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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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