Prevention
by dehydroepiandrosterone of the development of mammary carcinoma
induced by 7,12-dimethylbenz(a)anthracene (DMBA) in the rat
BREAST CANCER RES. TREAT. (USA),
1994, 29/2 (203-217)
The concentration of serum
dehydroepiandrosterone sulfate (DHEA-S) and DHEA decreases
markedly during aging, and low circulating levels of DHEA
have been associated with a higher incidence of breast cancer
in women. Using 7,12- dimethylbenz(a)anthracene (DMBA)-induced
mammary carcinoma in the rat as model, we have studied the
effect of increasing serum levels of DHEA released from Silastic
implants on the incidence of these tumors in the rat. Treatment
with increasing doses of DHEA leading to serum DHEA levels
comparable to those observed in normal adult women (7.1plus
or minus0.6 nM and 17.5plus or minus1.1 nM) caused a progressive
inhibition of tumor development from 68% bearing tumors in
control animals to 22% and 11%, respectively. The average
tumor area per rat decreased from 2.81 cm2 in intact control
animals to 0.96 and 0.09 cm2 in the groups treated with the
same doses of DHEA, respectively. The present data indicate
that circulating levels of DHEA similar to those found in
normal adult premenopausal women exert a potent inhibitory
effect on the development of DMBA-induced mammary tumors in
the rat, thus suggesting the possibility of a new and more
physiological approach for the prevention of breast cancer
in women.
Role of glucose-6-phosphate
dehydrogenase inhibition in the antiproliferative effects
of dehydroepiandrosterone on human breast cancer cells
British Journal of Cancer (United
Kingdom), 1997, 75/4 (589-592)
Epidemiological and experimental
studies suggest that dehydroepiandrosterone (DHEA) exerts
a protective effect against breast cancer. It has been proposed
that the non-competitive inhibition of glucose-6-phosphate
dehydrogenase (G6PD) contributes to DHEA antitumour action.
We evaluated the effects of DHEA on G6PD activity and on the
in vitro proliferation of two human breast cancer cell lines,
MCF-7 (steroid receptor positive) and MDA-MB-231 (steroid
receptor negative), in a serum-free assay. DHEA inhibition
of G6PD was only found to occur at concentrations above in
10 microM; at these high concentrations, the growth curve
was parallel to the enzyme inhibition curve in both cell lines.
In contrast, at concentrations in the in vivo breast tissue
concentration range, neither cell growth nor enzyme activity
was inhibited. The results failed to confirm DHEA's putative
anti-tumour action on breast cancer through G6PD inhibition,
as the enzyme blockade only becomes apparent at pharmacological
concentrations of the steroid.
Decreased
serum dehydroepiandrosterone is associated with an increased
progression of human immunodeficiency virus infection in men
with CD4 cell counts of 200-499
J. INFECT. DIS. (USA), 1991,
164/5 (864-868)
Dehydroepiandrosterone (DHEA)
and its interconvertible sulfate derivative (DHEA-S) are human
androgenic steroids that have been reported to inhibit viral
expression and have been associated with a decreased risk
of cancer. The relationship between serum DHEA and DHEA-S
levels and subsequent progression to AIDS was investigated
in a sample of human immunodeficiency virus (HIV)-infected
men from the San Francisco Men's Health Study followed prospectively
since 1984. Among 108 men seropositive for HIV at study entry
and with CD4 lymphocyte counts of 200-499 microl 24 months
later, serum DHEA levels below the lower limit of normal (<180
ng/dl) at this later date were predictive of subsequent progression
to AIDS (relative hazard = 2.34; 95% confidence interval =
1.18-4.63; P = .01) after controlling for hematocrit, age,
and log absolute CD4 cell number in a Cox proportional hazards
model. This is the first large prospective cohort in which
an endocrinologic variable has been observed to independently
predict progression to AIDS. These observations, in addition
to recent in vitro data, suggest that DHEA might have a protective
effect in HIV infection.
Does DHEA
supplementation affect muscle mass?
Expert Opinion on Investigational
Drugs (United Kingdom), 1996, 5/12 (1725-1728)
DHEA (dehydroepiandrosterone)
production declines dramatically with increasing age in people
as they loose muscle mass. Animal studies have not shown that
DHEA replacement affects body or muscle weight in animals,
but does reduce lipids and reduces oxidation, increased with
ageing. One research group has shown that growth hormones
increase while others decrease during DHEA supplementation
of older people. However, DHEA's effect on muscle mass in
humans is unclear. DHEA supplementation does restore DHEA
levels without apparent toxicity.
Regulation
of the immune response by dehydroepiandrosterone and its metabolites
Journal of Endocrinology (United
Kingdom), 1996, 150/SUPPL. (S209-S220)
Dehydroepiandrosterone (5-androsten-3beta-ol-17-one,
DHEA) has been shown to protect mice from a variety of lethal
infections. This includes, but is not limited to, infection
with viruses (herpes virus type 2, coxsackie virus B4 (CB4)),
bacteria (Enterococcus faecalis, Pseudomonas aeruginosa),
and a parasite (Cryptosporidium parvum). We have previously
reported that androstenediol (5-androstene-3beta,17beta-diol,
AED), derived from DHEA, is at least 100 x more effective
in up-regulating systemic resistance against CB4 infection
than its precursor. Furthermore, androstenetriol (5-androstene-3beta,7beta,17beta-triol,
AET) which is formed by 7beta hydroxylation of AED, was more
effective against CB4 infection than its precursor, AED. Neither
steroid, however, has shown any significant direct antiviral
effects. The in vitro influences of DHEA, AED and AET on a
mitogen-induced mixed splenocyte proliferation assay were
determined. The results showed that DHEA suppressed the proliferation
of concanavalin A (ConA)- or lipopoly-saccharide-activated
cultures in a dose-dependent manner. AED had little influence
on the activation response. However, AET potentiated the response
to both mitogens significantly above the control level. The
regulation of interleukin (IL)-2 and IL-3 secretion from ConA-activated
lymphocytes was analogous to these observations. These functions
were depressed by DHEA, unaffected by AED, and potently increased
by AET. Moreover, the classic immunosuppressive effects of
hydrocortisone on ConA-induced lymphocyte proliferation, as
well as IL-2 and IL-3 production, were unaffected by co-culture
with DHEA and only minimally counteracted by AED. In contrast,
AET significantly counteracted the effect of hydrocortisone
when co-cultured together. These data show that while DHEA,
AED and AET each function in a similar manner in vivo, in
vitro their effects are dramatically different from one another
with only AET potentiating the cellular response by increasing
lymphocyte activation and counteracting the immunosuppressive
activity of hydrocortisone.
Dehydroepiandrosterone
(DHEA) treatment reverses the impaired immune response of
old mice to influenza vaccination and protects from influenza
infection.
Vaccine (ENGLAND) 1995, 13 (15)
p1445-8
Dehydroepiandrosterone (DHEA)
is a native steroid with an immunomodulating activity. Recently
it was suggested that its age-associated decline is related
with immunosenescence. To examine whether DHEA administration
could effectively reverse the age-associated decline of immunity
against influenza vaccine, aged mice were simultaneously vaccinated
and treated with DHEA. Reversal of the age-associated decline
and a significant constant increase of humoral response was
observed in treated mice. Increased resistance to post-vaccination
intranasal challenge with live influenza virus was observed
in DHEA-treated aged mice. Thus, DHEA treatment overcame the
age-related defect in the immunity of old mice against influenza.
Replacement
of DHEA in aging men and women. Potential remedial effects.
Ann N Y Acad Sci (UNITED STATES)
Dec 29 1995, 774 p128-42
DHEA in appropriate replacement
doses appears to have remedial effects with respect to its
ability to induce an anabolic growth factor, increase muscle
strength and lean body mass, activate immune function, and
enhance quality of life in aging men and women, with no significant
adverse effects. Further studies are needed to confirm and
extend our current results, particularly the gender differences.
DHEA's Effects
on Weight
Coleman DL Schwizer RW Leiter
EH Diabetes (1984 Jan) 33(1):26-32
Dehydroepiandrosterone (DHEA)
was fed at 0.1-0.4% in the diet to genetically diabetic (db/db)
or obese (ob/ob) C57BL/KsJ (BL/Ks) or C57BL/6J (BL/6) mice.
Treatment of BL/Ks-db/db or ob/ob mice with 0.4% DHEA prevented
hyperglycemia, islet atrophy, and severe diabetes associated
with this inbred background, but did not affect weight gain
and food consumption. Homozygous obese (ob) or diabetes (db)
mice on the BL/6 background were more sensitive to DHEA, and
the mild, transient hyperglycemia associated with ob or db
gene expression on the BL/6 inbred background could be prevented
by 0.1% DHEA. Both body weight and food consumption were decreased
in BL/6 mutants maintained on 0.1% DHEA whereas this effect
was not seen in BL/Ks mutants fed up to 0.4% DHEA. Early therapy
with 0.4% DHEA, initiated at 2 wk of age, prevented the development
of most diabetes symptoms and decreased the rate of weight
gain in pups of all genotypes. In addition to therapeutic
effects on both obese mutants, DHEA effected significant changes
in an aging study using normal BL/6 female mice. Four weeks
of DHEA treatment initiated at 2 years of age improved glucose
tolerance and at the same time reduced plasma insulin to a
"younger" level. This suggests that DHEA may act
in insulin-resistant mutant mice and in aging normal mice
to increase the sensitivity to insulin.
Anti-Obesity
Properties of DHEA
Coleman DL
Prog Clin Biol Res (1988) 265:161-75
Dehydroepiandrosterone (DHEA)
fed at 0.4%, and its metabolites, 3 alpha-hydroxyetiocholanolone
(alpha-ET) and 3 beta- hydroxyetiocholanolone (beta-ET), fed
at 0.1%, had marked anti- hyperglycemic and anti-obesity properties
in mutant mice with single gene obesity mutations (diabetes,
db; obese, ob; viable yellow, Avy). The therapeutic effects
differed depending on the mutation as well as the inbred background
on which the mutation was maintained. These steroids prevented
onset of hyperglycemia and reduced the rate of weight gain
in C57BL/6J-db/db and ob/ob mice, whereas in C57BL/KsJ- db/db
mice, only hyperglycemia was prevented. The viable yellow
(Avy) mutant, exhibiting a more slowly developing obesity
condition, responded to all steroids with a marked decrease
in rate of weight gain associated with decreased plasma insulin
concentrations. Steroid treatment of most mouse mutants was
associated with normal or increased food intake, a feature
that suggests a decrease in metabolic efficiency. In order
to assess any potential energy wastage by steroid stimulation
of futile cycles we looked at the rates of lipogenesis, gluconeogenesis
and oxygen consumption in steroid- treated normal and mutant
mice. With the possible exception of the rate of gluconeogenesis
that in obesity mutants was consistently reduced to normal
by treatment, no metabolic changes were of sufficient magnitude
to account for the marked decrease in metabolic efficiency.
All treatments potentiated the action of insulin. This potentiation
may change the hormonal balance such that minor changes in
the rates of many metabolic pathways may interact to produce
a large decrease in metabolic efficiency.
Topical DHEA
Inhibits Tumors
Pashko LL Rovito RJ Williams
JR Sobel EL Schwartz AG, Carcinogenesis (1984 Apr) 5(4):463-6
Long-term oral administration
of the adrenal steroid, dehydroepiandrosterone (DHEA), has
previously been shown to inhibit the development of spontaneous
breast cancer and chemically induced lung and colon tumors
in various mouse strains. Topical application of DHEA inhibits
both 7,12-dimethylbenz[a]anthracene initiation and 12-O- tetradecanoylphorbol-13-acetate
promotion of these tumors. The synthetic steroid, 3 beta-methylandrost-5-en-17-one,
which, unlike DHEA, is not demonstrably estrogenic in the
rat, also inhibits papilloma development.
Dehydroepiandrosterone
(DHEA) increases production and release of Alzheimer's amyloid
precursor protein.
Life Sci (ENGLAND) 1996, 59 (19)
p1651-7
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.
Serum dehydroepiandrosterone
(DHEA) and DHEA-sulfate (DHEA-S) in Alzheimer's disease and
in cerebrovascular dementia.
Endocr J (JAPAN) Feb 1996, 43
(1) p119-23
A decreased concentration of
dehydroepiandrosterone sulfate (DHEA-S) in patients with Alzheimer's
disease (AD) has been reported but is still controversial.
In the present study, serum concentrations of DHEA and DHEA-S
were determined in 19 patients with AD, 21 patients with cerebrovascular
dementia (CVD) and 45 age- and gender matched elderly control
individuals from the Japanese community at large. Serum concentration
of DHEA among controls, patients with AD and patients with
CVD did not significantly differ from one another. However,
patients with AD and patients with CVD were found to have
lower concentration of serum DHEA-S and a lower DHEA-S/DHEA
ration compared to normal control individuals. No significant
difference was observed in the concentration of serum DHEA-S
or the DHEA-S/DHEA ratio between patients with AD and those
with CVD. These results suggest that reduced concentrations
of serum DHEA-S may not be unique to AD, but instead reflect
a common phenomenon in dementing diseases. However, since
serum concentration of DHEA in these patients remained unchanged,
the significance of DHEA in dementia remains unclear.
Natural products
and their derivatives as cancer chemopreventive agents
Progress in Drug Research (Switzerland),
1997, 48/- (147-171)
This review summarizes currently
available data on the chemopreventive efficacies, proposed
mechanisms of action and relationships between activities
and structures of natural products like vitamin D, calcium,
dehydroepidandrosterone, coenzyme Q10, celery seed oil, parsley
leaf oil, sulforaphane, isoflavonoids, lignans, protease inhibitors,
tea polyphenols, curcumin, and polysaccharides from Acanthopanax
genus.
