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Endocrine Care |
Department of Medicine, University Hospital Wurzburg (W.A., F.C., I.K., J.C.V., M.F., M.R., B.A.), 97080 Wurzburg; Department of Medicine, University Hospital Innenstadt (C.J.S.), 80336 Munich; Department of Internal Medicine I, University of Heidelberg (M.J.S.), 69115 Heidelberg; Jenapharm GmbH & Co. KG (D.H., M.E., M.O.), 07745 Jena; Institute for Hormone and Fertility Research (H.M.S.), 22767 Hamburg, Germany
Address all correspondence and requests for reprints to: Dr. Wiebke Arlt, Department of Medicine, Endocrine and Diabetes Unit, University of Wurzburg, Josef Schneider Strasse 2, 97080 Wurzburg, Germany. E-mail: w.arlt{at}medizin.uni-wuerzburg.de
Abstract
Serum dehydroepiandrosterone declines with age. Whether this represents a harmful deficiency or an age-related adaptation is not known. Dehydroepiandrosterone replacement in adrenal insufficiency, a state of pathological loss of dehydroepiandrosterone production, improves well-being, mood, and sexuality. To determine the effects of dehydroepiandrosterone in healthy men with a physiological, age-related decline in serum dehydroepiandrosterone sulfate, we conducted a double blind cross-over study in 22 healthy male volunteers (age range, 50–69 yr) with endogenous dehydroepiandrosterone sulfate levels below 4.1 µmol/liter (1500 ng/ml) receiving 4 months of dehydroepiandrosterone (50 mg/d) and 4 months of placebo treatment in random order, with a 1-month washout period. Dehydroepiandrosterone treatment increased serum dehydroepiandrosterone and dehydroepiandrosterone sulfate to concentrations usually found in young men. Circulating androgen levels did not change; however, androgen metabolites increased, indicating enhanced peripheral androgen synthesis. At baseline, psychometric assessment revealed normal well-being and sexuality scores. After 4 months of dehydroepiandrosterone, no effect on sexuality was observed, whereas some mood scores improved slightly, but were not significantly different from scores after placebo. Compared with placebo, dehydroepiandrosterone had no effect on serum lipids, bone markers, body composition, or exercise capacity. Thus, in contrast to previous findings in adrenal insufficiency, we found no obvious benefit of 4 months of dehydroepiandrosterone supplementation in healthy men with a physiological decline of dehydroepiandrosterone production.
DEHYDROEPIANDROSTERONE (DHEA) and its sulfate ester (DHEAS) are the most abundant products of adrenal steroidogenesis in humans and some nonhuman primates (1). DHEA displays a characteristic secretion pattern over a lifetime, with a surge during the prepubertal period (adrenarche), reaching a maximum at 25–35 yr of age, followed by a continuous decline to steadily low levels with advancing age (adrenopause) (2, 3).
It has been suggested that this age-related decrease in DHEA plays a part in the decline of various physiological functions with aging (4, 5). Previous studies investigating DHEA effects in elderly men and women observed changes in IGF-I production, body composition, muscle strength, and immune response (6, 7, 8, 9). Furthermore, some studies described an increased sense of well-being associated with DHEA treatment (6, 8, 10). However, improved well-being was not assessed using validated psychometric evaluation, and most studies were open label, so a placebo effect could not be ruled out.
Employing validated questionnaires, we have recently shown that DHEA replacement in women with adrenal insufficiency leads to significant improvements in well-being, mood, and sexuality (11). Adrenal insufficiency can be considered the ideal pathophysiological model of DHEA deficiency, as these patients suffer from a premature loss of DHEA production. In contrast, it is not clear whether the physiological, age-related decline in DHEA represents a harmful deficiency or an age-related adaptation. Thus, we used the same study design and identical measures as those previously used in women with adrenal insufficiency (11) to investigate the effects of DHEA replacement in healthy age-advanced volunteers selected for DHEA concentrations below 4.1 µmol/liter (1500 ng/ml), which is equivalent to the lower limit of the normal range for serum DHEAS in 15- to 39-yr-old men (2) and to the lower quartile in similarly aged men.
Subjects and Methods
Subjects
All subjects participating were recruited by advertising via local broadcasting and local newspapers asking for age-advanced men in good health with possibly low serum DHEAS concentrations. Main inclusion criteria were an age between 50–70 yr and a serum DHEAS concentration below 4.1 µmol/liter (<1500 ng/ml); the latter was found in 38 of 119 screened men. Further inclusion criteria were a body mass index between 20–30 kg/m2, a state of general good health, normal blood cell counts, and normal hepatic and renal function parameters. Exclusion criteria were any chronic diseases (including diabetes mellitus and severe arterial hypertension), history of psychiatric disease, prostate hyperplasia, any medication known to affect hepatic biotransformation or to influence central nervous functions, treatment with steroids within the last 3 months, as well as significant hypogonadism [serum T, <8.7 nmol/liter (<2.5 ng/ml)].
Twenty-two healthy men, aged between 50–69 yr (mean ± SD age, 59.3 ± 5.6 yr) entered the study. Their mean body mass index was 26.5 ± 2.4 kg/m2 (range, 23.5–31.7 kg/m2). Twelve men were between 50–59 yr of age (mean age, 54.9 ± 2.9 yr); the other 10 were between 60–69 yr (mean age, 64.6 ± 2.7 yr). Twenty-one of 22 study subjects were nonsmokers. Eight subjects had previously participated in a single dose, pharmacokinetic study on DHEA (12) completed at least 6 months before entering the current study. The ethics committee of the University of Wurzburg approved the study protocol, and all patients gave written informed consent.
Treatment
The study was performed in a double blind, placebo-controlled, cross-over design, using a prearranged randomization schedule (SAS, Procedure PLAN, SAS/STAT User’s Guide, version 6, SAS Institute, Inc., Cary, NC) including a stratification regarding the age group (50–59 or 60–69 yr). Each subject received in random order 50 mg DHEA (Jenapharm, Jena, Germany) taken orally in the morning for 4 months and 4 months of placebo, separated by a 1 -month washout period.
Evaluation
All subjects were studied at the beginning and after 1 and 4 months of both treatment periods, with the exception of bioimpedance analysis and graded cycling exercise, which were carried out only at baseline and after 4 months of both treatments. Participants reported to the ambulatory unit in the morning (0900–1100 h) after an overnight fast, without having taken their regular morning DHEA/placebo capsule. They collected a 24-h urine on the day preceding the appointment. After physical examination, history taking, and pill count check, bioimpedance analysis was performed, and blood samples were drawn. Afterward, the subjects were served a standardized breakfast and took the DHEA/placebo capsule, followed by psychometric evaluation and the graded cycling exercise test.
Measurements
Blood counts, serum prostate-specific antigen levels, hepatic
and renal function parameters, and serum lipids were measured with
established colorimetric assays. Serum osteocalcin was measured by RIA
(IsotopenDiagnostik CIS, Dreieich, Germany). Urinary pyridinoline and
deoxypyridinoline were determined by reverse phase, ion-paired HPLC as
described previously (13). Serum steroid hormones were
determined by established specific RIAs: DHEA, DHT,
5
-androstane-3,17ß-diol-17-glucuronide (ADG), and estrone
(E1) from Diagnostics Systems Laboratories, Inc.
(Sinsheim, Germany); DHEAS, androstenedione (A’dione), and T
from Diagnostic Products (Los Angeles, CA); and 17ß-E2
from BioChem ImmunoSystems (Freiburg, Germany). SHBG and IGF-I were
measured by established RIAs from BioMerieux (Charbonnier les Bains,
France). For the measurement of IGF-binding protein-3 (IGFBP-3), an
ELISA kit from Diagnostics Systems Laboratories, Inc., was
used, but the secondary antibody was labeled with biotin. After the
addition of streptavidin-europium, time-resolved fluorescence was
measured using a 1232 DELFIA fluorometer (Wallac, Inc.,
Turku, Finland).
Psychometric evaluation was performed using four validated well-being and mood questionnaires. The 90-item Symptom Checklist 90 (revised version) (14, 15) is a multidimensional self-report symptom inventory measuring nine psychological dimensions (subscales) and a global severity index. The responders rate items on five-step scales from "I completely disagree" (or "not at all") to "I completely agree" (or "extremely"). The ratings are transformed into values from 0 (not at all) to 4 (extremely), and subscale scores are calculated by adding the ratings and dividing by the number of items. The global severity index is calculated from the sum of all ratings divided by the number of rated items. The Multidimensional Mood Questionnaire (MDBF) (16) consists of 24 items defining three subscales: pleasant-unpleasant, awake-sleepy, and calm-restless. Responders rate the items on a five-step scale ranging from 1 (not at all) to 5 (very much); subscale scores are equivalent to the sum of the respective item ratings. The short form of the Giessen Complaint List (GBB-24) (17) consists of 24 items defining four subscales (severity of exhaustion, gastric symptoms, limb pain, and heart symptoms) with six items each; subscale scores are added up to a global score of discomfort. Scores can be converted to quartile values by referring to a reference sample of healthy 18- to 60-yr-old men (n = 732) stratified by age decade (18). The German version of the Hospital Anxiety and Depression Scale (19) consists of 14 items defining the subscales anxiety and depression. Subscale scores can be converted to T values by referring to the reference sample of 18- to 70-yr-old men (n = 121) (20). The higher the score, the greater the impairment of well-being as assessed by the questionnaires (except for the MDBF, in which increasing scores reflect improved well-being).
Sexual functioning was quantified by four visual analog scales asking for the frequency of sexual thoughts, sexual interest, and satisfaction with mental and physical aspects of the sexual experience, as described previously (11).
Body composition was determined by bioimpedance analysis (bioelectrical impedance analyzer, BIA 2000-M, Data Input, Hofheim, Germany) (21, 22, 23). In addition, we determined body mass index [weight (kilograms)/height (meters)2] and waist to hip ratio (waist divided by hip circumference in centimeters).
Physical capacity was assessed as total duration of exercise and maximum workload during an incremental cycling exercise test starting with a workload of 25 watts, followed by a gradual increase by 25 watts every 2 min. Subjective signs of peripheral exhaustion, a systolic blood pressure greater than 230 mm Hg, a diastolic blood pressure greater than 120 mm Hg or a heart rate greater than 190 - age (yr)/min led to termination of exercise.
Statistical analysis
Comparisons were performed by ANOVA using the Wallenstein/Fisher model for analysis of data from two-period, repeated measurements, cross-over designs (24) and by t test of mean individual changes. Analysis was carried out according to the intention to treat principle, included additional analysis stratified by age decade, and controlled for the confounding variables sequence order, patient number in the sequence, and treatment period. Significance was defined as P < 0.05.
Results
Serum steroid hormones and SHBG
Compared with the normal range for 18- to 70-yr-old men, baseline
serum A’dione and T were near the respective mean; serum
DHEA, DHEAS, DHT, and ADG were at the lower limit, and
serum E were below the lower limit (Figs. 1
and 2). During DHEA
treatment, serum DHEA, DHEAS, and A’dione significantly
increased to the mean of male normal ranges (Fig. 1). Although serum
androgens did not change, ADG increased significantly (Figs. 1 and 2).
Also, serum E1 increased significantly (Fig. 2). However, E2 levels increased only
slightly and nonsignificantly (Fig. 2). Serum SHBG did not change
significantly after 4 months of DHEA treatment
(DHEA vs. placebo, 33.1 ± 11.7
vs. 34.8 ± 12.1 nmol/liter; P = 0.11).
The observed increases were already significant after 1 month of
DHEA treatment, with no further difference between 1–4
months of treatment. Four weeks after the end of treatment, all hormone
levels had returned to baseline.
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). The
younger age group showed a concurrent significant decrease in SHBG
after 1 month of DHEA as well as increases in E1 and E2,
whereas there were no such changes in the 60- to 69-yr-old men (Table 1). Notably, DHEA increased significantly higher in the
50- to 59-yr-old men, whereas the increase in DHEAS was higher in the
60- to 69-yr-old men. The DHEA/DHEAS ratio significantly
decreased during DHEA administration, with a significant
difference evolving between the two age groups, showing a lower mean
DHEA/DHEAS ratio in the 60- to 69-yr-old men (Table 1).
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Serum IGF-I did not change during DHEA treatment (baseline vs. 4 months, 18.5 ± 4.7 vs. 18.6 ± 4.0 nmol/liter; P = 0.74) or after placebo administration (19.2 ± 4.7 vs. 19.1 ± 4.6 nmol/liter; P = 0.89). Similarly, serum IGFBP-3 and the molar ratio of IGF-I/IGFBP-3 did not change significantly.
Serum lipids
After 4 months of DHEA, high density lipoprotein cholesterol increased significantly (baseline vs. 4 months: DHEA, 51 ± 15 vs. 57 ± 18 mg/dl; P = 0.011), but did not differ from that after 4 months of placebo (i.e. 56 ± 17 mg/dl). Total cholesterol, low density lipoprotein cholesterol, and triglycerides did not change significantly. Lipoprotein(a) showed a trend toward a decrease after DHEA treatment [baseline vs. 4 months: DHEA, 12.6 ± 13.3 vs. 10.3 ± 10.3 mg/dl (P = 0.11); placebo, 12.6 ± 12.7 vs. 12.0 ± 15.2 mg/dl (P = 0.47)].
Bone metabolism
Serum osteocalcin did not change after DHEA (baseline vs. 4 months: DHEA, 19.7 ± 4.3 vs. 19.4 ± 4.6 ng/ml; P = 0.62). Similarly, there were no significant changes in urinary pyridinoline (baseline vs. 4 months: DHEA, 34.4 ± 5.9 vs. 38.1 ± 15.1 nmol/mmol creatinine; P = 0.26), deoxypyridinoline (6.80 ± 3.23 vs. 7.60 ± 5.50 nmol/mmol; P = 0.47), or the pyridinoline/deoxypyridinoline ratio.
Anthropometric parameters and body composition
After 4 months of treatment there were no changes in body mass index (placebo vs. DHEA, 26.1 ± 1.9 vs. 26.1 ± 2.1 kg/m2) or waist to hip ratio (0.93 ± 0.05 vs. 0.93 ± 0.05 cm). Bioimpedance analysis did not reveal any effect of 4 months of DHEA treatment on body composition [placebo vs. DHEA: total body water, 45.7 ± 3.0 vs. 46.0 ± 2.8 l (P = 0.69); fat weight, 15.6 ± 3.4 vs. 15.3 ± 4.9 kg (P = 0.78); lean body mass, 63.4 ± 5.1 vs. 63.6 ± 4.7 kg (P = 0.84); basal metabolic rate, 1850 ± 128 vs. 1855 ± 118 kcal/d (P = 0.84)].
Exercise capacity
After 4 months of treatment there was no difference between placebo and DHEA in total duration of exercise (placebo vs. DHEA, 642 ± 121 vs. 622 ± 110 sec; P = 0.21) or maximum workload (140 ± 26 vs. 134 ± 23 watts; P = 0.16).
Well-being and mood
At baseline, all subscale scores in the Symptom Checklist 90
(revised version) questionnaire ranged around the mean of the
respective normal ranges (Table 2). After
4 months of DHEA treatment, subscale scores did not change
significantly, although several slight changes added up to a
significant decrease (i.e., improvement) in the global
severity index (Table 2). However, comparison with placebo did not
reveal a significant difference. Similarly, two of three MDBF subscale
scores significantly improved during DHEA treatment
(e.g. pleasant-unpleasant baseline vs. 4 months,
32.9 ± 5.9 vs. 34.3 ± 5.3; P <
0.05), but were not significantly different from those found after
placebo (34.3 ± 5.3 vs. 34.2 ± 5.6;
P = NS). Baseline subscale scores of our study
participants varied between the 60th and the 80th percentile of the
MDBF reference sample (25). Consistently, baseline scores
in the HADS and the GBB-24 ranged around and above the mean of the
respective normal ranges. During DHEA treatment
significant improvements were observed for the T values of the HADS
anxiety subscale (baseline vs. 4 months, 47.3 ± 13.4
vs. 43.6 ± 13.5; P = 0.044) and
depression subscale (55.9 ± 13.8 vs. 51.8 ±
13.0; P = 0.017) and for the quartile value of the
GBB-24 subscale severity of exhaustion (2.6 ± 1.1 vs.
2.3 ± 1.2; P = 0.049). However, the latter also
improved significantly after placebo (2.6 ± 1.0 vs.
2.0 ± 1.2; P = 0.007), and none of the scores
after 4 months of DHEA was significantly different from
that after placebo treatment.
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DHEA treatment did not induce a significant change in any of the assessed aspects of sexuality [e.g. sexual interest, baseline vs. 4 months: DHEA, 48.8 ± 20.1 vs. 49.5 ± 21.7 (P = NS); placebo, 49.6 ± 22.1 vs. 49.2 ± 23.4 (P = NS)].
Safety
The total exposure to DHEA in each volunteer was 6300 mg over a period of 126 d. During the course of the study 187 adverse events (AEs) were reported for all 22 volunteers; 83 AEs occurred during DHEA administration, and the rest (104 AEs) during placebo. The most frequent AEs were headache (n = 43), influenza-like symptoms (n = 16), diarrhea (n = 13), abdominal pain (n = 12), back pain (n = 8), pharyngitis (n = 7), and fatigue (n = 5). Among all 187 AEs, 45 were rated as being not related to the study drug, 137 as unlikely to be related, and 5 as possibly related. After the blinding code was revealed, only 2 AEs (fatigue and increased sweating) previously assessed as possibly related with the study treatment coincided with the period of DHEA administration. Blood counts and hepatic and renal function parameters showed no significant changes. Mean prostate-specific antigen levels did not change during DHEA administration (baseline vs. 4 months, 1.41 ± 1.09 vs. 1.23 ± 0.91 µg/liter; P = 0.19; normal range, <4 µg/liter). However, two subjects from the older age group withdrew from the study after the first treatment period because of increases in serum PSA. Both of them had received placebo treatment. In one of them further clinical evaluation revealed a prostate carcinoma and he underwent successful surgical removal.
Discussion
In our sample of healthy men with low endogenous serum DHEAS due to a physiological age-related decline, the daily administration of 50 mg DHEA for 4 months restored DHEAS to levels usually found in young men, but did not lead to a significant improvement in well-being or mood. By contrast, using the identical design and measure, we previously found significant improvements in well-being and mood after DHEA replacement in women with adrenal insufficiency (11). It is unlikely that sex differences account for this difference, as a recent study described positive effects of DHEA replacement on well-being and mood in adrenal insufficiency regardless of sex (26).
Our results support the idea that the physiological decline in serum DHEAS with aging is not comparable to the pathological, premature loss of DHEA production in patients with adrenal insufficiency. DHEAS levels in the age-advanced men were still more than 1 order of magnitude higher than those usually found in patients with adrenal insufficiency (11, 26) or in glucocorticoid-treated patients with systemic lupus erythematodes (27, 28), in whom DHEA replacement has been shown to be beneficial. Accordingly, in patients with myotonic dystrophy (29) DHEA significantly improved scores on an activity of daily living scale, whereas DHEA induced no change in activity of daily living scores in healthy elderly men (30). Similarly, DHEA treatment led to significant improvements in mood and well-being in patients with major depression (31) and midlife dysthymia (32), but not in perimenopausal women without clearly defined symptomatology (33).
We did not find any changes in sexuality as opposed to the DHEA-induced improvements in women with adrenal insufficiency (11). However, the male volunteers did not suffer from impaired sexuality at baseline. Previous studies in healthy elderly men and women receiving DHEA (6, 34) did not find any changes in libido. In contrast, Reiter et al. (35) found a significant improvement in erectile function and other aspects of sexuality during DHEA treatment in 40- to 60-yr-old men with erectile dysfunction. Thus, DHEA may have the potential to improve impaired sexuality and mood, but does not further enhance normal performance.
DHEA treatment in the age-advanced men with low endogenous serum DHEAS led to restoration of youthful serum DHEA and DHEAS levels, as expected from our previous pharmacokinetic study (12). Conversion of DHEA to androgens or E can only take place after removal of the sulfate group, i.e. the conversion from DHEAS to DHEA, by widespread tissue sulfatase activity (36). Of note, the DHEA/DHEAS ratio was significantly lower in the older age group, with a concurrent lower increase in ADG. This might reflect reduced sulfatase activity in older men and thus reduced availability of DHEA for peripheral bioconversion. In contrast to findings in women, in whom DHEA is readily converted to androgens (6, 10, 11), we observed no change in circulating androgens after DHEA treatment in the age-advanced men. This matches results from previous studies in men (6, 10, 34). However, we found a significant increase in the androgen metabolite ADG, reflecting increased androgen synthesis in peripheral target cells (37). As expected from our previous pharmacokinetic study in age-advanced men with low endogenous DHEAS (12) we also observed slight, but significant, increases in circulating E, matching recent findings after DHEA treatment in elderly men (30, 34). The impact of DHEA administration on the estrogenic pool might be even greater, as measurements were performed in the nadir, 24 h after DHEA administration, thereby probably missing peak levels shortly after ingestion (12, 38).
We did not confirm the results reported by Morales et al. (6), who observed a DHEA-induced increase in IGF-I significantly different from the effect of placebo treatment in elderly men and women. However, our results are consistent with those of all other studies investigating the somatotropic axis in DHEA-treated men and women (9, 10, 11, 34, 39).
Consistent with previous findings in elderly men (10, 34) bone metabolism markers did not change in our DHEA-treated men. However, in postmenopausal women slight, but significant, increases in hip bone mineral density have been observed after 12 months of DHEA (8, 34), but not after 6 months of DHEA (9, 10). Thus, the effect of DHEA on bone seems to be sex specific and, hence, most likely mediated by the DHEA-induced increase in circulating androgens in women, but not in men.
We did not find any effect of DHEA on body composition or exercise capacity, in agreement with previous findings in elderly men (6, 30) and postmenopausal women (6, 9). However, 12 months of DHEA in postmenopausal women led to a decrease in midthigh fat and an increase in femoral muscle mass (39). After 6-month treatment with supraphysiological DHEA doses, a decrease in fat mass and an increase in muscle strength were observed in elderly men, but not in women (10). Thus, 4 months of treatment, as in our study, might have been too short a period to detect significant changes.
There were no serious adverse events related to DHEA treatment during this study or during three previous studies using treatment with 50–100 mg DHEA daily for 3–12 months in elderly men (30, 34, 35). However, the observed increase in ADG reflects enhanced peripheral androgen synthesis. Thus, it cannot be excluded that long-term exposure to DHEA will have an impact on target tissues of androgen action, including the prostate.
In conclusion, in contrast to previous findings in patients with adrenal insufficiency suffering from a pathological loss of DHEA secretion, we found no benefit after 4 months of DHEA treatment in healthy men with an age-related physiological decline of DHEA secretion. We cannot exclude that slight beneficial effects might be detected after longer exposure to DHEA, exposure to supraphysiological doses of DHEA, or treatment of larger numbers of subjects, nor are we able to judge whether a study design employing parallel groups instead of a cross-over design would have resulted in a different outcome. Furthermore, we cannot exclude possible effects in very old subjects with even lower circulating DHEAS levels, although we selected for serum DHEAS below the lower limit of the normal range for 15- to 39-yr-old men (2) and within the lowest quartile of 50- to 70-yr-old men. In addition, men might be less likely to benefit from DHEA replacement, as overall deprivation of sex steroids is more pronounced in aging women. However, our data do not provide sufficient scientific evidence to recommend widespread use of DHEA in healthy age-advanced men.
Acknowledgments
We are indebted to U. Schumacher and U. Mellinger for skillful performance of statistical analyses.
Footnotes
This work was supported by Jenapharm GmbH & Co. KG (Jena, Germany).
Abbreviations: ADG,
5-Androstane-3,17ß-diol-17-glucuronide; A’dione,
androstenedione; AE, adverse event; DHEA, dehydroepiandrosterone;
DHEAS, dehydroepiandrosterone sulfate; E1, estrone; GBB-24, Giessen
Complaint List; IGFBP-3, IGF-binding protein-3; MDBF, Multidimensional
Mood Questionnaire.
Received January 24, 2001.
Accepted July 11, 2001.
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