The incremental cycling exercise test was performed starting with a workload of 25 watts followed by a gradual increase of 25 watts every 2 min. Subjective signs of peripheral exhaustion, a systolic blood pressure greater than 250 mm Hg, a diastolic blood pressure greater than 130 mm Hg, or a heart rate greater than 190 beats - age (yr)/min were predefined criteria for termination of exercise. The total duration of exercise and maximum workload were determined and used for further analysis, including calculation of the total work (product of workload x time).
Statistical analysis
Results are expressed as the mean ± SD and were compared by ANOVA for data from two-period, repeated measurements, cross-over designs, as described by Wallenstein and Fisher (16). Correlation coefficients were determined by linear regression analysis. Statistical significance was defined as P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After 4 months, no difference between DHEA and
placebo treatment was found in BMI (DHEA vs.
placebo, 23.2 ± 3.9 vs. 23.3 ± 4.1;
P = 0.39) or waist to hip ratio (0.83 ± 0.14
vs. 0.80 ± 0.07; P = 0.18).
Bioimpedance analysis did not reveal any significant differences
between DHEA and placebo treatment in fat mass, lean body
mass, or basal metabolic rate (Table 1
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As expected, serum leptin correlated significantly with BMI at baseline
(r = 0.38; P < 0.01). This correlation did not
change after DHEA or placebo treatment. However, serum
leptin decreased significantly after 4 months of DHEA
(baseline vs. 4 months, 17.3 ± 14.2 vs.
12.1 ± 9.7 ng/mL; P = 0.004), but not after
placebo administration (14.2 ± 12.2 vs. 15.3 ±
14.8; P = 0.35). Also, the absolute change in serum
leptin during 4 months of DHEA differed significantly from
that after placebo treatment (DHEA vs. placebo,
-5.3 ± 8.0 vs. +1.1 ± 5.7 ng/mL;
P = 0.01).
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Fasting serum glucose decreased significantly after 4 months of
DHEA (P = 0.01) as well as after placebo
(P = 0.02), with no difference between
DHEA and placebo treatment (P = 0.94;
Table 2). Fasting insulin and the
glucose/insulin ratio did not change during either placebo or
DHEA treatment (Table 2).
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During DHEA treatment a trend toward an increase in
serum osteocalcin was noted (P = 0.14; Table 3). The absolute change after 4 months of
DHEA treatment differed significantly from the change
after placebo (DHEA vs. placebo, +1.6 ±
5.3 vs. -1.2 ± 6.2 ng/mL; P = 0.02).
However, as there was a significant difference in serum osteocalcin
between the two treatments at baseline, with higher levels in the
placebo group (Table 3), no significant difference was found when
comparing the mean osteocalcin concentrations after 4 months of
DHEA and placebo treatments.
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Exercise capacity
After 4 months of treatment, the incremental cycling test revealed
no changes after placebo, but there were DHEA-induced
increases in the total duration of exercise, maximum workload, and
total work (Table 4). However, these
increases failed to reach the level of statistical significance
(baseline vs. 4 months of DHEA: total duration
of exercise, P = 0.15; maximum workload,
P = 0.057; total work, P = 0.13).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We observed a significant decrease in plasma glucose during both DHEA and placebo treatments, with no difference between the two groups. This finding may be related to an increased health awareness in subjects participating in a clinical trial. Results from animal experiments have suggested that serum DHEA may improve insulin resistance. Chronic treatment of obese Zucker rats with high doses of DHEA led to a decrease in serum insulin levels, a change that was interpreted as an improvement in insulin resistance (1). In our patients who received DHEA in a physiological replacement dose, no significant changes in serum insulin or in the glucose/insulin ratio were found. These results are in accordance with the findings by Morales et al. (7) in healthy elderly subjects. Thus, physiological doses of DHEA seem to have no effect on insulin sensitivity.
In humans, a strong positive correlation between serum leptin levels and the amount of body fat has been demonstrated (20, 21). In our study that correlation was found both at baseline and after 4 months of treatment. However, DHEA treatment significantly decreased circulating serum leptin levels. Large variations in serum leptin levels exist between individuals with the same degree of adiposity. This indicates that factors other than body fat contribute to the regulation of serum leptin. Women have higher circulating leptin levels than men (20, 21, 22). This sex difference in serum leptin levels is not explained by differences in the amount of body fat between the sexes (23, 24). The prevailing sex steroid milieu, not the genetic sex, is a significant determinant of the sex difference in serum leptin levels, as cross-gender hormone administration in transsexuals induces a reversal of the sex differences in serum leptin levels (25). Hypogonadal men have 3-fold higher leptin levels than normal men of similar BMI and achieve normalization of leptin levels by testosterone replacement (26). Accordingly, the decrease in serum leptin induced by DHEA in our patients is most likely the result of an increase in circulating androgen concentrations in these women (11). The mechanism by which androgens lower the leptin concentration remains to be elucidated. One possible explanation is a direct suppressive effect of androgens on leptin secretion signaled via binding of androgens to specific androgen receptors on adipocytes (27, 28).
In our study DHEA led to an increase in serum osteocalcin, whereas osteocalcin decreased during placebo treatment, leading to a significant difference in the change in osteocalcin between the two treatment groups. At baseline, osteocalcin was significantly higher in the placebo group, possibly due to a carryover effect of DHEA treatment, as was also observed for the effect of DHEA on sexuality (11). As the markers of bone resorption, urinary cross-links, remained unchanged in our patients, DHEA may exert a primarily osteoanabolic action. Our observations are in contrast to those made by Baulieu et al. (29) in 60- to 79-yr-old men and women. They observed a decrease in the bone resorption marker C-terminal telopeptide of type I collagen with no change in bone formation markers (i.e. osteocalcin) in both sexes after 12 months of DHEA treatment. A reason for this discrepancy might be that most of our females have either been receiving estrogen replacement or still had intact ovarian function (20 of 24 females). However, Baulieu et al. (29) did not mention whether their female subjects received estrogen replacement therapy. In addition, an increase in serum osteocalcin during DHEA treatment has been observed in young women with anorexia nervosa and concurrent amenorrhea (30). A significant positive correlation between serum osteocalcin and circulating androgens has been demonstrated during the menstrual cycle in young healthy women (31). Accordingly, transient hypogonadism in healthy young men induced by GnRH agonist treatment leads not only to testosterone suppression, but also to a significant decrease in serum osteocalcin (32). The underlying mechanism of the interaction of DHEA and sex steroid hormones with osteocalcin production is still unclear. Kasperk et al. (33) described effects of DHEA on osteoblastic cell growth mediated independently from its conversion to androgens. However, the effects of androgen in this model were much more pronounced. Scheven et al. (34) described potentiating effects of DHEA and DHEA sulfate on vitamin D3-induced growth, differentiation, and osteocalcin production of human osteoblastic cells. Whether metabolic maneuvers that increase serum osteocalcin actually increase bone density (and ultimately decrease fracture incidence) remains to be demonstrated. Recent results reported by Baulieu et al. (29) showed minor, but significant, increases in bone mineral density at the femoral neck in women less than 70 yr of age and at the upper radius in women more than 70 yr of age after 12 months of 50 mg DHEA daily. However, long-term studies are needed for proper assessment of the potential role of DHEA in osteoporosis prevention.
Some previous studies have suggested that DHEA may improve muscle function. Morales et al. (8) treated nonobese age-advanced (50–65 yr of age) healthy men and women with a supraphysiological dose of 100 mg DHEA daily for 6 months using a randomized, double blind, placebo- controlled, cross-over design. They observed a dimorphic response to DHEA administration in fat body mass and muscle strength. In men, but not in women, fat body mass significantly decreased, and knee muscle strength as well as lumbar back strength significantly increased during DHEA administration (8). These differences in response to DHEA administration may reflect a gender-specific response to DHEA and/or the presence of confounding factors in women, such as estrogen replacement therapy. In this study we found that a physiological DHEA replacement dose led to a nonsignificant increase in physical capacity, measured as maximum workload in an incremental cycling test (P = 0.057). As no concurrent alteration in body composition was observed, this response to DHEA administration might reflect an effect of DHEA on the central nervous system. Our patients showed a significant improvement in well-being after 4 months of DHEA treatment (11), and an increase in self-perception of energy and drive might indirectly influence the performance in the cycling exercise test by enhancing motivation.
In conclusion, replacement with a physiological dose of DHEA for 4 months in women with a pathological loss of DHEA production had no significant effect on body composition, exercise capacity, or fasting glucose and insulin. The observed decrease in serum leptin is most likely related to the peripheral conversion of DHEA to androgens. Changes in the bone markers reflected a slight osteoanabolic effect of DHEA treatment, but its clinical significance remains to be determined. To better evaluate the physiological role of DHEA, longer trials in patients with adrenal insufficiency are warranted. Studies in male patients with adrenal insufficiency will help to differentiate between DHEA- specific effects and effects resulting from the conversion of DHEA to androgens.
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Acknowledgments |
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Received August 28, 2000.
Revised November 17, 2000.
Accepted January 28, 2001.
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References |
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