Improvement in Mood and Fatigue after Dehydroepiandrosterone Replacement in Addison’s Disease in a Randomized, Double Blind Trial
Penelope J. Hunt1,2,
Eleanor M. Gurnell1,3,
Felicia A. Huppert,
Christine Richards,
A. Toby Prevost,
John A. H. Wass,
Joseph Herbert and
V. Krishna K. Chatterjee4
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
Dehydroepiandrosterone (DHEA) and DHEA
sulfate (DHEAS) are adrenalprecursors of steroid biosynthesis and
centrally acting neurosteroids.Glucocorticoid and mineralocorticoid
deficiencies in Addison’sdisease require life-long hormone
replacement, but the associatedfailure of DHEA synthesis
is not corrected. We conducted a randomized,double blind study in
which 39 patients with Addison’sdisease received either 50 mg oral
DHEA daily for 12 weeks,followed by a 4-week washout
period, then 12 weeks of placebo,or vice versa. After
DHEA treatment, levels of DHEAS and
4-androstenedionerose from subnormal to within the
adult physiological range.Total testosterone increased from subnormal
to low normal witha fall in serum sex hormone-binding globulin in
females, butwith no change in either parameter in males. In both
sexes,psychological assessment showed significant enhancement of
self-esteemwith a tendency for improved overall well-being. Mood and
fatiguealso 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
thatDHEA replacement corrects this steroid deficiency
effectivelyand improves some aspects of psychological function.
Beneficialeffects in males, independent of circulating testosterone
levels,suggest that it may act directly on the central nervous system
ratherthan by augmenting peripheral androgen biosynthesis. These
positiveeffects, in the absence of significant adverse events, suggest
arole for DHEA replacement therapy in the treatment of
Addison’sdisease.
DEHYDROEPIANDROSTERONE (DHEA)
and its sulfate ester DHEAS arethe most abundant circulating steroids.
First characterizedin the 1930s (1), their role as
important precursors of peripheralsteroid (androgen and estrogen)
biosynthesis has been well established.However, more recently, their
added potential action as centrallyacting neurosteroids has evoked
interest. Animal work has shownthat DHEA(S) is
concentrated within the hippocampus (2), andfurther
studies indicate that it enhances neuronal survivalin vitro
(3, 4) and improves long term memory in vivo
(3, 5).Elevated glucocorticoid levels are associated with
cognitiveimpairment (6) and hippocampal atrophy in
rodents and humans(7, 8) as well as mood disturbance
(9). DHEA(S) exerts a powerful
antiglucocorticoideffect, although the precise mechanism is unclear
(10, 11).Therefore, a fall in circulating levels of
DHEA(S) results ina state of relative glucocorticoid
excess that might adverselyinfluence neural function, including
effects on cognition, memory,and mood.
The fetal adrenals synthesize significant quantities of
DHEA(S),which then decline during childhood before rising
again withadrenarche to reach a peak in young adulthood
(12), followedby a relentless age-related decline
(13). DHEA(S) is the onlyknown steroid to
show such decline in both sexes, and the fallin circulating levels has
been implicated in some of the catabolicand neurodegenerative changes
of aging, including increasedcardiovascular 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 itsmetabolite
4-androstenedione, to a young adult level, has
beenassociated with improvement in psychological well-being
(17).Other replacement studies in this population have
shown variablebeneficial effects on body composition, with enhanced
lean bodymass (18, 19), changes in circulating
insulin-like growth factorI (17, 18, 20), improved bone
mineral density (BMD) and markersof bone turnover (21),
and decreased insulin resistance (19).A recent study also
suggests an antidepressant effect of DHEAtherapy
(22).
Addison’s disease, or primary adrenal failure, occursin about 1 in
25,000 individuals. It is characterized by chronicglucocorticoid and
mineralocorticoid deficiency, which requireslife-long oral
replacement. Despite optimized therapy with thesesteroids, patients
with Addison’s disease report a reducedquality of life compared with
normal individuals, often complainingof persistent fatigue and reduced
well-being (23, 24). We surmisedthat these symptoms are
at least in part due to the associatedfailure of adrenal
DHEA synthesis, which is not corrected. Furthermore,we
hypothesized that such DHEA deficiency, accompanied by
unopposedglucocorticoid action in the central nervous
system, might resultin specific cognitive and memory
impairment. We, therefore,undertook a randomized, double blind,
placebo-controlled crossover study of oral DHEA
replacement in Addison’s disease.We assessed its effects on
well-being, quality of life, andcognitive function and included
measurement of biochemical indexes,circulating hormones, body muscle
and fat masses, and BMD. Wepostulated that this patient cohort would
be ideal for assessingDHEA replacement therapy for two
reasons: first, as DHEA deficiencyin this disorder is
near absolute, the greater magnitude ofchange in circulating
DHEA(S) levels after treatment would betterdemonstrate a
beneficial change; and second, as patients aregenerally young, any
detrimental effects of DHEA deficiencyare less likely to
be confounded by the multifactorial processof aging.
Forty-four subjects were recruited from the Endocrine Clinicsin
Oxford and Cambridge, United Kingdom, together with someindividuals
from the United Kingdom Addison’s DiseasePatient Self-Help Group. The
diagnosis of Addison’s diseasewas substantiated by documented
hypocortisolemia associatedwith either raised serum ACTH or
hyperpigmentation and, whereavailable, positive adrenal antibodies. A
minimum 4-yr durationof Addison’s disease was an inclusion criterion.
Exclusioncriteria 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
mineralocorticoidhormone replacement, with both dosage and timing of
administrationbeing kept unchanged for 3 months before and throughout
thestudy, except in three patients during brief intercurrent illness.
Patientswere also instructed not to alter their diet or exercise
habits.The project had local ethical committee approval, and prior
informedconsent was obtained from all participants.
Study design
We recruited as many patients as possible who fulfilled the
entrycriteria. However, as Addison’s disease is an uncommondisorder,
the total number of subjects studied was limited.We therefore adopted
a double blind, placebo-controlled, cross-overprotocol to enhance the
likelihood of detecting true changein outcome measures after
DHEA treatment. A total of 44 patientswere initially
recruited from the 2 centers. Of those randomizedto DHEA
first, 2 patients failed to attend their initial assessment,and no
further contact was made, and 1 patient was withdrawnafter the
development of insulin-dependent diabetes mellitusand subclinical
hypothyroidism. Of those randomized to placebofirst, 1 patient failed
to attend for assessment, and 1 withdrewafter initial assessment.
Thus, 39 subjects (15 males, aged33–56 yr; 24 females, aged 26–69
yr), of whom only4 were over 50 yr, completed both arms of the study,
and theirresults were subsequently analyzed. Further details regarding
patientcharacteristics are listed in Table 1. Each patient was randomlyassigned to
consecutive 3-month treatment periods of eithermicronized
DHEA(New Way International, Inc., Rockville,
MD;50 mg daily, orally) followed by lactose-containing placebotablets
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
performedprospectively by an independent statistician, with half
receivingDHEA first and the other half receiving placebo.
Patient allocationdetails were coded and kept confidential until the
trial wascompleted.
Patients were assessed at three points: baseline and after each
treatment(DHEA or placebo) phase. On every occasion,
fasting blood samplesand a 24-h urine collection were obtained, with
assessment ofcognitive and psychological function and morphological
measurements.In addition, patients completed a 15-item Profile of Mood
Statequestionnaire, which covers 6 subscales of mental health:
tension,depression, anger, vigor, fatigue, and confusion. This profile
wasobtained each morning and evening for 2 days before baselineand at
the end of each treatment phase, with simultaneous salivasamples 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 measuredby
specific immunoassays in a single laboratory, with all samplesfrom an
individual patient analyzed in the same assay. Estradiolwas only
measured in males, because the hormonal status of femaleswas variable
(some were postmenopausal and/or receiving exogenousestrogen
replacement therapy). Salivary cortisol and DHEA were
measuredby enzyme-linked immunosorbent assay or RIA, respectively, as
describedpreviously (26, 27). The intra- and interassay
coefficientsof variation were less than 10% throughout. Insulin
resistancewas quantified using homeostatic model assessment (HOMA) of
fastingglucose and insulin (28).
Cognitive function and psychological symptoms were assessedby
structured interview. Subjects were asked questions abouttheir general
health, mental function, recent life events, sleep,and possible
adverse effects of treatment. These were followedby a series of
cognitive tests of episodic verbal memory (recallof a word list,
recall of a list of names and a paired associaterecognition test),
semantic memory (retrieval of words froma semantic category), and
spatial memory (recall of spatiallocation of objects). All of the
memory tests were availablein parallel versions, and a different set
of items was usedon each occasion of testing to avoid practice
effects. Executivefunction was assessed using a letter cancellation
task, theStroop Color-Word Test, and tests of simple and choice
reactiontime. Psychological symptoms were assessed by self-completion
ofthe 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 wasassessed using a self-completion questionnaire
derived fromthe Golombok Rust Inventory of Sexual Satisfaction
(31).
Morphological measurements included body mass index and waistto hip
ratio as well as assessment of body composition. Measurementof the
latter, together with lumbar and femoral BMD, was performedby dual
energy x-ray absorptiometry using either QDR 2000 orQDR 4500 scanners
(Hologic, Inc., Waltham, MA), with individualpatients
assessed on the same machine throughout. The coefficientsof variation
of BMD measurements at spine and femur on bothinstruments were
1%.
Based on previous studies in aging, we anticipated a rise in
circulatingDHEA(S) and androgen levels together with
psychological changesduring DHEA administration and
designated these primary outcomemeasures. Secondary end points
included changes in body composition,BMD, and cognitive function.
Statistical analysis
For both primary and secondary end points, data were analyzedby
comparison of differences between mean values postplacebotreatment
vs. post-DHEA using a paired t test.
For each parameter,significant period effects were adjusted for, and
treatmentby period interactions were found not to be significant by
theuse of further t tests (32) (SPSS, Inc., Chicago, IL). The 5%and 1% levels of significance were
used in tests involving primaryand secondary outcomes,
respectively.
After 50 mg oral micronized DHEA, serum DHEAS rose
markedlyfrom grossly subnormal to levels within the physiological
rangefor 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 ± 0.88µmol/L; P
< 0.0001; Fig. 1a]. Salivary
DHEA and DHEASmeasurements at 1 and 3 months confirmed
these findings; DHEAwas 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 changesin
circulating androgens and SHBG were also analyzed accordingto the
patient’s gender. In females, serum total testosteroneincreased 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 eitherSHBG 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 inthe morning and evening, and there was
no difference in profilesafter DHEAvs.
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 normalvitamin B12 levels, and thyroid function
remained unchangedthroughout the study.
Figure 1. Hormone and biochemical changes in males and
females after DHEA treatment. a, Serum DHEAS levels after
50 mg oral DHEA () 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
4-androstenedione after DHEA () or
placebo (; normal adult reference range in either sex, 3–12
nmol/L). c, Serum SHBG after DHEA () or placebo ()
treatment (normal adult range: males, 14–103 nmol/L; females, 18–117
nmol/L). d, Serum total testosterone after DHEA () or
placebo (; normal adult range: males, 8–32 nmol/L; females, 0:2–3.
nmol/L). Note the different y-axes for males
(left) and females (right).
Well-being, mood, and fatigue
Well-being was assessed using the GHQ, which comprises 5 subscales
(anxiety,depression, self-esteem, coping, and social dysfunction)
togetherwith a total score. The higher the score, the more symptoms
arepresent. Table 2 shows scores for
each category in 858 controlsubjects [calculated from age- and
sex-matched participantsin the Health and Lifestyle Survey (30, 33)] together with valuesin patients at baseline and after
placebo or DHEA treatment.Figure 2 represents the difference between
symptom scores inthe control sample and patients at each time point.
At baseline,although scores for overall GHQ as well as the individual
subscalesof anxiety, self-esteem, and social dysfunction appeared
worsethan those in the control group, these differences did not
achievestatistical significance. For each GHQ subscale, there was a
tendencyfor greater improvement after DHEA replacement
than after placebo.This effect was particularly evident with
self-esteem, whichwas 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 greaterimprovement
after DHEA, with the effect just failing to achieve
statisticalsignificance (P = 0.08; Table 2).
Figure 2. Deviation in GHQ symptom scores from
controls in Addison’s disease patients. For each scale, the difference
between values in patients vs. control subjects is shown
at baseline () and after placebo () or DHEA
() treatment.
Patients completed a profile of mood state questionnaire inthe morning
and evening on 2 consecutive days, and the aggregatescores for mood
and fatigue at each time point are shown inTable 3. After DHEA treatment
there was a tendency for a beneficialresponse, with lower overall mood
and fatigue scores in boththe morning and evening. Interestingly, for
both parameters,the effect was most evident and statistically
significant atthe 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].
Table 3. Mood and fatigue scores in Addison’s disease
Cognitive and sexual function
Table 4 shows the scores at baseline
and after placebo or DHEAfor tests of memory and
executive function. In contrast to theresults of psychological
symptoms, where scores uniformly improvedmore after DHEA
than after placebo, cognitive tests did notshow a consistent trend.
Some parameters (e.g. letter cancellationand choice
reaction time) were marginally better after placebothan 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
greaterimprovement after placebo than after DHEA. None of
the otherdifferences between DHEA and placebo on tests of
verbal memory(episodic or semantic) or spatial memory or on any of the
measuresof executive function, whether measured in terms of accuracy
orspeed of processing, were significant.
Our sexual behavior questionnaire assessed interest and arousal,
frequencyof intercourse, erectile dysfunction, and lubrication. There
wasno significant difference in any of these indexes after
DHEAvs. placebo.
Body composition and BMD
There was no difference in either mean lumbar vertebral (L2–L4)
orfemoral neck BMD after placebo or DHEA treatment (Table 5).This was also reflected by no change
in serum osteocalcin orbone 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 quantitationof either overall lean and fat mass or analysis at
differentsites (limb and trunk) showed no significant change in either
sex.Serum IGF-I and IGFBP-3 levels were also unaltered.
Compared with the effect of placebo, there were no changes inserum
cholesterol, triglycerides, or lipoproteins (high andlow density
lipoproteins) or in tissue insulin sensitivity measuredby HOMA after
DHEA treatment (data not shown).
Adverse events
On direct questioning, the most common side-effect elicitedwas
mild facial acne, affecting 8 of 24 females and 1 of 15males during
DHEA replacement, but this symptom was also reportedby 4
females and 1 male who received placebo treatment. Mildexcess facial
hair growth was only reported in 2 females, 1receiving
DHEA and the other placebo. A single male subjectreported
increased facial hair growth after DHEA. However, no
subjectwithdrew from the study due to these or other adverse effects.
Serialhepatic enzyme measurements showed no effect of
DHEA treatment.
Before treatment our patients with Addison’s disease hadmarkedly
subnormal DHEAS and DHEA levels. We have shown that50 mg
DHEA corrects this deficiency, achieving mean circulating
DHEASlevels of 4.93 µmol/L in our cohort, which were sustained
throughoutthe replacement period, falling back to baseline after the
washoutinterval. These levels are within the physiological range for
themedian age of our patients. Salivary levels of DHEA,
which correlatewell with those in blood, were also normalized. The
rise inDHEAS was associated with normalization of its metabolite
4-androstenedione.Our observations suggest
that 50 mg represents an optimum dailydose. Indeed, in other studies,
higher oral doses of DHEA rangingfrom 100–200 mg have
been shown to induce supraphysiologicallevels of DHEAS (34, 35). In conjunction with these hormonaleffects we have
documented significant improvement in some aspectsof psychological
function. Using well validated psychometricinstruments, we found
significantly enhanced self-esteem witha tendency for improved overall
well-being with DHEA replacement.We also observed
significant changes in mood and fatigue afterDHEA, with
evidence of diurnal variation in benefit, the mostmarked improvement
being in the evening.
Persistent tiredness despite glucocorticoid replacement is describedin
Addison’s disease (23, 24). One explanation for our
observationsmight be that DHEA treatment either delays
cortisol clearanceor augments its action in our patients. However, a
previousstudy showed no change in serum cortisol profiles after
DHEAin aging males (36), and we found no
differences in morningor evening saliva cortisol levels in our
patients after DHEAor placebo. Furthermore, there is
strong evidence that DHEAis a potent antiglucocorticoid,
antagonizing corticoid-inducedthymic involution (37),
enzyme induction (38), and hypertension(10).
Another explanation might be that DHEA may affect the
hypothalamic-pituitary-thyroidaxis, but as thyroid function remained
unchanged throughoutthe study, this seems unlikely. It is of interest
that DHEAhas a greater benefit on mood and fatigue in the
evenings. Unfortunately,there are no good data on the diurnal pattern
of tiredness inAddison’s disease. Although morning fatigue may be
consideredmore specific in the diagnosis of organic disease, clinical
endocrinologistswill recall patients with Addison’s disease receiving
standardsteroid replacement therapy who complain of fatigue at all
timesof the day. Demonstrating a significant change in psychological
variablesin any small study is difficult in view of the numerous
factorsaffecting such parameters. It may be that since both fatigue
andmood 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
improvementin the morning, but this remains speculative. Nevertheless,
itis pertinent to note that all measures of well-being (GHQ scores)as
well as the mood and fatigue scores moved in a beneficialdirection
after DHEA therapy, suggesting the potential valuefor
such treatment in this disease context.
Another study of DHEA treatment in 24 women with
Addison’sdisease that was reported recently has also shown a rise in
circulatingadrenal androgens together with significantly improved
well-beingand sexuality (39). Our study supports their
observations, butextends their findings in one major respect: we also
observedpsychological benefit in male patients. Furthermore, this
effectin males was not associated with any significant increase in
circulatingtestosterone or estradiol levels. In females, serum
testosteroneonly rose slightly into the lower end of the normal range,
withan associated fall in SHBG. These modest changes are consistent
withthe relative lack of androgenic side-effects (acne and hirsutism)
afterDHEA in our female patients, although we cannot
discount thepossibility that they might have developed after longer
termtreatment. It may also provide an explanation for our inabilityto
demonstrate a positive effect of DHEA on libido and sexual
functionin females, as has been previously documented after
testosteronesupplementation in postmenopausal women (40),
in whom circulatingtestosterone levels are restored to the upper end
of the normalrange. In our study the effects of DHEA
treatment appeared independentof menopausal status or hormone
replacement therapy. In viewof the small size of our study group,
subgroup analysis of femalepatients on or off exogenous estrogen
replacement was not feasible.Together, these findings favor a central
nervous system ratherthan a peripheral androgen-dependent effect of
DHEA in patients.
In aging, cognitive decline has been known to be associatedwith lower
circulating DHEAS levels (41), suggesting that such
functionmight also be altered in Addison’s disease. We found no
impairmentof memory or higher executive function at initial assessment
inour patients, nor any improvement after DHEA.
Nevertheless,we cannot completely discount a link between
DHEA and cognitionfor two reasons: first, baseline scores
of cognitive functionin our patients were already high, making it
difficult to measurefurther improvement; and second, as we tested
cognitive functionin the morning, it is possible that a beneficial
effect laterin the day (as seen with mood and fatigue) was missed.
Treatment with DHEA for 12 months has been shown to
increasefemoral BMD and reduce markers of bone turnover in
postmenopausalfemales (21), and another recent study in
280 elderly subjectsshowed enhanced femoral bone density in women less
than 70 yrof age and enhanced radial bone density in women above 70 yr
ofage (42). Accordingly, in our study the lack of effect
of DHEAon bone metabolism after only 3 months of
treatment was notunexpected. However, our patients do have abnormally
low BMD(mean z-scores: lumbar spine, -0.39; femoral neck, -0.37),
suggestingthat longer term assessment of DHEA treatment
is indicated.The short duration of exposure to DHEA is
also likely to explainits lack of effect on body composition in
contrast to that reportedpreviously in older subjects
(18, 19, 20). In keeping with thevariable effects of
DHEA on IGF-I and its binding proteins reportedin the
literature (18, 19, 20, 38), we found no change in serum
levelsof IGF-I or IGFBP-3 in our study population.
In summary, we found that oral DHEA replacement in
Addison’sdisease is biochemically effective, well tolerated, and
associatedwith improvement in psychological well-being, mood, and
fatigue.Importantly, two thirds of our patients at the end of the
studywished to continue DHEA replacement therapy. With
beneficialeffects in males as well as females, we propose that its
psychologicalaction may be centrally mediated as a neurosteroid rather
thanbe androgen dependent. Our observations suggest a significant
physiologicalrole for DHEA in humans, and its addition to
existing steroidreplacement therapy in Addison’s disease should be
consideredfurther.
Acknowledgments
We thank Bente Jackson for administrative assistance, and the
staffat the Acland Hospital for facilitating assessment of patients.
Wealso thank Helen Shiers and Sarah Cleary for hormone assays,and
Shirley Love for bone density measurements.
Footnotes
1 P.J.H. and E.M.G. are joint first authors.
2 Supported by a Wellcome Trust Overseas Postdoctoral Fellowshipand
the Health Research Council of New Zealand.
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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. 
. 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]. 
Top
Abstract
Introduction
) 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 (
