| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Studies |
Center for Psychobiological and Psychosomatic Research, University of Trier (O.T.W., O.N., A.C.G.,K.-M.P., D.H.H., C.K.), Trier; and the Department of Internal Medicine, University of Munich Medical School, Klinik Innenstadt (C.J.S., R.A.D.), Munich, Germany
Address all correspondence and requests for reprints to: Dr. Clemens Kirschbaum, Center for Psychobiological and Psychosomatic Research, University of Trier, Dietrichstrasse 10–11, 54290 Trier, Germany. E-mail: kirschba{at}uni-trier.de
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
DHEA replacement had no strong beneficial effect on any of the measured
psychological or cognitive parameters. Only women tended to report an
increase in well-being (P = 0.11) and mood
(P = 0.10), as assessed with questionnaires. They
also showed better performance in one of six cognitive tests (picture
memory) after DHEA. However, after Bonferroni 
adjustment, this
difference was no longer significant. No such trend was observed in men
(P > 0.20). Likewise, no beneficial effects of
DHEA substitution could be observed in any of the other tests of the
neuropsychological test battery in either sex (all
P > 0.20). In conclusion, the present data do not
support the idea of strong beneficial effects of a physiological DHEA
substitution on well-being or cognitive performance in healthy elderly
individuals.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-aminobutyric acid-A receptor (7) and as an agonist on the
receptor (8). Replacement studies investigating endocrine or immunological changes in enhanced DHEA levels have been conducted in elderly humans (9, 10, 11). In none of these experiments were data on psychological changes during DHEA administration reported. In a recent experiment Morales et al. (12) observed that after 3 months of DHEA replacement (50 mg/day), 67% of men and 84% of women reported an increase in psychological well-being, as observed in unstructured interviews. A similarly beneficial effect of DHEA substitution on well-being in morbidly obese adolescents could not be found in a more recent study by Vogiatzi et al. (13).
Epidemiological studies trying to link DHEAS levels and cognitive performance in elderly humans reported divergent results (14, 15). An open labeled clinical trial in six elderly patients with major depression reported memory and mood improvement after DHEA treatment (16). A first placebo-controlled experiment in young healthy men did not find positive effects of DHEA on memory performance (17).
As DHEA and DHEAS concentrations decline with age, and DHEA seems to exert such a broad variety of beneficial effects in rodents, the idea of DHEA as a possible "fountain of youth" is now being discussed [see editorial by Baulieu (18)]. However, as only the adrenal cortex of primates produces larger amounts of DHEA (19, 20), extrapolation from results obtained in subprimate species to humans is difficult. The present study thus was performed to investigate possible effects of a physiological DHEA replacement on cognitive performance and well-being in healthy elderly women and men.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The study was performed in a double blind, placebo-controlled design. The two treatment periods of 2 weeks each (placebo or 50 mg/day DHEA) were separated by a 2-week washout period. Half of the subjects received placebo first, and the other half received DHEA. Subjects were instructed to ingest one DHEA or placebo capsule each night at bedtime. One DHEA capsule (Prasteron, Audor Pharma, Regensburg, Germany) contained 50 mg DHEA and lactose; placebo capsules contained lactose only.
Every subject had four appointments at the laboratory, one before and one after each treatment period. At each of the four appointments a blood sample was obtained for hormone analysis. After each of the two treatment periods, subjects had to complete questionnaires as well as a neuropsychological test battery developed for testing elderly subjects (see below). On the two test sessions parallel versions of the tests were used. Testing was performed between 0800–1200 h. Each subject was tested at the same time of day by the same investigator.
Assessment of well-being and mood
A quality of life questionnaire (22) for assessment of psychological and physical complaints in individuals of advanced age was used. In this test higher test scores indicate lower quality of life (test score range, 39–116).
A mood questionnaire (23) was used to assess elevated vs. depressed mood, wakefulness vs. sleepiness, and calmness vs. restlessness.
The German short version of the Center for Epidemiological Studies Depression Scale (24) was employed to measure depression.
In an unstructured interview, subjects were asked to report any changes in their physical or psychological conditions during the past 2-week period. If changes were reported, subjects rated the intensity of these changes.
Neuropsychological tests
A broad variety of tests was used to assess different aspects of cognitive performance (speed as well as power aspects, short and long term memory). Tests 2–5 are part of a standardized test battery for the assessment of cognitive performance in elderly subjects (22). The test material is especially designed for this population (e.g. text printed in larger fonts).
Concentration. In the age concentration test (25), the subject has to cross out a specified target item (a half-circle) of several similar looking distractor items (half-circles that differ in color and/or position). The time for completion as well as the amount of correct decisions are measured.
Visual short and long term memory (picture memory test). Fourteen pictures showing everyday objects (e.g. fruits or clothes) were presented at a rate of one picture every 2 s. Immediate and delayed (15 min later, after test 5) free recalls were assessed.
Stroop test (26). The classical version with three cards was used. For each card the time needed to read the items (e.g. name the colors on cards 2 and 3) was recorded, and the difference between cards 3 and 2 was used as the test score.
Digit span (number rehearsal forward and backwards). Series of digits were read to the subjects, which they had to repeat. If a subjects failed on two consecutive trials the test was stopped, and the highest number of digits correctly repeated was used as the test score.
Psychomotoric speed (number connecting). Here the subject has to connect with a pencil numbers on a piece of paper (from 1–30) as fast as possible. Two test sheets were used in each session, and the mean time needed for completion of the task was used as the test score.
Auditory verbal learning test (27, 28). A list of 15 words was read to the subjects 4 times. Immediate recall was tested after each presentation. Thereafter, a second list was presented only once, with immediate recall being tested; delayed recall of the first list was then tested. This test is an indicator of verbal memory; the total number of words recalled as well as the slope of the learning curve and the amount of interference produced by the second list can be evaluated.
Hormone assays
At all four appointments blood was collected from the subjects for hormone analyses. Plasma DHEAS levels were measured at all four appointments, DHEA, androstenedione (A’dione), testosterone (T), insulin-like growth factor I (IGF-I), and IGF-binding protein-3 (IGFBP-3) levels were assessed only after each treatment period. The following commercially available assays were used: DHEAS (enzyme-linked immunosorbent assay; IBL, Hamburg, Germany), DHEA and A’dione (RIA; IBL), T (Delfia, Pharmacia, Freiburg, Germany), and IGF-I (RIA; BioMerieux, Marcy-l’Etoile, France). IGFBP-3 levels were determined using an in-house time-resolved immunoassay with fluorescence detection, as described previously (29). The sensitivity of the assays were 0.05 µg/mL for DHEAS, 0.009 ng/mL for DHEA, 0.02 ng/mL for A’dione, 0.1 ng/mL for T, 0.02 ng/mL for IGF-I, and 10.9 µg/L for IGFBP-3, respectively. The inter- and intraassay coefficients of variations were 7% and 8% for DHEAS, 4% and 8% for DHEA, 5% and 7% for A’dione, 8% and 9% for T, 3.8% and 5.7% for IGF-I, and 3.5% and 11.7% for IGFBP-3, respectively. Of additional note is that the cross-reactivity of the DHEA RIA for DHEAS is less than 0.02%.
Statistical analyses
Hormone data were analyzed by ANOVA, with the two factors sex (two levels) and treatment (two levels). Post-hoc comparisons were performed using Newman-Keuls tests. Cognitive as well as psychological data were analyzed by two-tailed Student’s t test for correlated samples for each sex separately.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The effects of DHEA replacement on steroid hormones are summarized
in Table 1
. ANOVA showed that DHEAS, DHEA, A’dione, and
T levels increased significantly (P < 0.001) in
response to DHEA treatment in both sex. DHEAS levels did not differ for
baseline, washout, and placebo treatment periods (see Table 1 for F
values of the treatment main effect).
|
The results are summarized in Table 1
. IGF-I levels did not change
in men or women after DHEA treatment, although a small, but
nonsignificant, trend toward an increase was observed (F = 1.56;
P > 0.20). IGFBP-3 levels were unaltered in men and
women.
Mood and well-being
No significant changes in any of the questionnaires used to assess
mood or well-being was observed for the total group. However, a trend
toward an increase in quality of life was found in women, as indicated
by a decrease in the number of psychological and physical complaints
(74.5 \ 6 after placebo vs. 67.2 \ 4 after DHEA;
t = 1.68; P = 0.11). In addition, a
trend toward increased mood and wakefulness was observed in this group
(t = 1.7; P = 0.10 for both
comparisons; Fig. 1). No such changes were seen in men.
No changes were observed in the depression scale (both
t < 1); however, most of the subjects already had very
low depression scores at baseline.
|
for details).
|
The results of the neuropsychological test battery are shown in
Table 3. There was no overall increase in performance
after DHEA substitution. In none of the six tests were significant
changes observed in men. In women, an increase in performance in the
picture memory test was found under both recall conditions (immediate
recall: t14 = -2.7; P < 0.05;
delayed recall: t14 = -2.38; P
< 0.05). It should be noted, however, that after Bonferroni
correction for multiple comparisons, the adjusted level is
P = 0.0056, given that nine comparisons were made for
each sex. Thus, the observed difference in picture memory after DHEA
treatment can no longer be considered statistically significant. In
addition to the total number of recalled words, the auditory verbal
learning test was analyzed using an ANOVA, with the three factors sex,
treatment, and level of practice. However, neither treatment main
effect nor treatment by level of practice interaction was significant
(all F < 1).
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
correction to avoid type I errors. In the unstructured interview, 32%
of the men and 53% of the women reported changes during DHEA
substitution. The reported changes after DHEA differed markedly for
each individual, with both positive as well as negative changes
reported. Only 4 of 40 participants (1 woman and 3 men) perceived a
marked improvement in well-being and physical activity.
The present findings support recent findings by Vogiatzi et
al. (13), who failed to observe significant effects of DHEA on
well-being in morbidly obese adolescents. On the other hand, our
results contradict previous findings in elderly subjects (12). With
similar effects on sex steroid levels as described in this study,
Morales et al. (12) reported a marked increase in well-being
in 84% of the women and 67% of the men after 3 months of 50 mg/day
DHEA treatment, suggesting a large effect of DHEA substitution on
well-being. Of course, the experimental protocols of the two studies
differ to some degree. First, in the present study subjects were
substituted for 2 weeks instead of 3 months using the same dose. The
rational for the chosen strategy was that if DHEA(S) would indeed exert
its effects on well-being or cognition as a neurosteroid, as suggested
by others (1, 7), this should lead to significant treatment effects
within only a few days. Direct effects of DHEA(S) on the
-aminobutyric acid-A receptor in the CNS (7) or a genomic effects of
the biologically active androgen metabolites A’dione or T should have
been detectable after 2 weeks of DHEA administration (30). Animal
studies indeed found memory-enhancing effects of DHEA after even a
single application (3, 4, 5). A second difference between the two studies
was the use of standardized questionnaires and test material to
investigate changes in psychological parameters in the present study.
Despite the use of elaborated psychological test material, no overall
beneficial effect of DHEA treatment could be observed in the present
study. In addition, with more subjects investigated here (and the same
double-blind cross-over study design), the probability of detecting
changes in psychological parameters was very high given the effect size
of DHEA substitution reported by Morales and co-workers (12).
With respect to the IGF system, a 2-week DHEA treatment does not seem sufficient to enhance IGF-I. A prolonged treatment period of 3 months, however, significantly increased the level of bioavailable IGF-I by a simultaneous rise in IGF-I and a decrease in IGFBP-1 (12). After 2 weeks of DHEA substitution, IGF-I levels tended to be higher than the respective baseline values without reaching statistical significance. It appears that DHEA achieves its effect on IGF-I through rather indirect mechanisms, which may take more than 2 weeks to develop. A rise in IGF-I could be necessary to produce beneficial effects of DHEA on well-being. GH or IGF-I administration to GH-deficient individuals has multiple beneficial effects (31), some of which are similar to the reported DHEA effects, including elevated mood, improved quality of life, and behavioral changes (32, 33). However, to date no studies have addressed this possible mechanism of DHEA action on psychological parameters.
The results of the present study do not support the idea of a strong direct effect of DHEA on cognition or well-being in healthy elderly subjects. Possible beneficial effects of DHEA might be indirect and are probably not the consequences of a direct action of DHEA on the CNS. Whether prolonged DHEA substitution in healthy elderly individuals affects psychological parameters remains to be shown.
|
Footnotes |
|---|
Received January 8, 1997.
Revised March 14, 1997.
Accepted March 20, 1997.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A Hartkamp, R Geenen, G L R Godaert, H Bootsma, A A Kruize, J W J Bijlsma, and R H W M Derksen Effect of dehydroepiandrosterone administration on fatigue, well-being, and functioning in women with primary Sjogren syndrome: a randomised controlled trial Ann Rheum Dis, January 1, 2008; 67(1): 91 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Panjari and S. R. Davis DHEA therapy for women: effect on sexual function and wellbeing Hum. Reprod. Update, May 1, 2007; 13(3): 239 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Genazzani, N. Pluchino, S. Luisi, and M. Luisi Estrogen, cognition and female ageing Hum. Reprod. Update, March 1, 2007; 13(2): 175 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. W. Yau, J. Noble, M. Graham, and J. R. Seckl Central Administration of a Cytochrome P450-7B Product 7{alpha}-Hydroxypregnenolone Improves Spatial Memory Retention in Cognitively Impaired Aged Rats J. Neurosci., October 25, 2006; 26(43): 11034 - 11040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Nair, R. A. Rizza, P. O'Brien, K. Dhatariya, K. R. Short, A. Nehra, J. L. Vittone, G. G. Klee, A. Basu, R. Basu, et al. DHEA in Elderly Women and DHEA or Testosterone in Elderly Men N. Engl. J. Med., October 19, 2006; 355(16): 1647 - 1659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Muller, A. W. van den Beld, Y. T. van der Schouw, D. E. Grobbee, and S. W. J. Lamberts Effects of Dehydroepiandrosterone and Atamestane Supplementation on Frailty in Elderly Men J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3988 - 3991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. O'Donnell, T. G. Travison, S. S. Harris, J. L. Tenover, and J. B. McKinlay Testosterone, Dehydroepiandrosterone, and Physical Performance in Older Men: Results from the Massachusetts Male Aging Study J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 425 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Kaufman and A. Vermeulen The Decline of Androgen Levels in Elderly Men and Its Clinical and Therapeutic Implications Endocr. Rev., October 1, 2005; 26(6): 833 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Schmidt, R. C. Daly, M. Bloch, M. J. Smith, M. A. Danaceau, L. Simpson St. Clair, J. H. Murphy, N. Haq, and D. R. Rubinow Dehydroepiandrosterone Monotherapy in Midlife-Onset Major and Minor Depression Arch Gen Psychiatry, February 1, 2005; 62(2): 154 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Dhatariya and K. S. Nair Dehydroepiandrosterone: Is There a Role for Replacement? Mayo Clin. Proc., October 1, 2003; 78(10): 1257 - 1273. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Knopman and V. W. Henderson DHEA for Alzheimer's disease: A modest showing by a superhormone Neurology, April 8, 2003; 60(7): 1060 - 1061. [Full Text] [PDF]
|
|
|
|
|
|
F. Labrie, V. Luu-The, C. Labrie, A. Belanger, J. Simard, S.-X. Lin, and G. Pelletier Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone Endocr. Rev., April 1, 2003; 24(2): 152 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Strous, R. Maayan, R. Lapidus, R. Stryjer, M. Lustig, M. Kotler, and A. Weizman Dehydroepiandrosterone Augmentation in the Management of Negative, Depressive, and Anxiety Symptoms in Schizophrenia Arch Gen Psychiatry, February 1, 2003; 60(2): 133 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Lasley, N. Santoro, J. F. Randolf, E. B. Gold, S. Crawford, G. Weiss, D. S. McConnell, and M. F. Sowers The Relationship of Circulating Dehydroepiandrosterone, Testosterone, and Estradiol to Stages of the Menopausal Transition and Ethnicity J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3760 - 3767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Crone, G. Gabriel, and T. N. Wise Non-Herbal Nutritional Supplements--The Next Wave: A Comprehensive Review of Risks and Benefits for the C-L Psychiatrist Psychosomatics, August 1, 2001; 42(4): 285 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Moffat, A. B. Zonderman, S. M. Harman, M. R. Blackman, C. Kawas, and S. M. Resnick The Relationship Between Longitudinal Declines in Dehydroepiandrosterone Sulfate Concentrations and Cognitive Performance in Older Men Arch Intern Med, July 24, 2000; 160(14): 2193 - 2198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Arlt, F. Callies, J. C. van Vlijmen, I. Koehler, M. Reincke, M. Bidlingmaier, D. Huebler, M. Oettel, M. Ernst, H. M. Schulte, et al. Dehydroepiandrosterone Replacement in Women with Adrenal Insufficiency N. Engl. J. Med., September 30, 1999; 341(14): 1013 - 1020. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. M. Wolkowitz, V. I. Reus, A. Keebler, N. Nelson, M. Friedland, L. Brizendine, and E. Roberts Double-Blind Treatment of Major Depression With Dehydroepiandrosterone Am J Psychiatry, April 1, 1999; 156(4): 646 - 649. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Fossel Telomerase and the Aging Cell: Implications for Human Health JAMA, June 3, 1998; 279(21): 1732 - 1735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Kudielka, J. Hellhammer, D. H. Hellhammer, O. T. Wolf, K.-M. Pirke, E. Varadi, J. Pilz, and C. Kirschbaum Sex Differences in Endocrine and Psychological Responses to Psychosocial Stress in Healthy Elderly Subjects and the Impact of a 2-Week Dehydroepiandrosterone Treatment J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1756 - 1761. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. Rose, A. Allan, S. Gauldie, G. Stapleton, L. Dobbie, K. Dott, C. Martin, L. Wang, E. Hedlund, J. R. Seckl, et al. Neurosteroid Hydroxylase CYP7B. VIVID REPORTER ACTIVITY IN DENTATE GYRUS OF GENE-TARGETED MICE AND ABOLITION OF A WIDESPREAD PATHWAY OF STEROID AND OXYSTEROL HYDROXYLATION J. Biol. Chem., June 22, 2001; 276(26): 23937 - 23944. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
