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Original Studies |
Department of Endocrinology, University of Oxford, Radcliffe Infirmary (P.J.H., J.A.H.W.), Oxford, United Kingdom OX2 7JS; and Departments of Medicine (E.M.G., C.R., V.K.K.C.), Psychiatry (F.A.H.), Community Medicine (A.T.P.), and Anatomy (J.H.), University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom CB2 2QQ
Address all correspondence and requests for reprints to: Prof. Krishna Chatterjee, Department of Medicine, Level 5, Addenbrooke’s Hospital, Hills Road, Cambridge, United Kingdom CB2 2QQ. E-mail: kkc1{at}mole.bio.cam.ac.uk
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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4-androstenedione rose from subnormal to within the
adult physiological range. Total testosterone increased from subnormal
to low normal with a fall in serum sex hormone-binding globulin in
females, but with no change in either parameter in males. In both
sexes, psychological assessment showed significant enhancement of
self-esteem with a tendency for improved overall well-being. Mood and
fatigue also improved significantly, with benefit being evident in the
evenings. No effects on cognitive or sexual function, body composition,
lipids, or bone mineral density were observed. Our results indicate
that DHEA replacement corrects this steroid deficiency
effectively and improves some aspects of psychological function.
Beneficial effects in males, independent of circulating testosterone
levels, suggest that it may act directly on the central nervous system
rather than by augmenting peripheral androgen biosynthesis. These
positive effects, in the absence of significant adverse events, suggest
a role for DHEA replacement therapy in the treatment of
Addison’s disease. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The fetal adrenals synthesize significant quantities of
DHEA(S), which then decline during childhood before rising
again with adrenarche to reach a peak in young adulthood
(12), followed by a relentless age-related decline
(13). DHEA(S) is the only known steroid to
show such decline in both sexes, and the fall in circulating levels has
been implicated in some of the catabolic and neurodegenerative changes
of aging, including increased cardiovascular mortality
(14), malignancy (15), and risk of
osteoporosis (16). Conversely, oral DHEA
replacement in normal elderly individuals, which restores circulating
serum levels of DHEA(S), and its metabolite
4-androstenedione, to a young adult level, has
been associated with improvement in psychological well-being
(17). Other replacement studies in this population have
shown variable beneficial effects on body composition, with enhanced
lean body mass (18, 19), changes in circulating
insulin-like growth factor I (17, 18, 20), improved bone
mineral density (BMD) and markers of bone turnover (21),
and decreased insulin resistance (19). A recent study also
suggests an antidepressant effect of DHEA therapy
(22).
Addison’s disease, or primary adrenal failure, occurs in about 1 in 25,000 individuals. It is characterized by chronic glucocorticoid and mineralocorticoid deficiency, which requires life-long oral replacement. Despite optimized therapy with these steroids, patients with Addison’s disease report a reduced quality of life compared with normal individuals, often complaining of persistent fatigue and reduced well-being (23, 24). We surmised that these symptoms are at least in part due to the associated failure of adrenal DHEA synthesis, which is not corrected. Furthermore, we hypothesized that such DHEA deficiency, accompanied by unopposed glucocorticoid action in the central nervous system, might result in specific cognitive and memory impairment. We, therefore, undertook a randomized, double blind, placebo-controlled cross over study of oral DHEA replacement in Addison’s disease. We assessed its effects on well-being, quality of life, and cognitive function and included measurement of biochemical indexes, circulating hormones, body muscle and fat masses, and BMD. We postulated that this patient cohort would be ideal for assessing DHEA replacement therapy for two reasons: first, as DHEA deficiency in this disorder is near absolute, the greater magnitude of change in circulating DHEA(S) levels after treatment would better demonstrate a beneficial change; and second, as patients are generally young, any detrimental effects of DHEA deficiency are less likely to be confounded by the multifactorial process of aging.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Forty-four subjects were recruited from the Endocrine Clinics in Oxford and Cambridge, United Kingdom, together with some individuals from the United Kingdom Addison’s Disease Patient Self-Help Group. The diagnosis of Addison’s disease was substantiated by documented hypocortisolemia associated with either raised serum ACTH or hyperpigmentation and, where available, positive adrenal antibodies. A minimum 4-yr duration of Addison’s disease was an inclusion criterion. Exclusion criteria were age less than 18 yr or greater than 70 yr, pregnancy, and any intercurrent significant medical or psychiatric condition. All patients took their usual glucocorticoid and mineralocorticoid hormone replacement, with both dosage and timing of administration being kept unchanged for 3 months before and throughout the study, except in three patients during brief intercurrent illness. Patients were also instructed not to alter their diet or exercise habits. The project had local ethical committee approval, and prior informed consent was obtained from all participants.
Study design
We recruited as many patients as possible who fulfilled the
entry criteria. However, as Addison’s disease is an uncommon disorder,
the total number of subjects studied was limited. We therefore adopted
a double blind, placebo-controlled, cross-over protocol to enhance the
likelihood of detecting true change in outcome measures after
DHEA treatment. A total of 44 patients were initially
recruited from the 2 centers. Of those randomized to DHEA
first, 2 patients failed to attend their initial assessment, and no
further contact was made, and 1 patient was withdrawn after the
development of insulin-dependent diabetes mellitus and subclinical
hypothyroidism. Of those randomized to placebo first, 1 patient failed
to attend for assessment, and 1 withdrew after initial assessment.
Thus, 39 subjects (15 males, aged 33–56 yr; 24 females, aged 26–69
yr), of whom only 4 were over 50 yr, completed both arms of the study,
and their results were subsequently analyzed. Further details regarding
patient characteristics are listed in Table 1
. Each patient was randomly assigned to
consecutive 3-month treatment periods of either micronized
DHEA (New Way International, Inc., Rockville,
MD; 50 mg daily, orally) followed by lactose-containing placebo tablets
of identical appearance or placebo followed by DHEA
administration. A washout interval of 1 month separated the 2 treatment
phases. Randomization of patients stratified by age and sex was
performed prospectively by an independent statistician, with half
receiving DHEA first and the other half receiving placebo.
Patient allocation details were coded and kept confidential until the
trial was completed.
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Patients were assessed at three points: baseline and after each treatment (DHEA or placebo) phase. On every occasion, fasting blood samples and a 24-h urine collection were obtained, with assessment of cognitive and psychological function and morphological measurements. In addition, patients completed a 15-item Profile of Mood State questionnaire, which covers 6 subscales of mental health: tension, depression, anger, vigor, fatigue, and confusion. This profile was obtained each morning and evening for 2 days before baseline and at the end of each treatment phase, with simultaneous saliva samples for hormone measurements.
Serum DHEAS, testosterone, 4-androstenedione
(Diagnostic Products, Gwyneod, UK), sex
hormone-binding globulin (SHBG; Wallac, Inc., Milton
Keynes, UK), lipids (Bayer Corp., Newbury, Berks,
UK), insulin-like growth factor I (IGF-I), IGF-binding protein-3
(IGFBP-3) (25), free T4, TSH,
vitamin B12, estradiol, bone alkaline phosphatase, and osteocalcin
(Metra Biosystems, Palo Alto, CA) were measured by
specific immunoassays in a single laboratory, with all samples from an
individual patient analyzed in the same assay. Estradiol was only
measured in males, because the hormonal status of females was variable
(some were postmenopausal and/or receiving exogenous estrogen
replacement therapy). Salivary cortisol and DHEA were
measured by enzyme-linked immunosorbent assay or RIA, respectively, as
described previously (26, 27). The intra- and interassay
coefficients of variation were less than 10% throughout. Insulin
resistance was quantified using homeostatic model assessment (HOMA) of
fasting glucose and insulin (28).
Cognitive function and psychological symptoms were assessed by structured interview. Subjects were asked questions about their general health, mental function, recent life events, sleep, and possible adverse effects of treatment. These were followed by a series of cognitive tests of episodic verbal memory (recall of a word list, recall of a list of names and a paired associate recognition test), semantic memory (retrieval of words from a semantic category), and spatial memory (recall of spatial location of objects). All of the memory tests were available in parallel versions, and a different set of items was used on each occasion of testing to avoid practice effects. Executive function was assessed using a letter cancellation task, the Stroop Color-Word Test, and tests of simple and choice reaction time. Psychological symptoms were assessed by self-completion of the General Health Questionnaire (GHQ-30) of Goldberg (29), which includes five subscales of mental health: anxiety, self-esteem, depression, difficulty coping, and social dysfunction (30). The GHQ was scored using a Likert scale. Sexual function was assessed using a self-completion questionnaire derived from the Golombok Rust Inventory of Sexual Satisfaction (31).
Morphological measurements included body mass index and waist to hip ratio as well as assessment of body composition. Measurement of the latter, together with lumbar and femoral BMD, was performed by dual energy x-ray absorptiometry using either QDR 2000 or QDR 4500 scanners (Hologic, Inc., Waltham, MA), with individual patients assessed on the same machine throughout. The coefficients of variation of BMD measurements at spine and femur on both instruments were 1%.
Based on previous studies in aging, we anticipated a rise in circulating DHEA(S) and androgen levels together with psychological changes during DHEA administration and designated these primary outcome measures. Secondary end points included changes in body composition, BMD, and cognitive function.
Statistical analysis
For both primary and secondary end points, data were analyzed by comparison of differences between mean values postplacebo treatment vs. post-DHEA using a paired t test. For each parameter, significant period effects were adjusted for, and treatment by period interactions were found not to be significant by the use of further t tests (32) (SPSS, Inc., Chicago, IL). The 5% and 1% levels of significance were used in tests involving primary and secondary outcomes, respectively.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After 50 mg oral micronized DHEA, serum DHEAS rose
markedly from grossly subnormal to levels within the physiological
range for young adults in both male and female subjects [males:
postplacebo, 1.06 ± 0.13 µmol/L (mean ± SEM);
post-DHEA, 5.43 ± 0.43 µmol/L; P
< 0.0001; females: postplacebo, 0.13 ± 0.01 µmol/L;
post-DHEA, 4.62 ± 0.88 µmol/L; P
< 0.0001; Fig. 1a]. Salivary
DHEA and DHEAS measurements at 1 and 3 months confirmed
these findings; DHEA was essentially absent with placebo,
but during DHEA treatment, salivary levels were similar to
those in normal individuals (morning DHEA: postplacebo,
0.07 ± 0.01 ng/mL; post-DHEA, 1.34 ± 0.55
ng/mL; P < 0.001; morning DHEAS: postplacebo,
0.37 ± 0.08 ng/mL; post-DHEA, 4.51 ± 0.48
ng/mL; P < 0.001). As expected there was, a similar
rise in 4-androstenedione, the
DHEA metabolite (males: postplacebo, 2.19 ± 0.30
nmol/L; post-DHEA, 4.57 ± 0.56 nmol/L;
P < 0.0001; females: postplacebo, 1.08 ± 0.28
nmol/L; post-DHEA, 4.41 ± 0.69 nmol/L;
P < 0.0001; Fig. 1b). The associated changes in
circulating androgens and SHBG were also analyzed according to the
patient’s gender. In females, serum total testosterone increased from
subnormal to low normal levels (postplacebo, 0.24 ± 0.02 nmol/L;
post-DHEA, 0.46 ± 0.07 nmol/L; P =
0.003) in conjunction with a fall in circulating SHBG (postplacebo,
82.0 ± 9.53 nmol/L; post-DHEA, 67.4 ± 7.55
nmol/L; P < 0.001). However, there was no significant
change in either SHBG or total testosterone (Fig. 1, c and d) or
estradiol (postplacebo, 95.23 ± 7.24 nmol/L; post-DHEA,
99.38 ± 7.32 nmol/L; P = 0.45) in males. Salivary
cortisol levels were measured in the morning and evening, and there was
no difference in profiles after DHEA vs.
placebo (morning cortisol: postplacebo, 98.5 ± 38 nmol/L;
post-DHEA, 97.4 ± 30 nmol/L; P =
0.84; evening cortisol: postplacebo, 12.7 ± 4.4 nmol/L;
post-DHEA, 13.2 ± 3.3 nmol/L; P =
0.95). All patients had normal vitamin B12 levels, and thyroid function
remained unchanged throughout the study.
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Well-being was assessed using the GHQ, which comprises 5 subscales
(anxiety, depression, self-esteem, coping, and social dysfunction)
together with a total score. The higher the score, the more symptoms
are present. Table 2 shows scores for
each category in 858 control subjects [calculated from age- and
sex-matched participants in the Health and Lifestyle Survey (30, 33)] together with values in patients at baseline and after
placebo or DHEA treatment. Figure 2 represents the difference between
symptom scores in the control sample and patients at each time point.
At baseline, although scores for overall GHQ as well as the individual
subscales of anxiety, self-esteem, and social dysfunction appeared
worse than those in the control group, these differences did not
achieve statistical significance. For each GHQ subscale, there was a
tendency for greater improvement after DHEA replacement
than after placebo. This effect was particularly evident with
self-esteem, which was significantly enhanced with DHEA
treatment [post-DHEA, 7.3 ± 1.45 (mean ±
SD); postplacebo, 8.4 ± 1.44; P <
0.001]. The net overall GHQ score also showed greater improvement
after DHEA, with the effect just failing to achieve
statistical significance (P = 0.08; Table 2).
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. After DHEA treatment
there was a tendency for a beneficial response, with lower overall mood
and fatigue scores in both the morning and evening. Interestingly, for
both parameters, the effect was most evident and statistically
significant at the end of the day [evening mood:
post-DHEA, 67.5 ± 15.21 (mean ±
SD); postplacebo, 73.0 ± 16.4; P =
0.018; evening fatigue: post-DHEA, 23.97 ± 5.73;
postplacebo, 27.03 ± 6.56; P = 0.002].
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Table 4 shows the scores at baseline
and after placebo or DHEA for tests of memory and
executive function. In contrast to the results of psychological
symptoms, where scores uniformly improved more after DHEA
than after placebo, cognitive tests did not show a consistent trend.
Some parameters (e.g. letter cancellation and choice
reaction time) were marginally better after placebo than after
DHEA, with others (e.g. spatial location
recall, name recall, and color-word test) showing the opposite effect.
Indeed, the only significant change (word list immediate recall) showed
greater improvement after placebo than after DHEA. None of
the other differences between DHEA and placebo on tests of
verbal memory (episodic or semantic) or spatial memory or on any of the
measures of executive function, whether measured in terms of accuracy
or speed of processing, were significant.
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Body composition and BMD
There was no difference in either mean lumbar vertebral (L2–L4)
or femoral neck BMD after placebo or DHEA treatment (Table 5). This was also reflected by no change
in serum osteocalcin or bone alkaline phosphatase, which are indexes of
bone turnover. There was no significant change in body mass index after
DHEA (data not shown), and measurement of body composition
with quantitation of either overall lean and fat mass or analysis at
different sites (limb and trunk) showed no significant change in either
sex. Serum IGF-I and IGFBP-3 levels were also unaltered.
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Adverse events
On direct questioning, the most common side-effect elicited was mild facial acne, affecting 8 of 24 females and 1 of 15 males during DHEA replacement, but this symptom was also reported by 4 females and 1 male who received placebo treatment. Mild excess facial hair growth was only reported in 2 females, 1 receiving DHEA and the other placebo. A single male subject reported increased facial hair growth after DHEA. However, no subject withdrew from the study due to these or other adverse effects. Serial hepatic enzyme measurements showed no effect of DHEA treatment.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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4-androstenedione. Our observations suggest
that 50 mg represents an optimum daily dose. Indeed, in other studies,
higher oral doses of DHEA ranging from 100–200 mg have
been shown to induce supraphysiological levels of DHEAS (34, 35). In conjunction with these hormonal effects we have
documented significant improvement in some aspects of psychological
function. Using well validated psychometric instruments, we found
significantly enhanced self-esteem with a tendency for improved overall
well-being with DHEA replacement. We also observed
significant changes in mood and fatigue after DHEA, with
evidence of diurnal variation in benefit, the most marked improvement
being in the evening. Persistent tiredness despite glucocorticoid replacement is described in Addison’s disease (23, 24). One explanation for our observations might be that DHEA treatment either delays cortisol clearance or augments its action in our patients. However, a previous study showed no change in serum cortisol profiles after DHEA in aging males (36), and we found no differences in morning or evening saliva cortisol levels in our patients after DHEA or placebo. Furthermore, there is strong evidence that DHEA is a potent antiglucocorticoid, antagonizing corticoid-induced thymic involution (37), enzyme induction (38), and hypertension (10). Another explanation might be that DHEA may affect the hypothalamic-pituitary-thyroid axis, but as thyroid function remained unchanged throughout the study, this seems unlikely. It is of interest that DHEA has a greater benefit on mood and fatigue in the evenings. Unfortunately, there are no good data on the diurnal pattern of tiredness in Addison’s disease. Although morning fatigue may be considered more specific in the diagnosis of organic disease, clinical endocrinologists will recall patients with Addison’s disease receiving standard steroid replacement therapy who complain of fatigue at all times of the day. Demonstrating a significant change in psychological variables in any small study is difficult in view of the numerous factors affecting such parameters. It may be that since both fatigue and mood were slightly worse in the evenings compared with the mornings, it was easier to document an improvement in the evening scores. With a larger study group, we may also have seen a significant improvement in the morning, but this remains speculative. Nevertheless, it is pertinent to note that all measures of well-being (GHQ scores) as well as the mood and fatigue scores moved in a beneficial direction after DHEA therapy, suggesting the potential value for such treatment in this disease context.
Another study of DHEA treatment in 24 women with Addison’s disease that was reported recently has also shown a rise in circulating adrenal androgens together with significantly improved well-being and sexuality (39). Our study supports their observations, but extends their findings in one major respect: we also observed psychological benefit in male patients. Furthermore, this effect in males was not associated with any significant increase in circulating testosterone or estradiol levels. In females, serum testosterone only rose slightly into the lower end of the normal range, with an associated fall in SHBG. These modest changes are consistent with the relative lack of androgenic side-effects (acne and hirsutism) after DHEA in our female patients, although we cannot discount the possibility that they might have developed after longer term treatment. It may also provide an explanation for our inability to demonstrate a positive effect of DHEA on libido and sexual function in females, as has been previously documented after testosterone supplementation in postmenopausal women (40), in whom circulating testosterone levels are restored to the upper end of the normal range. In our study the effects of DHEA treatment appeared independent of menopausal status or hormone replacement therapy. In view of the small size of our study group, subgroup analysis of female patients on or off exogenous estrogen replacement was not feasible. Together, these findings favor a central nervous system rather than a peripheral androgen-dependent effect of DHEA in patients.
In aging, cognitive decline has been known to be associated with lower circulating DHEAS levels (41), suggesting that such function might also be altered in Addison’s disease. We found no impairment of memory or higher executive function at initial assessment in our patients, nor any improvement after DHEA. Nevertheless, we cannot completely discount a link between DHEA and cognition for two reasons: first, baseline scores of cognitive function in our patients were already high, making it difficult to measure further improvement; and second, as we tested cognitive function in the morning, it is possible that a beneficial effect later in the day (as seen with mood and fatigue) was missed.
Treatment with DHEA for 12 months has been shown to increase femoral BMD and reduce markers of bone turnover in postmenopausal females (21), and another recent study in 280 elderly subjects showed enhanced femoral bone density in women less than 70 yr of age and enhanced radial bone density in women above 70 yr of age (42). Accordingly, in our study the lack of effect of DHEA on bone metabolism after only 3 months of treatment was not unexpected. However, our patients do have abnormally low BMD (mean z-scores: lumbar spine, -0.39; femoral neck, -0.37), suggesting that longer term assessment of DHEA treatment is indicated. The short duration of exposure to DHEA is also likely to explain its lack of effect on body composition in contrast to that reported previously in older subjects (18, 19, 20). In keeping with the variable effects of DHEA on IGF-I and its binding proteins reported in the literature (18, 19, 20, 38), we found no change in serum levels of IGF-I or IGFBP-3 in our study population.
In summary, we found that oral DHEA replacement in Addison’s disease is biochemically effective, well tolerated, and associated with improvement in psychological well-being, mood, and fatigue. Importantly, two thirds of our patients at the end of the study wished to continue DHEA replacement therapy. With beneficial effects in males as well as females, we propose that its psychological action may be centrally mediated as a neurosteroid rather than be androgen dependent. Our observations suggest a significant physiological role for DHEA in humans, and its addition to existing steroid replacement therapy in Addison’s disease should be considered further.
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Acknowledgments |
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Footnotes |
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2 Supported by a Wellcome Trust Overseas Postdoctoral Fellowship and
the Health Research Council of New Zealand.
3 Wellcome Trust Clinical Research Fellow.
4 Supported by the Wellcome Trust.
Received July 17, 2000.
Revised August 21, 2000.
Accepted August 27, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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5-derivatives in
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J. J. Christiansen, C. H. Gravholt, S. Fisker, N. Moller, M. Andersen, B. Svenstrup, P. Bennett, P. Ivarsen, J. S. Christiansen, and J. O. L. Jorgensen Very short term dehydroepiandrosterone treatment in female adrenal failure: impact on carbohydrate, lipid and protein metabolism Eur. J. Endocrinol., January 1, 2005; 152(1): 77 - 85. [Abstract] [Full Text] [PDF]
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) or placebo (
). The normal adult
reference ranges for the median age (40 yr) of our patients are:
females, 1:9–6.3 µmol/L; and males, 3:8–8.1 µmol/L. b, Serum
) and after placebo (