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Chemoprevention of rat prostate carcinogenesis by
early and delayed administration of
dehydroepiandrosterone.
Rao KV, Johnson WD, Bosland MC, Lubet RA, Steele VE, Kelloff
GJ, McCormick DL
Experimental Toxicology and Carcinogenesis Division, IIT
Research Institute, Chicago, Illinois 60616, USA.
Cancer Res 1999 Jul 1;59(13):3084-9
Two in vivo bioassays were conducted to evaluate the
efficacy of dehydroepiandrosterone (DHEA) as an inhibitor of
prostate carcinogenesis in rats. Prostate adenocarcinomas were
induced in male Wistar-Unilever rats by a sequential regimen
of cyproterone acetate and testosterone propionate, followed
by a single i.v. injection of N-methyl-N-nitrosourea (MNU) and
chronic androgen stimulation. In the first experiment, DHEA
(1000 or 2000 mg/kg diet) was administered continuously to
rats beginning 1 week before MNU exposure. In the second
experiment, continuous administration of DHEA (2000 mg/kg
diet) was begun either 1 week before, 20 weeks after, or 40
weeks after MNU exposure. Controls received basal diet without
added DHEA. Studies were terminated at 13 months after MNU
administration, and prostate cancer incidence was determined
by histopathological evaluation of step sections of accessory
sex glands. In the first study, continuous dietary
administration of DHEA beginning 1 week before MNU resulted in
a dose-related inhibition of prostate cancer induction. In the
second experiment, comparable reductions in prostate cancer
incidence were observed in groups exposed to DHEA beginning 1
week before, 20 weeks after, and 40 weeks after carcinogen
exposure. These data demonstrate that nontoxic doses of DHEA
confer significant protection against prostate carcinogenesis
in rats. The efficacy of delayed administration of DHEA
suggests that the compound
Endogenous sex hormones and prostate cancer: a
quantitative review of prospective studies.
Eaton NE, Reeves GK, Appleby PN, Key TJ
Imperial Cancer Research Fund, Cancer Epidemiology Unit,
Radcliffe Infirmary, Oxford, UK.
Br J Cancer 1999 Jun;80(7):930-4
This paper presents a quantitative review of the data from
eight prospective epidemiological studies, comparing mean
serum concentrations of sex hormones in men who subsequently
developed prostate cancer with those in men who remained
cancer free. The hormones reviewed have been postulated to be
involved in the aetiology of prostate cancer: androgens and
their metabolites testosterone (T), non-SHBG-bound
testosterone (non-SHBG-bound T), di-hydrotestosterone (DHT),
androstanediol glucuronide (A-diol-g), androstenedione
(A-dione), dehydroepiandrosterone sulphate (DHEAS), sex
hormone binding globulin (SHBG), the oestrogens, oestrone and
oestradiol, luteinizing hormone (LH) and prolactin. The ratio
of the mean hormone concentration in prostate cancer cases to
that of controls (and its 95% confidence interval (CI)) was
calculated for each study, and the results summarized by
calculating the weighted average of the log ratios. No
differences in the average concentrations of the hormones were
found between prostate cancer cases and controls, with the
possible exception of A-diol-g which exhibited a 5% higher
mean serum concentration among cases relative to controls
(ratio 1.05, 95% CI 1.00-1.11), based on 644 cases and 1048
controls. These data suggest that there are no large
differences in circulating hormones between men who
subsequently go on to develop prostate cancer and those who
remain free of the disease. Further research is needed to
substantiate the small difference found in A-diol-g
concentrations between prostate cancer cases and controls.
Chemoprevention of hormone-dependent prostate
cancer in the Wistar-Unilever rat.
McCormick DL, Rao KV
Experimental Toxicology and Carcinogenesis Division, IIT
Research Institute, Chicago, Ill. 60616, USA.
dmccormick@iitri.org
Eur Urol 1999;35(5-6):464-7
The high incidence and long latent period of prostate
cancer make it an ideal target for chemoprevention. We have
evaluated a series of agents for chemopreventive efficacy
using a model in which hormone-dependent prostate cancers are
induced in the Wistar-Unilever (WU) rat by sequential
treatment with antiandrogen (cyproterone acetate), androgen
(testosterone propionate), and direct-acting chemical
carcinogen (N-methyl-N-nitrosourea), followed by chronic
androgen stimulation (testosterone). This regimen reproducibly
induces prostate cancers in high incidence, with no gross
toxicity and a low incidence of neoplasia in the seminal
vesicle and other non-target tissues. Dehydroepiandrosterone
(DHEA) and 9-cis-retinoic acid (9-cis-RA) are the most active
agents identified to date. DHEA inhibits prostate cancer
induction both when chronic administration is begun prior to
carcinogen exposure, and when administration is delayed until
preneoplastic prostate lesions are present. 9-cis-RA is the
most potent inhibitor of prostate carcinogenesis identified; a
study to determine the efficacy of delayed administration of
9-cis-RA is in progress. Liarozole fumarate confers modest
protection against prostate carcinogenesis, while
N-(4-hydroxyphenyl)retinamide (fenretinide),
alpha-difluoromethylornithine, oltipraz, DL-alpha-tocopherol
acetate (vitamin E), and L-selenomethionine are inactive.
Chemoprevention efficacy evaluations in the WU rat will
support the identification of agents that merit study for
prostate cancer chemoprevention in humans.
The relationship of serum dehydroepiandrosterone
and its sulfate to subsequent cancer of the prostate.
Comstock GW, Gordon GB, Hsing AW
Department of Epidemiology, Johns Hopkins School of Hygiene
and Public Health, Baltimore, Maryland 21205.
Cancer Epidemiol Biomarkers Prev 1993
May-Jun;2(3):219-21
Levels of dehydroepiandrosterone (DHEA) and
dehydroepiandrosterone sulfate (DHEA-S) in sera collected and
frozen in 1974 were studied among 81 prostate cancer cases
diagnosed in the following 12 years and 81 age- and
race-matched controls. Although mean levels of DHEA were 11%
lower among cases than controls and DHEA-S levels were 12%
lower than among controls, no dose-response association was
noted for either DHEA or DHEA-S. It seems unlikely that serum
levels of DHEA or DHEA-S are important risk factors for
prostate cancer.
Dehydroepiandrosterone in the treatment of erectile
dysfunction: a prospective, double-blind, randomized,
placebo-controlled study.
Reiter WJ, Pycha A, Schatzl G, Pokorny A, Gruber DM, Huber
JC, Marberger M
Department of Urology, University of Vienna, Austria.
Urology 1999 Mar;53(3):590-4; discussion 594-5
OBJECTIVES: In 1994, the Massachusetts Male Aging Study
presented an inverse correlation of the serum levels of
dehydroepiandrosterone (DHEA) and the incidence of erectile
dysfunction (ED). We evaluated the efficacy of DHEA
replacement in the treatment of ED in a prospective,
double-blind, randomized, placebo-controlled study.
METHODS: The inclusion criteria included ED, normal
physical and neurologic examinations, serum levels of
testosterone, dihydrotestosterone, prolactin, and
prostate-specific antigen (PSA) within the normal range, and a
serum DHEA sulfate level below 1.5 micromol/L. Also all
patients had a full erection after a pharmacologic erection
test with 10O microg prostaglandin E1; pharmacocavernosography
showed no visualization in corporeal venous structures. Forty
patients from our impotence clinic were recruited and randomly
divided into two groups of 20 patients each. Group 1 was
treated with an oral dose of 50 mg DHEA and group 2 with a
placebo one time a day for 6 months. The International Index
of Erectile Function (IIEF), a 15-item questionnaire, was used
to rate the success of this therapy.
RESULTS: Therapy response was defined as the ability to
achieve or maintain an erection sufficient for satisfactory
sexual performance according to the National Institutes of
Health Consensus Development Panel on Impotence. DHEA
treatment was associated with higher mean scores for all five
domains of the IIEF. There was no impact of DHEA treatment on
the mean serum levels of PSA, prolactin, testosterone, the
mean prostate volume, and the mean postvoid residual urine
volume.
CONCLUSIONS: Our results suggest that oral DHEA treatment
may be of benefit in the treatment of ED. Although our patient
data base is too small to do relevant statistical analysis, we
believe that our data show a biologically obvious trend that
justifies further extended studies.
Androgens in patients with benign prostatic
hyperplasia before and after prostatectomy.
Vermeulen A, De Sy W
J Clin Endocrinol Metab 1976 Dec;43(6):1250-4
Plasma androgens [testosterone (T),
17beta-hydroxy-5alpha-androstan-3-one (DHT), androst-4-en-3,17
dione(A), and dehydroepiandrosterone (DHEA)] as well as 17
hydroxyprogesterone were measured in a group of patients (age
60-80 yrs.) with benign prostatic hyperplasia (BPH) just
before prostatectomy and compared to values obtained in
subjects of similar age without signs of BPH. The most
important difference was observed in the mean DHT level which
was significantly (P less than 0.025) higher than in the
control group; mean T and free testosterone levels in BPH
patients were slightly higher (P less than 0.05) in the age
group 70-80 yrs; whereas in age group 60-70 mean values were
similar to those observed in normal controls. Mean A, DHEA and
17 OHP and E2 levels were not significantly different in BPH
patients when compared to age matched controls. 2-5 months
after prostatectomy, T and DHT levels were significantly
higher than immediately preoperatively. The preoperative
stress may have influenced the preprostatectomy values.
Neuropsychiatric function and
dehydroepiandrosterone sulfate in elderly women: a prospective
study.
Yaffe K, Ettinger B, Pressman A, Seeley D, Whooley M,
Schaefer C, Cummings S
Department of Psychiatry, University of California, San
Francisco, USA.
Biol Psychiatry 1998 May 1;43(9):694-700
BACKGROUND: Though among the most abundant human steroid
hormones, the physiologic role of dehydroepiandrosterone and
its sulfate (DHEAS) is not known. Our goal was to determine if
DHEAS is associated with cognition and mood in older women,
and if baseline DHEAS levels are predictive of cognitive
decline.
METHODS: In a prospective cohort, we studied 394 randomly
selected community-dwelling women, aged 65 years or older,
currently enrolled in the Study of Osteoporotic Fractures.
Subjects were administered a modified Mini-Mental State Exam,
Trials B, Digit Symbol, and the Geriatric Depression
Scale-Shortened (GDSS), at study onset and 4-6 years later.
Serum was obtained at study initiation for DHEAS analysis.
RESULTS: DHEAS levels declined with age, as expected. There
was no consistent association of DHEAS quartile or log DHEAS
with any of the four outcomes, even after multivariate
adjustment. Change in cognitive performance overtime was not
associated with DHEAS levels. Analysis of the 32 women without
any detectable DHEAS compared to those with detectable levels
revealed higher measures on the GDSS (mean score 3.4 +/- 3.6
compared with 1.6 +/- 2.3, p = .028) and a higher percentage
with depression (21.7% compared with 4.6%, p = .001).
CONCLUSIONS: Serum DHEAS is not a sensitive predictor of
cognitive performance or decline on a selected
neuropsychological battery in elderly community women;
however, nondetectable levels may be associated with
depression.
Effect of acute and chronic administration of
dehydroepiandrosterone on
(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced
wet dog shaking behavior in rats.
Inagaki M, Kagaya A, Takebayashi M, Horiguchi J, Yamawaki
S
Department of Psychiatry and Neurosciences, Hiroshima
University School of Medicine, Japan.
J Neural Transm 1999;106(1):23-33
It has been reported that dehydroepiandrosterone (DHEA) or
dehydroepiandrosterone sulfate (DHEA-S) is associated with
affective disorders and that pathology of affective disorders
are related with dysfunction of serotonin(5-HT)-2A
receptor-mediated responses. In this study, we investigated
the effect of DHEA on (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2
aminopropane (DOI), 5-HT-2A receptor agonist, -induced wet dog
shaking behavior (WDS) in rats. Acute treatment with DHEA
inhibited the DOI-induced WDSs dose dependently. This
inhibition was recovered by opioid receptor antagonist,
naltrexone. 5-HT-2A receptor-mediated WDSs were desensitized
after chronic treatment with DOI, however chronic treatment
with DHEA had no effect on this desensitization. Chronic
treatment with DHEA had no facilitating effect of chronic
dexamethasone treatment on DOI-induced WDSs. These findings
may lead the possibility that DHEA has the inhibitory effect
of 5-HT-2A mediated signaling pathway via non-genomic
action.
Adrenal secretion during major depression in 8- to
16-year-olds, I. Altered diurnal rhythms in salivary cortisol
and dehydroepiandrosterone (DHEA) at presentation.
Goodyer IM, Herbert J, Altham PM, Pearson J, Secher SM,
Shiers HM
Department of Psychiatry, University of Cambridge.
Psychol Med 1996 Mar;26(2):245-56
The association between basal cortisol,
dehydroepiandrosterone (DHEA), its sulphate (DHEAS) and major
depression was investigated in 8- to 16-year-olds. Eighty-two
subjects with major depression, 25 non-depressed psychiatric
cases and 40 community controls were systematically assessed
for current mental state and hormone levels at 08.00, 12.00
and 20.00 h, assayed from salivary samples collected over a 48
h period. The average mean of the two time points was compared
between the three groups. Evening cortisol hypersecretion and
morning DHEA hyposecretion were significantly, and
independently, associated with major depression. High evening
cortisol (> 0.594 ng/mL) and low morning DHEA (< 0.200
ng/mL) identified subgroups of depressives with different
types of adrenal hormone dysregulation. The association
between high evening cortisol or low morning DHEA and MDD was
not affected by either age or gender.
Effects of replacement dose of
dehydroepiandrosterone in men and women of advancing
age.
Morales AJ, Nolan JJ, Nelson JC, Yen SS
Department of Reproductive Medicine, University of California
School of Medicine, La Jolla 92093-0802.
J Clin Endocrinol Metab 1994 Jun;78(6):1360-7
Published erratum appears in J Clin Endocrinol Metab 1995
Sep;80(9):2799
Aging in humans is accompanied by a progressive decline in
the secretion of the adrenal androgens dehydroepiandrosterone
(DHEA) and DHEA sulfate (DS), paralleling that of the
GH-insulin-like growth factor-I (GH-IGF-I) axis. Although the
functional relationship of the decline of the GH-IGF-I system
and catabolism is recognized, the biological role of DHEA in
human aging remains undefined. To test the hypothesis that the
decline in DHEA may contribute to the shift from anabolism to
catabolism associated with aging, we studied the effect of a
replacement dose of DHEA in 13 men and 17 women, 40-70 yr of
age. A randomized placebo-controlled cross-over trial of
nightly oral DHEA administration (50 mg) of 6-month duration
was conducted. During each treatment period, concentrations of
androgens, lipids, apolipoproteins, IGF-I, IGF-binding
protein-1 (IGFBP-1), IGFBP-3, insulin sensitivity, percent
body fat, libido, and sense of well-being were measured. A
subgroup of men (n = 8) and women (n = 5) underwent 24-h
sampling at 20-min intervals for GH determinations. DHEA and
DS serum levels were restored to those found in young adults
within 2 weeks of DHEA replacement and were sustained
throughout the 3 months of the study. A 2-fold increase in
serum levels of androgens (androstenedione, testosterone, and
dihydrotestosterone) was observed in women, with only a small
rise in androstenedione in men. There was no change in
circulating levels of sex hormone-binding globulin, estrone,
or estradiol in either gender. High density lipoprotein levels
declined slightly in women, with no other lipid changes noted
for either gender. Insulin sensitivity and percent body fat
were unaltered. Although mean 24-h GH and IGFBP-3 levels were
unchanged, serum IGF-I levels increased significantly, and
IGFBP-1 decreased significantly for both genders, suggesting
an increased bioavailability of IGF-I to target tissues. This
was associated with a remarkable increase in perceived
physical and psychological well-being for both men (67%) and
women (84%) and no change in libido. In conclusion, restoring
DHEA and DS to young adult levels in men and women of
advancing age induced an increase in the bioavailability of
IGF-I, as reflected by an increase in IGF-I and a decrease in
IGFBP-1 levels. These observations together with improvement
of physical and psychological well-being in both genders and
the absence of side-effects constitute the first demonstration
of novel effects of DHEA replacement in age-advanced men and
women.
Endogenous levels of dehydroepiandrosterone
sulfate, but not other sex hormones, are associated with
depressed mood in older women: the Rancho Bernardo
Study.
Barrett-Connor E, von Muhlen D, Laughlin GA, Kripke A
Department of Family and Preventive Medicine, University of
California, San Diego, School of Medicine, La Jolla
92093-0607, USA.
Am Geriatr Soc 1999 Jun;47(6):685-91
OBJECTIVE: The purpose of this study was to determine
whether endogenous steroid hormone levels are associated with
depressed mood in community-dwelling older women.
DESIGN: A cross-sectional population-based study.
SETTING: Rancho Bernardo, California
PARTICIPANTS: A total of 699 non-estrogen using,
community-dwelling, postmenopausal women (aged 50 to 90 years)
from the Rancho Bernardo cohort who were screened for
depressed mood and had plasma obtained for steroid hormone
assays in 1984-1987.
MEASUREMENTS: Plasma levels of total and bioavailable
(non-SHBG-bound) estradiol and testosterone, estrone,
androstenedione, cortisol, dehydroepiandrosterone, and (DHEA)
and its sulfate (DHEAS) were measured by radioimmunoassay.
Mood and depression were assessed using the Beck Depression
Inventory.
RESULTS: Only DHEAS levels were significantly and inversely
associated with depressed mood, and the association was
independent of age, physical activity, and weight change (P =
.0002). Age, sedentary lifestyle, and weight loss were
positively associated with depressed mood. Alcohol intake,
cigarette smoking, marital status, type of menopause, and
season of testing were unassociated with depressed mood. A
subset of 31 women with categorically defined depression had
lower DHEAS levels compared with 93 age-matched nondepressed
women (1.17 +/- 1.08 vs 1.57 +/- .98 micromol/L; P = .01).
CONCLUSIONS: These results add to the evidence that DHEA/S
is a neuroactive steroid and point to the need for careful
long-term clinical trials of DHEA therapy in older women with
depressed mood.
Antidepressant and cognition-enhancing effects of
DHEA in major depression.
Wolkowitz OM, et al.
Ann N Y Acad Sci 1995 Dec 29;774:337-9
No abstract.
Dehydroepiandrosterone (DHEA) treatment of
depression.
Wolkowitz OM, Reus VI, Roberts E, Manfredi F, Chan T, Raum
WJ, Ormiston S, Johnson R, Canick J, Brizendine L, Weingartner
H
Department of Psychiatry, University of California, San
Francisco, School of Medicine 94143-0984, USA.
Biol Psychiatry 1997 Feb 1;41(3):311-8
Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are
plentiful adrenal steroid hormones that decrease with aging
and may have significant neuropsychiatric effects. In this
study, six middle-aged and elderly patients with major
depression and low basal plasma DHEA f1p4or DHEA-S levels were
openly administered DHEA (30-90 mg/d x 4 weeks) in doses
sufficient to achieve circulating plasma levels observed in
younger healthy individuals. Depression ratings, as well as
aspects of memory performance significantly improved. One
treatment-resistant patient received extended treatment with
DHEA for 6 months: her depression ratings improved 48-72% and
her semantic memory performance improved 63%. These measures
returned to baseline after treatment ended. In both studies,
improvements in depression ratings and memory performance were
directly related to increases in plasma levels of DHEA and
DHEA-S and to increases in their ratios with plasma cortisol
levels. These preliminary data suggest DHEA may have
antidepressant and promemory effects and should encourage
double-blind trials in depressed patients.
Double-blind treatment of major depression with
dehydroepiandrosterone.
Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M,
Brizendine L, Roberts E
Department of Psychiatry, University of California Medical
Center, San Francisco, USA. owenw@itsa.ucsf.edu
Am J Psychiatry 1999 Apr;156(4):646-9
OBJECTIVE: This study was designed to assess possible
antidepressant effects of dehydroepiandrosterone (DHEA), an
abundant adrenocortical hormone in humans.
METHOD: Twenty-two patients with major depression, either
medication-free or on stabilized antidepressant regimens,
received either DHEA (maximum dose = 90 mg/day) or placebo for
6 weeks in a double-blind manner and were rated at baseline
and at the end of the 6 weeks with the Hamilton Depression
Rating Scale. Patients previously stabilized with
antidepressants had the study medication added to that
regimen; others received DHEA or placebo alone.
RESULTS: DHEA was associated with a significantly greater
decrease in Hamilton depression scale ratings than was
placebo. Five of the 11 patients treated with DHEA, compared
with none of the 11 given placebo, showed a 50% decrease or
greater in depressive symptoms.
CONCLUSIONS: These results suggest that DHEA treatment may
have significant antidepressant effects in some patients with
major depression. Further, larger-scale trials are
warranted.
Elevated serum dehydroepiandrosterone sulfate
levels in practitioners of the Transcendental Meditation
(TM) and TM-Sidhi programs.
Glaser JL, Brind JL, Vogelman JH, Eisner MJ, Dillbeck MC,
Wallace RK, Chopra D, Orentreich N
Department of Physiological and Biological Sciences,
Maharishi International University, Fairfield, Iowa
52556.
J Behav Med 1992 Aug;15(4):327-41
Serum dehydroepiandrosterone sulfate (DHEA-S) levels were
measured in 270 men and 153 women who were experienced
practitioners of the Transcendental Meditation (TM) and
TM-Sidhi programs, mental techniques practiced twice daily,
sitting quietly with the eyes closed. These were compared
according to sex and 5-year age grouping to 799 male and 453
female nonmeditators. The mean DHEA-S levels in the TM group
were higher in all 11 of the age groups measured in women and
in 6 of 7 5-year age groups over 40 in men. There were no
systematic differences in younger men. Simple regression using
TM-group data revealed that this effect was independent of
diet, body mass index, and exercise. The mean TM-group levels
measured in all women and in the older men were generally
comparable to those of nonmeditator groups 5 to 10 years
younger. These findings suggest that some characteristics of
TM practitioners are modifying the age-related deterioration
in DHEA-S secretion by the adrenal cortex.
The impact of a new emotional self-management
program on stress, emotions, heart rate variability, DHEA and
cortisol.
McCraty R, Barrios-Choplin B, Rozman D, Atkinson M, Watkins
AD
Institute of HeartMath, Boulder Creek, California 95006, USA.
rollin@heartmath.org
Integr Physiol Behav Sci 1998
Apr-Jun;33(2):151-70
This study examined the effects on healthy adults of a new
emotional self-management program, consisting of two key
techniques, "Cut-Thru" and the "Heart Lock-In." These
techniques are designed to eliminate negative thought loops
and promote sustained positive emotional states. The
hypotheses were that training and practice in these techniques
would yield lowered levels of stress and negative emotion and
cortisol, while resulting in increased positive emotion and
DHEA levels over a one-month period. In addition, we
hypothesized that increased coherence in heart rate
variability patterns would be observed during the practice of
the techniques. Forty-five healthy adults participated in the
study, fifteen of whom acted as a comparison group for the
psychological measures. Salivary DHEA/DHEAS and cortisol
levels were measured, autonomic nervous system function was
assessed by heart rate variability analysis, and emotions were
measured using a psychological questionnaire. Individuals in
the experimental group were assessed before and four weeks
after receiving training in the self-management techniques.
The experimental group experienced significant increases in
the positive affect scales of Caring and Vigor and significant
decreases in the negative affect scales of Guilt, Hostility,
Burnout, Anxiety and Stress Effects, while no significant
changes were seen in the comparison group. There was a mean 23
percent reduction in cortisol and a 100 percent increase in
DHEA/DHEAS in the experimental group. DHEA was significantly
and positively related to the affective state Warmheartedness,
whereas cortisol was significantly and positively related to
Stress Effects. Increased coherence in heart rate variability
patterns was measured in 80 percent of the experimental group
during the use of the techniques. The results suggest that
techniques designed to eliminate negative thought loops can
have important positive effects on stress, emotions and key
physiological systems. The implications are that relatively
inexpensive interventions may dramatically and positively
impact individuals' health and well-being. Thus, individuals
may have greater control over their minds, bodies and health
than previously suspected.
Effects of estrogen replacement therapy on
dehydroepiandrosterone, dehydroepiandrosterone sulfate, and
cortisol responses to exercise in postmenopausal women.
Johnson LG, Kraemer RR, Haltom R, Kraemer GR, Gaines HE,
Castracane VD
Department of Kinesiology and Health Studies, Southeastern
Louisiana University, Hammond, USA.
Fertil Steril 1997 Nov;68(5):836-43
Published erratum appears in Fertil Steril 1998
Mar;69(3):606
OBJECTIVE: To determine the effects of hormone replacement
therapy (HRT) on dehydroepiandrosterone (DHEA), DHEA sulfate
(DHEAS), and cortisol (F) responses to treadmill exercise.
DESIGN: Controlled clinical study.
SETTING: Female volunteers in an academic research
environment.
PATIENT(S): Sixteen healthy, postmenopausal women (7 were
receiving HRT, 9 were not). INTERVENTION(S): Blood samples
were taken from an intravenous catheter before, during, and
after 30 minutes of treadmill exercise following an overnight
fast. A second session was conducted one month later for the
same subjects using the same blood sampling protocol without
exercise.
MAIN OUTCOME MEASURE(S): Serum DHEA, DHEAS, and F
concentrations.
RESULT(S): The HRT and untreated DHEA area under the curve
(AUC) for the exercise trials was significantly greater than
that for the control trials. The untreated, but not the HRT,
DHEAS AUC for the exercise trials was significantly greater
than that for the control trials. The HRT and untreated F AUC
for the exercise trials was significantly greater than that
for the control trials. The AUC for the HRT exercise trials
was significantly higher than the untreated exercise trials
for DHEA and F, but not DHEAS.
CONCLUSION(S): Data suggest that treadmill exercise
elevates DHEA, DHEAS, and F levels in postmenopausal women and
that HRT enhances the DHEA and F responses.
Inhibition of migration and proliferation of
vascular smooth muscle cells by dehydroepiandrosterone
sulfate.
Furutama D, Fukui R, Amakawa M, Ohsawa N
First Department of Internal Medicine, Osaka Medical College,
Japan. in1003@poh.osaka-med.ac.jp
Biochim Biophys Acta 1998 Feb 27;1406(1):107-14
Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are
the most abundant steroids in humans, and their serum
concentrations progressively decrease with age. Although
relationships between DHEA(-S) and many age-related illnesses
have been postulated, the mechanisms for their effects remain
unknown, and specific receptors for these molecules have not
been identified. In this paper, to investigate the role of
DHEA(-S) in atherogenesis, we studied the proliferation and
migration of a rabbit vascular smooth muscle cell line, SM-3,
in the presence of DHEA(-S). Cellular proliferation was
inhibited by DHEA-S, and to a lesser extent by DHEA. Modified
Boyden's chamber assays revealed that DHEA-S inhibited the
migration of SM-3 cells toward PDGF-BB. In cell attachment
assays, DHEA-S inhibited the attachment of SM3 cells to
fibronectin. It was suggested that the inhibitory effect of
DHEA-S for SM-3 proliferation and migration was due to the
decreased interaction with fibronectin. Scatchard analysis
revealed the presence of two populations of DHEA-S binding
sites in the nuclear fraction, and a smaller number in the
cytosolic fraction. Since the dissociation constant of the
higher affinity site was similar to the serum DHEA-S
concentration in humans (Kd = 5.8 microM), this binding site
could be functional under physiologic conditions. These
findings suggest that there may be receptor-mediated
anti-atherogenic actions of DHEA-S.
Endogenous androgens and carotid intimal-medial
thickness in women.
Bernini GP, Sgro' M, Moretti A, Argenio GF, Barlascini CO,
Cristofani R, Salvetti A
Department of Internal Medicine, and Institute of Clinical
Physiology C.N.R., University of Pisa, Italy.
J Clin Endocrinol Metab 1999 Jun;84(6):2008-12
The influence of endogenous androgens on atherosclerotic
disease in women is unknown. In this study involving 101 pre-
and post-menopausal females, we evaluated the relationship
between serum androgen levels and both carotid artery
intimal-medial thickness (IMT) and major cardiovascular risk
factors. In addition to evaluation of blood pressure, body
mass index, and waist-to-hip ratio, serum
dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A),
total testosterone (TTS), free testosterone (FTS), insulin,
cholesterol (total and high density lipoproteins),
triglycerides, and glucose were measured. All women underwent
carotid ultrasonography. Spearman correlation coefficients
showed that serum DHEA-S and A levels were negatively related
(P < 0.03-0.0004) to several IMT measures. Higher tertiles
of DHEA-S, A, and FTS corresponded to significantly lower
measures of carotid thickness. DHEA-S, and all androgens were
inversely related to age (P < 0.03 or less), showing no
unfavorable association with major cardiovascular risk
factors. In contrast, serum DHEA-S was negatively associated
with WHR (P < 0.02), while A was negatively associated with
body mass index (P < 0.02). Stepwise multiple regression
analysis indicated that A and FTS showed an inverse
association with IMT measures (P < 0.05-0.001). In
conclusion, our data indicate that in women serum DHEA-S and
androgens decline with age and that normal hormonal levels are
not associated with major cardiovascular risk factors. They
also show that higher DHEA-S and androgen concentrations are
related to lower carotid wall thickness; for A this
association is independent of cardiovascular risk factors. Our
results suggest that, in the physiological range, DHEA-S and
androgens in women are correlated with lower risk of carotid
artery atherosclerosis.
Dehydroepiandrosterone treatment of midlife
dysthymia.
Bloch M, Schmidt PJ, Danaceau MA, Adams LF, Rubinow DR
Behavioral Endocrinology Branch, National Institute of Mental
Health, Bethesda, MD 20892-1276, USA.
Biol Psychiatry 1999 Jun 15;45(12):1533-41
BACKGROUND: This study evaluated the efficacy of the
adrenal androgen, dehydroepiandrosterone, in the treatment of
midlife-onset dysthymia.
METHODS: A double-blind, randomized crossover treatment
study was performed as follows: 3 weeks on 90 mg
dehydroepiandrosterone, 3 weeks on 450 mg
dehydroepiandrosterone, and 6 weeks on placebo. Outcome
measures consisted of the following. Cross-sectional
self-ratings included the Beck Depression Inventory, and
visual analogue symptom scales. Cross-sectional objective
ratings included the Hamilton Depression Rating Scale, the
Cornell Dysthymia Scale and a cognitive test battery.
Seventeen men and women aged 45 to 63 years with midlife-onset
dysthymia participated in this study. Response to
dehydroepiandrosterone or placebo was defined as a 50%
reduction from baseline in either the Hamilton Depression
Rating Scale or the Beck Depression Inventory.
RESULTS: In 15 patients who completed the study, a robust
effect of dehydroepiandrosterone on mood was observed compared
with placebo. Sixty percent of the patients responded to
dehydroepiandrosterone at the end of the 6-week treatment
period compared with 20% on placebo. A significant response
was seen after 3 weeks of treatment on 90 mg per day. The
symptoms that improved most significantly were anhedonia, loss
of energy, lack of motivation, emotional "numbness," sadness,
inability to cope, and worry. Dehydroepiandrosterone showed no
specific effects on cognitive function or sleep disturbance,
although a type II error could not be ruled out.
CONCLUSIONS: This pilot study suggests that
dehydroepiandrosterone is an effective treatment for
midlife-onset dysthymia.
Enhanced plasma DHEAS, brain acetylcholine and
memory mediated by steroid sulfatase inhibition.
Rhodes ME, Li PK, Burke AM, Johnson DA
Division of Pharmacology-Toxicology, Graduate School of
Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA
15282, USA.
Brain Res 1997 Oct 31;773(1-2):28-32
Steroid sulfatase inhibitors can alter the metabolism of
neurosteroids which modulate brain function. Administration of
the non-steroidal steroid sulfatase inhibitor
(p-O-sulfamoyl)-N-tetradecanoyl tyramine (DU-14) to rats for
15 days increased plasma dehydroepiandrosterone sulfate
(DHEAS) concentrations by 88.2%, decreased plasma
dehydroepiandrosterone (DHEA) concentrations by 84.6%,
increased hippocampal acetylcholine (ACh) release determined
via in vivo microdialysis by almost 3-fold, and produced a
significant blockade of scopolamine-induced amnesia as
measured by a passive avoidance test. These results suggest
DHEAS rather than DHEA enhances brain cholinergic function and
that steroid sulfatase inhibition may become an important tool
for enhancing neuronal functions, such as memory, mediated by
excitatory neurosteroids.
Enhancement of hippocampal acetylcholine release by
the neurosteroid dehydroepiandrosterone sulfate: an in vivo
microdialysis study.
Rhodes ME, Li PK, Flood JF, Johnson DA
Division of Pharmacology-Toxicology, Graduate School of
Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA
15282, USA.
Brain Res 1996 Sep 16;733(2):284-6
The effect of dehydroepiandrosterone sulfate (DHEAS)
administered i.p. on the release of acetylcholine (ACh) from
the hippocampus of anesthetized rats was examined using in
vivo microdialysis. DHEAS significantly increased ACh release
above the pre-treatment levels for all doses tested. The
administration of 100 mg/kg significantly enhanced ACh release
greater than 4-fold when compared to the saline-treated group
80 min following drug administration. This study is the first
to demonstrate that the neurosteroid DHEAS, a negative
allosteric modulator of the GABAA receptor, can enhance the
release of ACh from neurons in the hippocampus.
Dehydroepiandrosterone (DHEA) increases production
and release of Alzheimer's amyloid precursor protein.
Danenboerg HD, Haring R, Fisher A, Pittel Z, Gurwitz D,
Heldman E
Department of Organic and Medicinal Chemistry, Israel
Institute for Biological Research, Ness-Ziona, Israel.
Life Sci 1996;59(19):1651-7
Dehydroepiandrosterone (DHEA), the major secretory product
of the human adrenal cortex, significantly declines with
advanced age. We have previously demonstrated that DHEA
prevents the reduction in non-amyloidogenic APP processing,
following prolonged stimulation of the muscarinic receptor, in
PC12 cells that express the ml acetylcholine-receptor. The
present study examined whether this effect may be mediated via
modulation of APP metabolism. It was found that DHEA treatment
increases the content of membrane-associated APP holoprotein
by 24%, and the accumulation of secreted APP in the medium by
63%. No increase in viable cell number nor in nonspecific
protein production was observed in DHEA-treated cells. Thus,
DHEA seems to increase specifically both APP synthesis and
secretion. We propose that the age-associated decline in DHEA
levels may be related to the pathological APP metabolism
observed in Alzheimer's disease.
DHEAS inhibits TNF production in monocytes,
astrocytes and microglial cells.
Di Santo E, Foddi MC, Ricciardi-Castagnoli P, Mennini T,
Ghezzi P
Istituto di Ricerche Farmacologiche, Mario Negri, Milan,
Italy.
Neuroimmunomodulation 1996 Sep-Oct;3(5):285-8
We previously reported that neurosteroids, including
dehydroepiandrosterone sulfate (DHEAS), inhibit the production
of TNF in vitro and in vivo. In this paper we evaluated the
effect of DHEAS on TNF production by cultured rat astrocytes
and murine glial cell clones, and compared it with the effect
on monocytic THP-1 cells. We found that DHEAS at a
concentration of 10(-4)-10(-7) M inhibits TNF production
induced by lipopolysaccharide (LPS, 1 microgram/ml) in these
cells. Since the inhibitory effect of DHEAS is not mediated by
the glucocorticoid (GC) receptor and DHEAS is an allosteric
antagonist of the GABAA receptor, we investigated the possible
role of GABAA receptors in this effect. The results showed
that the inhibitory effect of DHEAS (10(-6) M) on TNF
production by THP-1 cells was completely reversed by addition
of 10(-6) M GABA. However, a GABAA receptor antagonist
(bicuculline) did not mimic the action of DHEAS. In
conclusion, DHEAS can inhibit TNF production in astrocytic and
microglial cells suggesting it could be an endogenous
regulator of TNF production in the
Use of dehydroepiandrosterone in psychiatric
practice.
Strauss EB, et al.
J Neurol Neurosurg Psychiatry 18:137-44. 1955.
No abstract.
Treatment of inadequate personality in juveniles by
dehydroisoandrosterone: preliminary report.
Sands DE, et al.
BMJ 2:66-68. 1952.
No abstract.
DHEA and Aging, Annals of the New York Academy of
Science
Bellino, F.L., Daynes. R.A., Hornsby, P.J., et al., eds
Aging (Dec. 29, 1995, 774:1-350).
No abstract.
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