Dietary
soy protein and estrogen replacement therapy
improve cardiovascular risk factors and decrease
aortic cholesteryl ester content in ovariectomized
cynomolgus monkeys
Wagner JD; Cefalu WT; Anthony MS; Litwak KN;
Zhang L; Clarkson TB
Comparative Medicine Clinical Research Center,
Bowman Gray School of Medicine, Wake Forest
University, Winston-Salem, NC 27157-1040, USA.
Metabolism: Clinical and Experimental (USA),
1997, 46/6 (698-705)
Estrogen replacement therapy (ERT) decreases
the progression of coronary artery atherosclerosis
in monkeys. Dietary soy protein also retards the
progression of atherosclerosis relative to animal
proteins such as casein. Soy protein contains
weakly estrogenic compounds called isoflavones or
phytoestrogens that may be responsible for the
cardioprotective effects. This study was designed
as a 2 x 2 factorial to determine the magnitude of
soy protein's effects on cardiovascular risk
factors relative to casein and lactalbumin, with
or without estradiol treatment. Ovariectomized
female monkeys were randomized to four treatment
groups based on past dietary cholesterol
consumption, their origin, end past reproductive
history, end studied for 7 months. The animals
were divided into (1) a group fed casein end
lactalbumin as the protein source (n = 14), (2) a
group fed casein and lactalbumin as the protein
source plus 17 beta-estradiol(E2) (n = 13), (3) a
group fed soybean protein isolate as the protein
source (n = 11), and (4) a group fed soybean
protein isolate as the protein source plus E2 (n =
10). Soy protein compared with casein consumption
resulted in a significant improvement in plasma
lipid and lipoprotein concentrations, e
significant improvement in insulin sensitivity and
glucose effectiveness as determined by
minimal-model analyses, and a decrease in arterial
lipid peroxidation, E2- treated monkeys had a
significant reduction in fasting insulin levels
and insulin to glucose ratios, total body weight,
and amounts of abdominal fat, and had smaller
low-density lipoprotein (LDL) particles. In
addition. E2 treatment resulted in a significant
reduction (P = .001) in aortic cholesteryl ester
content. A similar trend (P = .14) was found for
soy protein compared with casein. There also was a
significant interaction (P = .02) with soy and E2,
such that animals consuming soy protein + E2 had
the least arterial cholesteryl ester content.
These results suggest that both ERT and dietary
soybean protein have beneficial effects on
cardiovascular risk factors. Interestingly, the
two treatments affected different risk factors and
together resulted in the greatest reduction in
arterial cholesterol content. Further studies are
needed to determine the active component of the
soy protein and to assess its long-term effects on
the cardiovascular system and other organ systems
(such as the bones and reproductive system).
Daidzein
sulfoconjugates are potent inhibitors of sterol
sulfatase (EC 3.1.6.2)
Wong CK, Keung WM
Center for Biochemical and Biophysical Sciences
and Medicine, Harvard Medical School, Boston,
Massachusetts 02115, USA.
Biochem Biophys Res Commun 1997 Apr
28;233(3):579-83
Recent studies have associated high dietary
isoflavone intake with low incidence of breast
cancer. Since estrogenic steroids are important
factors in the evolution of breast cancer, and in
breast tumors they are derived mainly from the
sterol sulfatase pathway, we have therefore
investigated effects of the isoflavone daidzein
and its sulfoconjugates, daidzein-4'-O-sulfate and
daidzein-7,4'-di-O-sulfate, on sterol sulfatase
acitivity using dehydroepiandrosterone sulfate as
substrate. While daidzein does not affect sterol
sulfatase, its sulfoconjugates are potent
inhibitors of this enzyme. Kinetic analyses reveal
that daidzein-4'-O-sulfate and
daidzein-7,4'-di-O-sulfa te inhibit sterol
sulfatase competitively with respect to the
steroid substrate and with K(i) values of 5.9 and
1 microM, respectively. Daidzein sulfo-conjugates
also inhibit hydroxysteroid and phenol
sulfotransferases but at much higher
concentrations. These results provide a
biochemical basis for the putative chemopreventive
role of dietary isoflavones against breast
cancer.
Adrenal
puberty or adrenarche
Andrologie (France), 1997, 7/2 (165-186)
The androgens produced by the adrenal glands
are mainly Deltleft arrow over right arrow
steroids, first dehydroepiandrosterone (DHA) and
its sulfate (DHAS). Adrenal androgens, very high
at birth, decrease rapidly the first few months of
life, remaining very low from 1 to 6 years of
life. Adrenarche is defined as the changes in the
pattern of adrenal secretions which occur several
years before the onset of gonadal puberty
(gonadarche). Developmental patterns of adrenal
androgens differ markedly among species and only
the chimpanzee exhibits an adrenarche comparable
to that of man. Adrenarche starts in both sexes
around age 7. The increase in DHA/DHAS has a
rather abrupt onset and is thereafter progressive.
Before the onset of gonadarche mean levels of DHA
and DHAS have increased by about 10 and 20 fold
respectively. The prepubertal rise in plasma
Deltleft arrow over right arrow- androgens is
accompanied by that of Delta4-androstenedione and
11B-hydroxy- Delta4-androstenedione occurring
likely at about the same time but being very
progressive and more modest are only significant
after age 8 in both sexes. Adrenal androgens
continue to rise during puberty. Plasma levels of
DHA and DHAS continue to rise from pubertal stages
1 to 5 and remain similar in both sexes until age
15. At pubertal stage P5, plasma DHA levels are
similar to that seen in young adults with no sex
difference while that of DHAS continue to rise in
boys and become significantly higher than in
girls. Developmental changes in adrenal androgen
secretions are also observed in the response to
ACTH stimulation. Whether estimated as absolute
levels or A of response, the rise in all
unconjugated adrenal androgens to a short or
prolonged ACTH stimulation, is greater with
increasing age, with no sex difference, and is
somewhat correlated to basal levels. Plasma levels
of DHAS do not vary significantly the 2 hours
following a bolus injection of ACTH (21, 34) but
its response to long-term (3-days) ACTH
stimulation is also increasing with age.
Morphological and functional changes in the
adrenal cortex also occur during development.
Focal development of a Zona reticularis starts at
5 years of age, and progressively becomes
continuous. The development of the zona
reticularis is parallel to the increase in adrenal
androgen secretions, and is completed only by age
15. This is accompanied by a rise in
17-hydroxylase and 17,20-desmolase activity in the
adrenals. In a normal timing of physiological
events, the onset of adrenarche occurs several
years before the onset of gonadarche, 2-3 years in
girls and 3-4 years in boys. This relation does
not preclude that the processes are independent
events. Indeed, the onset of adrenarche and
gonadarche are dissociated in a variety of
disorders of sexual maturation. Adrenal androgen
secretions are under the control of ACTH, as shown
by a series of observations. However, the specific
increase of adrenal androgen secretions during
development without any detectable change in ACTH
stimulation, the dissociation between adrenarche
and gonadarche in several conditions, have led to
postulate that the biochemical differentiation of
the zona reticularis may require the action of an
<<adrenal factor>> in addition to
ACTH. Among the proposed <<trophic>>
factors of adrenal androgen secretion, LH/FSH and
estrogens are no longer believed to be involved.
The evidences for the existence of a separate and
specific pituitary cortical androgen-stimulating
hormone (CASH) are not yet convincing. Prolactin,
linked to nutritional status, may stimulate the
activity of the adrenal hydroxysteroid
sulfotransferase. The functional zonal
theory>> is attractive, but it does not
explain why changes in adrenal androgens occur at
a given age. Finally, the occurrence of familial
cases of premature pubarche, the study of the
changes in adrenal androgens in monozygotic or
dizygotic twins and the observation that in
idiopathic delayed puberty the delay in adrenarche
is only one part of a generalized growth and
developmental delay, strongly suggests that
maturation of the adrenal cortex is regulated, at
least in part, by genetic factors. The
physiological importance of adrenal androgens
remains a matter of controversy. Classical 'dogma'
dictates that adrenal androgens are responsible
for pubic hair development. It has also been
suggested that they contribute to somatic growth
or epiphyseal advancement in childhood. This is
mainly based on the observation that premature
adrenarche is accompanied by premature pubarche,
tall stature and advanced bone age. However,
adequate androgen secretion alone does not ensure
normal sexual hair development in many patients
with gonadal dysgenesis. Moreover, in children
with a lack or delayed adrenarche long-term
treatment with DHAS at dosages such as to restore
normal levels for age, failed to induce growth of
sexual hair or any change in growth rate, bone
maturation velocity, or to advance puberty.
Although new hypotheses favour the view that
Deltleft arrow over right arrow-androgens,
particularly Deltleft arrow over right
arrow-androstenediol, have some characteristic
properties of estrogens, the physiological role of
adrenal androgens, if any, remains to be
established. DHAS may well be only a prohormone.
There are ample evidences that all tissues possess
active sulfatases which transform it into DHA,
asteroid with high turn-over. Administration of
DHA to experimental animals has shown beneficial
effects on various endocrine-metabolic parameters,
enhanced immunoprotective functions and reduced
carcinogenesis. DHA prevents diabetes in
genetically diabetic and obese mice. The
importance of in vivo and in vitro experimental
findings is underscored by epidemiological data
showing that low DHA levels are correlated with
increased cardiovascular morbidity in men, breast
cancer in women and a decline in immune
competence. Human studies are at the moment
controversial. It remains possible that DHAS
influence breast cancer risk earlier in life,
and/or that there are more complex interactions
with other hormones or the intracellular
metabolism of DHA/DHAS. Indeed, the tissue
concentrations of DHAS may be important since it
may act indirectly via its metabolism into
estradiol or other steroids. Further long-term
studies are needed to conclude whether DHA/DHAS
are a youth fountain.
Urinary
steroids at time of surgery in postmenopausal
women with breast cancer
Juricskay S, Szabo I, Kett K
Central Research Laboratory, Medical University
of Pecs, Hungary.
Jzsuzsa@main.pote.hu
Breast Cancer Res Treat 1997 May;44(1):83-9
Urinary steroid metabolites were measured by
capillary gas chromatography in 22 postmenopausal
women with operable breast cancer on day before
the tumour excision and in 20 hospitalised control
who were before an operation from other cause than
cancer. Serum dehydroepiandrosterone-sulphat
(DHEAS) and testosterone (T) level were measured
by radioimmunassay in the same groups and same
time. There was no significant difference in the
level of urinary androgen metabolites.
Pregnanediol level was significantly lower (P <
0.05) in cancer patients. In the 5 patients with
positive axillary nodes the tetrahydrocortisol and
alpha-cortolone levels were significantly (P <
0.05) higher than in node negative ones. There was
no significant differences in the serum DHEAS and
T levels. These results indicate that metabolic
changes are existing in postmenopausal patients
which may be a cause or a consequence of the
disease.
Relation
of serum levels of testosterone and
dehydroepiandrosterone sulfate to risk of breast
cancer in postmenopausal women
Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM,
Koenig KL, Shore RE, Kim MY, Pasternack BS,
Toniolo P
Nelson Institute of Environmental Medicine and
Kaplan Comprehensive Cancer Center, New York
University School of Medicine, NY 10010, USA.
Am J Epidemiol 1997 Jun 1;145(11):1030-8
The authors examined the relation between
postmenopausal serum levels of testosterone and
dehydroepiandrosterone sulfate (DHEAS) and
subsequent risk of breast cancer in a case-control
study nested within the New York University
Women's Health Study cohort. A specific objective
of their analysis was to examine whether androgens
had an effect on breast cancer risk independent of
their effect on the biologic availability of
estrogen. A total of 130 cases of breast cancer
were diagnosed prior to 1991 in a cohort of 7,054
postmenopausal women who had donated blood and
completed questionnaires at a breast cancer
screening clinic in New York City between 1985 and
1991. For each case, two controls were selected,
matching the case on age at blood donation and
length of storage of serum specimens. Biochemical
analyses were performed on sere that had been
stored at -80degreeC since sampling. The present
report includes a subset of 85 matched sets, for
whom at least 6 months had elapsed between blood
donation and diagnosis of the case. In univariate
analysis, testosterone was positively associated
with breast cancer risk (odds ratio (OR) for the
highest quartile = 2.7, 95% confidence interval
(CI) 1.1-6.8, p < 0.05, test for trend).
However, after including % estradiol bound to sex
hormone-binding globulin (SHBG) and total
estradiol in the statistical model, the odds
ratios associated with higher levels of
testosterone were considerably reduced, and there
was no longer a significant trend (OR for the
highest quartile = 1.2, 95% CI 0.4-3.5).
Conversely, breast cancer risk remained positively
associated with total estradiol levels (OR for the
highest quartile = 2.9, 95% CI 1.0-8.3) and
negatively associated with % estradiol bound to
SHBG (OR for the highest quartile = 0.05, 95% CI
0.01-0.19) after adjustment for serum testosterone
levels. These results are consistent with the
hypothesis that testosterone has an indirect
effect on breast cancer risk, via its influence on
the amount of bioavailable estrogen. No evidence
was found of an association between DHEAS and risk
of breast cancer in postmenopausal women.
Role of
glucose-6-phosphate dehydrogenase inhibition in
the antiproliferative effects of
dehydroepiandrosterone on human breast cancer
cells
Di Monaco M, Pizzini A, Gatto V, Leonardi L,
Gallo M, Brignardello E, Boccuzzi G
Department of Clinical Pathophysiology,
University of Turin, Italy.
Br J Cancer 1997;75(4):589-92
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.
Effects
of soya consumption for one month on steroid
hormones in premenopausal women: Implications for
breast cancer risk reduction
Lu LJ, Anderson KE, Grady JJ, Nagamani M
Department of Preventive Medicine and Community
Health, University of Texas Medical Branch,
Galveston, TE 77555, USA.
Cancer Epidemiol Biomarkers Prev 1996
Jan;5(1):63-70
Soybean consumption is associated with reduced
rates of breast, prostate, and colon cancer, which
is possibly related to the presence of isoflavones
that are weakly estrogenic and anticarcinogenic.
We examined the effects of soya consumption on
circulating steroid hormones in six healthy
females 22- 29 years of age. Starting within 6
days after the onset of menses, the subjects
ingested a 12-oz portion of soymilk with each of
three meals daily for 1 month on a metabolic unit.
Daily isoflavone intakes were similar100 mg of
daidzein (mostly as daidzin) and similar100 mg of
genistein (mostly as genistin). Serum
17beta-estradiol levels on cycle days 5-7, 12-14,
and 20-22 decreased by 31% (P = 0.09), 81% (P =
0.03), and 49% (P = 0.02), respectively, during
soya feeding. Decreases persisted for two to three
menstrual cycles after withdrawal from soya
feeding. The luteal phase progesterone levels
decreased by 35% during soya feeding (P = 0.002).
Dehydroepiandrosterone sulfate levels decreased
progressively during soya feeding by 14-30% (P =
0.03). Menstrual cycle length was 28.3 plus or
minus 1.9 days before soymilk feeding, increased
to 31.8 plus or minus 5.1 days during the month of
soymilk feeding (P = 0.06), remained increased at
32.7 plus or minus 8.4 days (P = 0. 11) at one
cycle after termination of soymilk feeding, and
returned to pre-soya diet levels five to six
cycles later. These results suggest that
consumption of soya diets containing
phytoestrogens may reduce circulating ovarian
steroids and adrenal androgens and increase
menstrual cycle length. Such effects may account
at least in part for the decreased risk of breast
cancer that has been associated with legume
consumption.
Chemoprevention by dietary
dehydroepiandrosterone against promotion/progressi
on phase of radiation-induced mammary
tumorigenesis in rats
Inano H, Ishii-Ohba H, Suzuki K, Yamanouchi H,
Onoda M, Wakabayashi K
First Research Group National Institute of
Radiological Sciences, Chiba-shi, Japan.
J Steroid Biochem Mol Biol 1995
Jul;54(1-2):47-53
When pregnant rats received whole body
irradiation with 260 cGy gamma-ray at day 20 of
pregnancy, and were then implanted with a
diethylstilbestrol (DES) pellet for an
experimental period of 1 year under feeding of a
control diet, a high incidence (96.2%) of mammary
tumors was observed. Administration of dietary
0.6% dehydroepiandrosterone (DHEA) together with
DES implantation significantly decreased the
incidence (35.0%) of mammary tumors. The first
appearance of palpable tumors in the DHEA-fed
group was 4.5 months later than that in the
control group. For clarification of the mechanism
of the chemopreventive action, we measured hormone
levels in the serum of DHEA-fed rats. In the DHEA
diet rats, the concentration of estradiol-17beta
exceeded, by approximately 6-fold, that in the
control rats, while the levels of progesterone and
prolactin were decreased by 30 and 45%,
respectively, Interestingly, DHEA feeding
prevented DES-induced hypertrophy of pituitary
glands and DES-induced high level of prolactin in
pituitary glands detected by immunohistochemical
studies, but stimulated the development of mammary
glands more than that in control rats treated with
DES alone. These findings suggest that DHEA has a
potent preventive activity against the
promotion/progression phase of radiation-induced
mammary tumorigenesis. The mechanism of
chemoprevention by change of endocrinological
environment is discussed.
Epidemiology of soy and cancer:
Perspectives and directions
Persky V, Van Horn L
Epidemiology/Biostatics Program, University of
Illinois, School of Public Health, Chicago
60612.
J Nutr 1995 Mar;125(3 Suppl):709S-712S
Previous epidemiologic studies of the effects
of soy protein on cancer risk have been limited by
small variations in soy intake, inability to
separate soy from other dietary variables and
difficulties inherent in relating dietary intake
to the development of cancer several decades
later. As a result, although existing data suggest
that soy protein may be protective for cancer
risk, results are overall inconclusive. There is
also evidence that soy products may affect risk
factors for cancer, such as endogenous hormone
levels. Preliminary data from our group indicate
that young Adventist women who are vegetarians
with high soy intake and a lower risk of breast
cancer may have higher levels of an adrenal
androgen, dehydroepiandrosterone sulfate. Other
groups have noted that soy protein may be
associated with alterations in the regulation and
binding of ovarian hormones. Additional studies
examining effects of soy protein on risk factors
for cancer would help, not only in delineating
mechanisms of cancer development, but also in
designing dietary programs aimed at cancer
prevention.
Prevention by dehydroepiandrosterone
of the development of mammary carcinoma induced by
7,12-dimethylbenz(a)anthracene (DMBA) in the
rat
Li S; Yan X; Belanger A; Labrie F
MRC Group of Molecular Endocrinology, CHUL
Research Center, Quebec, Canada.
Breast Cancer Res Treat 1994 Feb;29(2):203-17
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.
Serum
sex hormone levels after menopause and subsequent
breast cancer
Berrino F, Muti P, Micheli A, Bolelli G, Krogh
V, Sciajno R, Pisani P, Panico S, Secreto G
Istituto Nazionale Tumori, Milan, Italy.
J Natl Cancer Inst 1996 Mar 6;88(5):291-6
Background: High levels of androgens and
estrogens have been reported to be associated with
breast cancer. However, the multiplicity of
factors that influence hormone levels and
methodologic issues complicate the study of the
relationship between steroid sex hormones and
breast cancer.
Purpose: Using an improved study design, we
assessed prospectively the relationship between
the principal steroid sex hormones in serum and
the subsequent occurrence of invasive breast
cancer in postmenopausal women. Methods: Four
thousand fifty- three healthy postmenopausal
women, aged 40-69 years, were enrolled from June
1987 through June 1992 in a prospective
investigation of hormones and diet in the etiology
of breast tumors (ORDET study) as part of a larger
volunteer cohort of 10 788 premenopausal and
postmenopausal women from Varese Province,
northern Italy. At recruitment, blood samples were
taken between 8:00 microM and 9:30 AM (after
overnight fasting), and sera were preserved in -80
degreeC freezers. Women who had received hormone
treatment in the 3 months prior to enrollment, who
had a bilateral ovariectomy, or who had a history
of cancer or liver disease were not recruited.
Twenty-five women in the final eligible cohort of
4040 postmenopausal women developed histologically
confirmed, invasive breast cancer during the first
3.5 years of follow-up for the cohort (13 537
woman-years). For each case subject, four control
subjects were randomly chosen after matching for
factors possibly affecting hormone preservation in
serum. One case subject and eight control subjects
were excluded because premenopausal hormonal
patterns were found; thus, after also excluding
the four control subjects matched to the
ineligible case subject, we included 24 case and
88 control subjects. In the spring of 1994, stored
sera of case and control subjects were assayed in
a blinded manner for dehydroepiandrosterone
sulfate and estradiol (E2) by in-house
radioimmunoassay and for total and free
testosterone and sex hormone-binding globulin by
commercially available nonextraction iodination
kits. Mean differences in risk factors were tested
by analysis of variance for paired data. Relative
risks (RRs) were estimated by conditional logistic
regression analysis. All P values resulted from
two-sided tests.
Results: Age-adjusted mean values of total
tesrosterone, free testosterone, and E2 were
significantly higher in case subjects than in
control subjects: total testosterone, 0.34 ng/mL
versus 0.25 ng/mL (P<.001); free testosterone,
1.07 pg/mL versus 0.77 pg/mL (P = .006); and E2,
25 pg/mL versus 22 pg/mL (P = .027). Age-adjusted
RRs for breast cancer in increasing tertiles were
as follows: for total testosterone, 1.0, 4.8, and
7.0 (P for trend = .026); for free testosterone,
1.0, 1.8, and 5.7 (P for trend = .005); and fur
total E2, 1.0, 7.1, and 5.5 (P for trend =
.128).
Conclusions and Implications: This prospective
study provides further evidence in support of the
already established association between elevated
estrogen levels and breast cancer. Even more
importantly, it provides new evidence that high
serum testosterone levels precede breast cancer
occurrence.
Relationship of serum
dehydroepiandrosterone (DHEA), DHEA sulfate, and
5-androstene-3beta,17beta-diol to risk of breast
cancer in postmenopausal women
Dorgan J.F.; Stanczyk F.Z.; Longcope C.;
Stephenson H.E. Jr.; Chang L.; Miller R.; Franz
C.; Falk R.T.; Kahle L.
USA
Cancer Epidemiology Biomarkers and Prevention
(USA), 1997, 6/3 (177-181)
Laboratory evidence suggests a role for
dehydroepiandrosterone (DHEA) and its metabolite
5-androstene-3beta,17beta-diol (ADIOL) in mammary
tumor growth. Serum DHEA also has been related to
breast cancer in postmenopausal women, but the
relationship of ADIOL to risk has not been
evaluated previously. To assess the relationship
of serum DHEA, its sulfate (DHEAS), and ADIOL,
with breast cancer risk in postmenopausal women,
we conducted a prospective nested case-control
study using serum from the Columbia, MO Breast
Cancer Serum Bank. Cases included 71 healthy
postmenopausal volunteers not taking replacement
estrogens when they donated blood and who were
diagnosed with breast cancer up to 10 years later
(median, 2.9 years). Two randomly selected
controls, who also were postmenopausal and not
taking estrogens, were matched to each case on
exact age, date (plus or minus1 year), and time
(plus or minus2 h) of blood collection.
Significant (trend P = 0.02) gradients of
increasing risk of breast cancer were observed for
increasing concentrations of DHEA and ADIOL, and
women whose serum levels of these hormones were in
the highest quartiles were at a significantly
elevated risk compared to those in the lowest;
their risk ratios were 4.0 (95% confidence
interval (CI), 1.3- 11.8) and 3.0 (95% CI,
1.0-8.6), respectively. The relationship of DHEAS
to breast cancer was less consistent, but women
whose serum DHEAS concentration was in the highest
quartile also exhibited a significantly elevated
risk ratio of 2.8 (95% CI, 1.1-7.4). Results of
this prospective study support a role for the
adrenal androgens, DHEA, DHEAS, and ADIOL in the
etiology of breast cancer.
Effects
of oestrogen and progesterone on age-related
changes in arteries of postmenopausal
women.
Liang YL; Teede H; Shiel LM; Thomas A; Craven
R; Sachithanandan N; McNeil JJ; Cameron JD; Dart
A; McGrath BP
Department of Medicine, Monash University,
Clayton, Victoria, Australia.
Clin Exp Pharmacol Physiol (Australia) Jun 1997,
24 (6) p457-9
1. Hormone replacement therapy (HRT) with
oestrogen or oestrogen plus progestin may have
different effects on arterial structure and
function. To examine this question, carotid artery
intima-medial thickness (IMT) and indices of
systemic and carotid arterial compliance were
measured in groups of older men, postmenopausal
women not on HRT (non-HRT) and those women on
long-term HRT with oestrogen alone (HRT-E) or
oestrogen plus progestin (HRT-EP).
2. Sixty men, 90 postmenopausal women taking
HRT and 91 not taking HRT participated in the
study. The groups were similar for age, body mass
index, numbers of smokers, physical activity,
alcohol intake and blood pressure.
3. Plasma total cholesterol was reduced and
high-density lipoprotein-cholesterol was increased
in the HRT group compared with the non-HRT group;
low-density lipoprotein-cholesterol, triglyceride
and lipoprotein (a) values were similar in these
two groups. Results for HRT-E and HRT-EP subgroups
were similar.
4. Carotid IMT was significantly reduced in the
HRT group compared with men and non-HRT groups.
Results for HRT-E and HRT-EP subgroups were
similar.
5. Mean systemic arterial compliance (SAC) was
significantly greater in men than in women and was
related to age; SAC was higher in both HRT-E and
HRT-EP groups compared with the non-HRT group.
Indices of carotid stiffness were similar in men
and in non-HRT groups. The HRT-EP group showed
increased carotid stiffness compared with the
HRT-E group.
6. There is an apparent protective effect of
long-term oestrogen therapy on carotid IMT and
age-related changes in arterial stiffness.
Progestin does not alter the IMT effects but may
adversely influence arterial stiffness.
Hormone
replacement therapy in postmenopausal women:
urinary N-telopeptide of type I collagen monitors
therapeutic effect and predicts response of bone
mineral density.
Chesnut CH 3rd; Bell NH; Clark GS; Drinkwater
BL; English SC; Johnson CC Jr; Notelovitz M; Rosen
C; Cain DF; Flessland KA; Mallinak NJ
University of Washington Medical Center, Seattle
98195-6113, USA.
Am J Med (United States) Jan 1997, 102 (1)
p29-37
PURPOSE: To assess the ability of the urinary
N-telopeptide of type I collagen (NTx) to monitor
and predict therapeutic effects of hormone
replacement therapy (HRT) in postmenopausal
women.
PATIENTS AND METHODS: To assess the
relationship between baseline or change in NTx
(predictive variable), and change in lumbar and
hip bone mineral density (BMD; outcome variable),
we conducted a 2-year randomized controlled study
at academic university and private practice
medical centers in 236 healthy women 1 to 3 years
postmenopausal; 227 women completed the study.
Women received estrogen plus progesterone plus
calcium (treated group) or calcium alone (control
group).
RESULTS: In the treated group NTx significantly
(P < 0.0001) decreased, and spine and hip BMD
significantly (P < 0.00001 and P < 0.005,
respectively) increased; in the control group NTx
did not change but BMD decreased significantly (P
< 0.01). Subjects in the highest quartiles for
baseline NTx (67 to 188 units) or decreasing NTx
(-66% to -87%) through 6 months demonstrated the
greatest gain in BMD in response to HRT (P <
0.05 and P < 0.005). For every increase of 30
units in baseline NTx the odds of gain in BMD in
response to HRT increased by a factor of 5.0 (95%
confidence interval [CI] 1.9 to 13.3); for every
30% decrease in NTx through 6 months, the odds of
gaining BMD in response to HRT increased by a
factor of 2.6 (95% CI 1.6 to 4.4). In the control
group an increase of 30 units in mean NTx across
the study indicated a higher odds of losing BMD by
a factor of 3.2 (95% CI 1.6 to 6.5). A high
baseline NTx (> 67 units) indicated a 17.3
times higher risk of BMD loss if not treated with
HRT.
CONCLUSION: These data support the clinical
utility of NTx to monitor the antiresorptive
effect of HRT in recently postmenopausal women,
and to predict changes in BMD in response to
HRT.
Estrogen inhibits cuff-induced
intimal thickening of rat femoral artery: effects
on migration and proliferation of vascular smooth
muscle cells.
Akishita M; Ouchi Y; Miyoshi H; Kozaki K; Inoue
S; Ishikawa M; Eto M; Toba K; Orimo H
Department of Geriatrics, Faculty of Medicine,
University of Tokyo, Japan.
Atherosclerosis (Ireland) Apr 1997, 130 (1-2)
p1-10
The present study was performed to elucidate
the mechanism underlying the anti-atherogenic
action of estrogen. We investigated the effect of
estrogen on intimal thickening of the rat femoral
artery induced by cuff placement and further
examined the effect of estrogen on migration and
proliferation of vascular smooth muscle cells
(VSMCs) in culture. Intimal thickening was
significantly greater in males than in control
females. Intimal thickening in females was
increased to the level in males by ovariectomy.
Estrogen replacement to ovariectomized rats
reversed this effect. Proliferating cell nuclear
antigen immunohistochemistry showed that in vivo
proliferation of VSMCs contributed to the
difference in intimal thickening. There was no
difference in blood pressure and serum lipids,
suggesting that estrogen directly acted on artery
and inhibited intimal thickening. 17
beta-Estradiol (E2, 1-100 nmol/l) inhibited
migration of cultured rat VSMCs, assayed using a
microchemotaxis chamber, in a
concentration-dependent manner. E2 (0.01-100
nmol/l), but not progesterone or testosterone,
also inhibited [3H]thymidine incorporation in rat
VSMCs in a concentration-dependent manner.
Indomethacin, NG-monomethyl-L-arginine and
methylene blue did not influence the inhibitory
action of E2 on [3H]thymidine incorporation,
suggesting that prostanoids and nitric oxide are
not involved in the action of E2. E2 did not
provoke VSMC injury, as measured by the release of
incorporated [3H]2-deoxy-D-glucose. These results
suggest that the inhibition of migration and
proliferation of VSMCs contributes to the
inhibitory effect of estrogen on intimal
thickening.
Ovarian
aging and hormone replacement therapy. Hormonal
levels, symptoms, and attitudes of
African-American and white women.
Pham KT; Grisso JA; Freeman EW
Division of General Internal Medicine, University
of Pennsylvania, Philadelphia, USA.
J Gen Intern Med (United States) Apr 1997, 12 (4)
p230-6
OBJECTIVES: To characterize reproductive
hormone levels, symptoms, and attitudes related to
menopause among healthy, menstruating white and
African-American women aged 44 to 49 years.
DESIGN: Pilot study; cross-sectional
survey.
SETTING: Community-based convenience sample of
women in the Philadelphia metropolitan area.
PARTICIPANTS: Thirty-three African-American and
35 white women.
MEASUREMENTS: The survey instrument collected
demographic data, medical and reproductive
history, health practices and behaviors. It
included previously validated function,
depression, and quality-of-life instruments, and a
Menopause Attitude Scale that included two
factors, attitudes toward the menopause and
attitudes toward medical therapy. Anthropometric
measurements were taken at enrollment, and
reproductive hormones and daily symptom logs were
followed over two menstrual cycles.
MAIN RESULTS: The two groups were comparable in
mean age (African-American 46.2 years, white 46.9
years). Serum levels of estradiol,
follicle-stimulating hormone,
dihydroepiandrosterone-sulfate, and progesterone
were comparable. Symptoms were similar in type and
frequency. However, the African-American women had
significantly more positive attitudes toward
menopause, were more likely to rely on family for
information about menopause, and were less likely
to have been recommended hormone replacement
therapy by their physicians. A majority of women
in each group expressed satisfaction with the care
they had received.
CONCLUSIONS: Perimenopausal African-American
and white women have different expectations of
menopause and the role of medical care in
menopause. This bears directly on women's
acceptance of hormone replacement therapy.
Conclusions are limited by the small sample size
and convenience nature of the study population:
further work with larger samples is needed to
confirm these apparent differences.
In vivo
estrogen regulation of epidermal growth factor
receptor in human endometrium.
McBean JH; Brumsted JR; Stirewalt WS
Department of Obstetrics and Gynecology,
University of Vermont College of Medicine,
Burlington 05401, USA.
J Clin Endocrinol Metab (United States) May 1997,
82 (5) p1467-71
The effects of estrogen and progesterone on the
expression of epidermal growth factor receptor
(EGFR) in human endometrium were studied in
hypogonadal women under conditions that simulated
a normal menstrual cycle. All women received the
same regimen of estrogen and progesterone and
underwent serial biopsies. In one group of women
(group I), a biopsy was obtained before receiving
estrogen (CD0) and after 11 days (CD11) of
estrogen replacement. A second group of women was
biopsied on CD11 and CD21 to assess the combined
effects of progesterone and estrogen (group II).
Immunohistochemistry was used to test for the
presence of EGFR, and a ribonuclease protection
assay was used to assess the amounts of EGFR
messenger ribonucleic acid (RNA) relative to
ribosomal RNA in the tissue. In group I, a
significant increase in EGFR messenger RNA from
CD0 to CD11 was observed. A similar increase was
observed to occur between CD11 and CD21 in group
II. Immunostaining for EGFR was absent in all CD0
biopsies, but was present in all estrogen-exposed
endometrium. No difference in immunostaining was
noted between CD11 and CD21. We conclude that
estrogen stimulates the synthesis of EGFR in human
endometrium and that progesterone does not appear
to modulate this effect. The examination of other
parameters in hormone-replaced hypogonadal
subjects will be valuable in understanding the
complex physiological regulation of the human
endometrium.
The
perimenopausal hot flash: epidemiology,
physiology, and treatment.
Shaw CR
Marquette University College of Nursing,
Milwaukee, Wis, USA.
Nurse Pract (United States) Mar 1997, 22 (3)
p55-6, 61-6
The "hot flash" (HF), or vasomotor instability,
is experienced by 75% of perimenopausal and
menopausal women in the United States. The
experience for some women is a minor annoyance but
for others, the HF is an intensely unpleasant
sensation that is disruptive to their lives. The
HF is thought to be triggered by a number of
external and internal stimuli such as anxiety,
stress, ambient high temperatures, caffeine, and
alcohol. The thinner woman tends to experience
more severe and frequent HFs than the woman with
more adipose tissue, probably because of the
ability of adipose tissue to transform
androstenedione to estrone and estradiol. Smoking
history also tends to be associated with the
experience of HFs at an earlier age. The etiology
of HFs in the decreasing estrogen state is related
to the downward resetting of the hypothalamic
thermoregulating mechanism, probably by the action
of norepinephrine, which is usually modulated by
estrogen. The body attempts to dissipate unwanted
body heat by vasodilation, thus causing the
sensation of the HF. The most successful treatment
modalities have been hormone replacement therapy
with estrogen and progesterone. Alpha 2-adrenergic
blockers have also shown some limited
effectiveness. Many alternative therapies such as
vitamin E, primrose oil, dong quai, and black
cohash have anecdotal support but have not been
thoroughly studied. Relaxation, exercise,
avoidance of triggering factors, and control of
external environment have all been utilized with
some success by women.
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