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Estrogen replacement therapy and fatal ovarian
cancer.
Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thun
MJ, Heath CW Jr
Division of Epidemiology, Emory University School of Public
Health, Atlanta, GA, USA.
Am J Epidemiol 1995 May 1;141(9):828-35
The authors examined the relation between use of estrogen
replacement therapy and ovarian cancer mortality in a large
prospective mortality study of 240,073 peri- and
postmenopausal women, none of whom had a prior history of
cancer, hysterectomy, or ovarian surgery at enrollment in
1982. During 7 years of follow-up, 436 deaths from ovarian
cancer occurred. Cox proportional hazard regression was used
to adjust for other risk factors. Ever use of estrogen
replacement therapy was associated with a rate ratio for fatal
ovarian cancer of 1.15 (95% confidence interval (CI)
0.94-1.42). The mortality rate ratio increased with duration
of use prior to entry to this study to 1.40 (95 CI% 0.92-2.11)
with 6-10 years of use and 1.71 (95% CI 1.06-2.77) with >
or = 11 years of use. The increase in mortality associated
with > or = 6 years of use was observed in both current
users (rate ratio (RR) = 1.72, 95% CI 1.01-2.90) and former
users at study entry (RR = 1.48, 95% CI 0.99-2.22), relative
to never users. Risk associated with use was not modified by
any of the other risk factors. These data suggest that
long-term use of estrogen replacement therapy may increase the
risk of fatal ovarian cancer.
Inhibition of breast cancer cell growth by combined
treatment with vitamin D3 analogues and tamoxifen.
Vink-van Wijngaarden T, Pols HA, Buurman CJ, van den Bemd GJ,
Dorssers LC, Birkenhager JC, van Leeuwen JP
Department of Internal Medicine III, Erasmus University,
Rotterdam, The Netherlands.
Cancer Res 1994 Nov 1;54(21):5711-7
The steroid hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]
has potential to be used as an antitumor agent, but its
clinical application is restricted by the strong calcemic
activity. Therefore, new vitamin D3 analogues are developed
with increased growth inhibitory and reduced calcemic
activity. In the present study, we have examined the
antiproliferative effects of four novel vitamin D3 analogues
(CB966, EB1089, KH1060, and 22-oxa-calcitriol) on breast
cancer cells, either alone or in combination with the
antiestrogen tamoxifen. The estrogen-dependent ZR-75-1 and
estrogen-responsive MCF-7 cell lines were used as a model. It
was shown that, with EB1089 and KH1060, the same growth
inhibitory effect as 1,25-(OH)2D3 could be reached at up to
100-fold lower concentrations, whereas CD966 and
22-oxa-calcitriol were nearly equipotent with 1,25-(OH)2D3.
The growth inhibition by the vitamin D3 compounds could be
augmented by combined treatment with tamoxifen. At the maximal
effective concentrations of the vitamin D3 compounds, the
effect of combined treatment was addictive (MCF-7 cells) or
less than additive (ZR-75-1 cells). Tamoxifen increased the
sensitivity of the cells to the vitamin D3 compounds 2- to
4000-fold, which was expressed by a shift to lower median
effective concentration values. Thereby, the vitamin D3
compounds may be used at even lower dosages in combination
therapy with tamoxifen. A major problem of tamoxifen therapy
is the development of tamoxifen resistance. We have observed
that tamoxifen-resistant clones of ZR-75-1 cells retain their
response to the vitamin D3 compounds. Regulation of the
growth-related oncogene c-myc (mRNA level) and the estrogen
receptor (protein level) were studied but appeared not to be
related to the antiproliferative action of the vitamin D3
compounds. Together, our data point to a potential benefit of
combination therapy with 1,25-(OH)2D3 or vitamin D3 analogues
and tamoxifen for the treatment of breast cancer.
Melatonin modulation of estrogen-regulated
proteins, growth factors, and proto-oncogenes in human breast
cancer.
Molis TM; Spriggs LL; Jupiter Y; Hill SM
Department of Anatomy, Tulane University School of Medicine,
New Orleans, LA 70112, USA.
J Pineal Res 1995 Mar;18(2):93-103
The growth-inhibitory actions of the pineal hormone,
melatonin, on human breast tumor cells and the possible
association between this inhibition and melatonin's
down-regulation of the estrogen receptor (ER) expression were
examined in the ER-positive, estrogen-responsive MCF-7 human
breast tumor cell line. As previously reported, melatonin
dramatically inhibits the growth of these breast tumor cells
and down-regulates ER levels in these cells, suggesting that
the modulation of ER may be an important mechanism by which
melatonin inhibits breast cancer cell growth. In the present
studies, Northern blot analysis was used to examine the
expression of estrogen-regulated transcripts known to be
involved in estrogen's mitogenic actions. Melatonin, at a
physiologic concentration (10(-9) M), rapidly, significantly,
and, in some cases, transiently elevated the steady-state mRNA
levels of growth stimulatory products such as TGF alpha,
c-myc, and pS2, which are normally up-regulated in response to
estrogen. Conversely, melatonin decreased the expression of
other factors normally up-regulated by estrogen, such as
progesterone receptor and c-fos. Significant stimulation of
the expression of the growth-inhibitory factor TGF beta was
seen with melatonin treatment, potentially supporting the
concept that melatonin's growth-inhibitory activity is
mediated through the breast tumor cells' estrogen-response
pathway. The early regulation of many of these products by
melatonin suggests that mechanisms more rapid than the
down-regulation of ER are important in melatonin's modulation
of their expression. However, the long-term modulation of
these transcripts (12-48 hr) may be heavily influenced by
melatonin's down-regulation of ER expression. These results
clearly define the need for additional in depth studies to
dissect the cellular events leading to melatonin-induced
growth inhibition in breast tumor cells.
Melatonin inhibition of MCF-7 human breast-cancer
cells growth: influence of cell proliferation rate.
Cos S, Sanchez-Barcelo EJ
Department of Physiology and Pharmacology, School of
Medicine, University of Cantabria, Santander, Spain.
Cancer Lett 1995 Jul 13;93(2):207-12
We have studied whether the cell proliferation rate
modifies the inhibitory actions of melatonin on MCF-7 cell
growth. The proliferative rate of cells was altered by plating
them at different densities (5 x 10(4) to 100 x 10(4)
cells/dish) in media with low charcoal-stripped serum
concentrations. In this way, population doubling time ranged
from 33 h (for density = 100 x 10(4) cells/dish) to 75 h (for
density = 5 x 10(4) cells/dish). Melatonin (10(-9)M) only
inhibited fast proliferating MCF-7 cells, increasing their
cell doubling time, and did not significantly modify the
length of doubling time in the cultures with low proliferation
rate, in which doubling time was already long. These data
clearly show that there is a direct relation between
proliferative rate of cells and melatonin inhibitory actions
on MCF-7 cells.
Modulation of cancer endocrine therapy by
melatonin: a phase II study of tamoxifen plus melatonin in
metastatic breast cancer patients progressing under tamoxifen
alone.
Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M,
Esposti D, Tancini G
Divisione di Radioterapia Oncologica, San Gerardo Hospital,
Monza, Milan, Italy.
Br J Cancer 1995 Apr;71(4):854-6
Recent observations have shown that the pineal hormone
melatonin (MLT) may modulate oestrogen receptor (ER)
expression and inhibit breast cancer cell growth. On this
basis, we have evaluated the biological and clinical effects
of a concomitant MLT therapy in women with metastatic breast
cancer who had progressed in response to tamoxifen (TMX)
alone. The study included 14 patients with metastasis who did
not respond (n = 3) to therapy with TMX alone or progressed
after initial stable disease (SD) (n = 11). MLT was given
orally at 20 mg day-1 in the evening, every day starting 7
days before TMX, which was given orally at 20 mg day-1 at
noon. A partial response was achieved in 4/14 (28.5%) patients
(median duration 8 months). The treatment was well tolerated
in all cases, and no MLT-induced enhancement of TMX toxicity
was seen; on the contrary, most patients experienced a relief
of anxiety. Mean serum levels of insulin-like growth factor 1
(IGF-1), which is a growth factor for breast cancer,
significantly decreased on therapy, and this decline was
significantly higher in responders than in patients with SD or
progression. This pilot phase II study would suggest that the
concomitant administration of the pineal hormone MLT may
induce objective tumour regressions in metastatic breast
cancer patients refractory to TMX alone.
Modulation of estrogen receptor mRNA expression by
melatonin in MCF-7 human breast cancer cells.
Molis TM, Spriggs LL, Hill SM
Department of Anatomy, Tulane University School of Medicine,
New Orleans, Louisiana 70112.
Mol Endocrinol 1994 Dec;8(12):1681-90
Melatonin, the hormonal product of the pineal gland, has
been shown to inhibit the development of mammary tumors in
vivo and the proliferation of MCF-7 human breast cancer cells
in vitro by mechanisms not yet identified. However, previous
studies have demonstrated that melatonin significantly
decreased estrogen-binding activity and the expression of
immunoreactive estrogen receptor (ER) in MCF-7 breast cancer
cells. To determine the mechanism(s) by which melatonin
regulates ER expression in MCF-7 cells, the relationship
between the level of steady state ER mRNA and the rate of ER
gene transcription were examined in response to melatonin.
Physiological concentrations of melatonin decreased steady
state levels of ER mRNA expression in a dose- and
time-specific manner. This decrease was not dependent upon the
presence of estrogen since similar decreases in steady state
ER mRNA levels were seen in MCF-7 cells cultured in both
complete and estrogen-depleted media. The decreased expression
of ER mRNA in response to melatonin appears to be directly
related to the suppression of transcription of the ER gene.
This regulation is independent of the synthesis of new
proteins, as cycloheximide was unable to block the
melatonin-induced decrease of steady-state ER mRNA levels. The
down-regulation of ER by melatonin appears to not be mediated
via a direct interaction with the ER and subsequent feedback
on its own expression, since melatonin treatment did not alter
the transcriptional regulatory ability of the fully activated
wild type ER or a constitutively active hormone-binding
domain-deleted ER variant. In addition, the stability of the
ER transcript was unaffected by melatonin. Thus, it appears
that the antiproliferative actions of this pineal indoleamine
are mediated, at least in part, through the suppression of the
transcription of the ER gene in MCF-7 human breast cancer
cells.
Melatonin modulates growth factor activity in MCF-7
human breast cancer cells.
Cos S, Blask DE
Department of Physiology and Pharmacology College of
Medicine, University of Cantabria, Santander, Spain.
J Pineal Res 1994 Aug;17(1):25-32
Melatonin has been shown to have direct oncostatic actions
on estrogen-responsive, MCF-7 human breast cancer cells in
culture. In the present study, we examined whether these
inhibitory actions on cell growth may be mediated through
actions on bioassayable growth factor activity. In order to
test this hypothesis, we estimated the growth factor activity
of conditioned medium (CM) from estradiol (E2), or
melatonin-treated cells, in the presence or absence of
melatonin on MCF-7 cell growth. We also determined whether
melatonin inhibits the action of epidermal growth factor (EGF)
action in the absence of E2. The addition of melatonin (10(-9)
M) to the cultures of MCF-7 cells with CM from E2 (10(-8)
M)-treated cells significantly inhibited the growth
stimulatory activity of CM, suggesting that melatonin
inhibited cell proliferation by blocking the action of
E2-induced autocrine growth stimulatory factors. Conditioned
medium from melatonin-treated cells significantly inhibited
cell proliferation, while an additional supply of melatonin to
these cultures had an even greater inhibitory effect.
Melatonin was also active in the complete absence of serum as
long as cell growth was stimulated by EGF, an E2-inducible
growth factor. The inhibitory effect of melatonin increased as
the dose of EGF increased. This non-antiestrogenic inhibitory
effect of melatonin was reversed by E2, but not by EGF itself,
suggesting that melatonin requires accessible estrogen
receptor sites for its inhibitory activity on the growth
stimulating action of EGF. Taken together, these findings
suggest that melatonin may inhibit the action and/or release
of growth stimulatory factors as well as stimulate the release
of growth inhibitory factors in culture.
Role of pineal gland in aetiology and treatment of
breast cancer.
Cohen M, Lippman M, Chabner B
Lancet 1978 Oct 14;2(8094):814-6
The hypothesis that diminished function of the pineal gland
may promote the development of breast cancer in human beings
is suggested by the relation between breast cancer and
prolonged oestrogen excess, and by the observation that the
pineal secretion, melatonin, inhibits ovarian oestrogen
production, pituitary gonadotrophin production, and sexual
development and maturation. The hypothesis is supported by the
following points.
(1) Pineal calcification is commonest in countries with
high rates of breast cancer and lowest in areas with a low
incidence; the incidences of pineal calcification and of
breast cancer are moderate among the black population in the
United States.
(2) Chlorpromazine raises serum-melatonin; there are
reports that psychiatric patients taking chlorpromazine have a
lower incidence of breast cancer.
(3) Although information is lacking on breast cancer, the
pineal and melatonin may influence tumour induction and growth
in experimental animals.
(4) The demonstration of a melatonin receptor in human
ovary suggests a direct influence of this hormone on the
ovarian function, and possibly oestrogen production.
(5) Impaired pineal secretion is believed to be an
important factor triggering puberty (early menarche is a risk
factor for breast cancer).
3beta-hydroxysteroid dehydrogenase/isomerase and
aromatase activity in primary cultures of developing zebra
finch telencephalon: Dehydroepiandrosterone as substrate for
synthesis of androstenedione and estrogens
Vanson A.; Arnold A.P.; Schlinger B.A.
Department of Psychology, University of California, Los
Angeles, CA 90024 USA
General and Comparative Endocrinology (USA), 1996, 102/3
(342-350)
3beta-hydroxysteroid dehydrogenase/Deltleft arrow over
right arrow-Delta4 isomerase (3beta-HSD) activity was measured
in primary dissociated cell cultures prepared from
telencephalons of developing zebra finches. 3beta-HSD activity
was confirmed after cultures were incubated with
(7-3H)pregnenolone (Preg) or (1,2,6,7- 3H-)
dehydroepiandrosterone (DHEA) and 3H-progesterone (Prog) and
3H- androstenedione (AE) were detected in the medium. Product
identity was confirmed by recrystallizations and by HPLC
analysis. When DHEA was used as substrate, 3H-estradiol and
3H-estrone were also detected in the culture medium,
presumably derived from the aromatization of 3H-AE or 3H-T
produced from 3H-DHEA. To test this idea, cultures were
incubated with 3H-DHEA together with radioinert AE or with
fadrozole HCl, a potent and specific aromatase inhibitor. In
the presence of radioinert AE, 3H-AE increased but metabolites
of 3H-AE decreased in the media; in the presence of fadrozole,
3H-estrogens decreased but 3H-AE and its androgenic metabolite
3H-5beta- androstanedione increased. These data demonstrate
3beta-HSD activity in the songbird brain. The presence of Prog
and estradiol in these cultures suggest that Preg and DHEA can
potentially serve as substrates for the ultimate formation of
active sex steroids in the songbird telencephalon.
Abnormal production of androgens in women with
breast cancer
Secreto G.; Zumoff B.
Div of Endocrinology and Metabolism, Department of Medicine,
Beth Israel Medical Center, New York, NY USA
Anticancer Res. (Greece), 1994, 14/5 B
(2113-2117)
Two long and broad streams of medical literature, from the
1950's to date have established the existence of two unrelated
abnormalities of androgen production in women with breast
cancer: One is the genetically determined presence of
subnormal production of adrenal androgens (i.e. DHEA and
DHEAS) in women with premenopausal breast cancer and their
sisters, who are at increased risk for breast cancer: The
other is excessive production of testosterone, of ovarian
origin, in subsets of women with either premenopausal or
postmenopausal breast cancer and women with atypical
breast-duct hyperplasia, who are at increased risk for breast
cancer; along with the hypertestosteronism, there is
frequently chronic anovulation in the premenopausal patients.
The combination of ovarian hypertestosteronism and chronic
anovulation is characteristic of the polycystic ovary syndrome
and is also frequently seen in women with abdominal
('android') obesity; both PCOS and abdominal obesity are known
to be characterized by high risk for postmenopausal cancer.
The elevated testosterone levels and the increased levels of
insulin, IGF-I, and IGF-II that are seen in PCOS and abdominal
obesity could favor the development of breast cancer in
several ways, all of which have been demonstrated
experimentally binding of testosterone to cancer cells bearing
testosterone receptors, with direct stimulation; intratissular
aromatization of testosterone to estradiol, with stimulation
of estrogen-sensitive cells; stimulation of the production of
epithelial growth factor (EGF) by testosterone, with direct
mitogenic effect of EGF on cancer cells; stimulation of
aromatase by insulin and IGF-I; direct mitogenic stimulation
of cancer cells by insulin, IGF-I, and IGF-II; and stimulation
by IGF-I and IGF-II of the intratissular reduction of estrone
to estradiol. Since PCOS is probably largely genetically
determined, and abdominal obesity may also be, the
hypertestosteronism of these conditions may represent a second
genetically determined hormonal risk factor for breast
cancer.
Endogenous sex hormones: Impact on lipids,
lipoproteins, and insulin
Haffner S.M.; Valdez R.A.
Department of Medicine, Univ. of Texas Hlth. Science Center,
7703 Floyd Curl Drive, San Antonio, TX 78284-7873 USA
Am. J. Med. (USA), 1995, 98/1 A (40S-47S)
Estrogen use has been reported to decrease triglyceride and
low-density lipoprotein cholesterol (LDL-C) and increase
high-density lipoprotein cholesterol (HDL-C). Estrogen use
increases the secretion of large, very low- density
lipoprotein cholesterol (VLDL-C) and also stimulates the
uptake of VLDL-C by the liver and increases the catabolism of
LDL-C in the liver. Sex hormones may affect several enzymes
involved in the metabolism of HDL-C and triglyceride and may
also affect lipolysis. In both pre- and postmenopausal women,
several studies have shown that increased glucose and insulin
concentrations are associated with increased free testosterone
and decreased sex hormone binding globulin. The temporal
direction of this relationship in premenopausal women is not
clear, however. In contrast to women, increased androgen
concentrations in men do not seem to be associated with
increased cardiovascular risk factors, although testosterone
concentrations are associated with increased HDL-C and
decreased insulin concentrations. Dehydroepiandrosterone
(DHEA) and dehydroepiandrosterone sulfate (DHEAS) appear to be
associated with improved cardiovascular risk factors in men,
but this connection in women is less clear.
Dehydroepiandrosterone antiestrogenic action
through androgen receptor in MCF-7 human breast cancer cell
line
Boccuzzi G.; Di Monaco M.; Brignardello E.; Leonardi L.;
Gatto V.; Pizzini A.; Gallo M.
Dipartimento Fisiopatologia Clinica, Universita di Torino,
Via Genova 3, 10126 Torino Italy
Anticancer Res. (Greece), 1993, 13/6 A
(2267-2272)
The possible mechanisms of the inhibitory effect of
dehydroepiandrosterone (DHEA) on the estrogen-induced growth
of MCF-7 human breast cancer cells were explored. The
impairment of metabolic pathways via the inhibition of
glucose-6-posphate dehydrogenase (G6PD) activity was excluded:
G6PD activity in MCF-7 homogenate was reduced by DHEA only at
a very high concentration (50 microM) while no inhibitory
action on the enzyme activity was detected when DHEA was added
at the antimitotic concentrations (0.02-0.5 microM). A steroid
receptor mediated effect was explored: DHEA might either
activate androgen receptors (AR) or partially displace E2 from
estrogen receptor (ER). The pure antiandrogens Flutamide and
Hydroxyflutamide reversed the inhibitory effect of DHEA on
MCF-7 cell growth, whereas both the nonsteroidal estrogen
Diethylstilbestrol and the antiestrogen Tamoxifen were
ineffective. Results demonstrate that the AR activation plays
a pivotal role in the inhibitory action of DHEA on the
E2-induced MCF-7 growth.
Effect of flax seed ingestion on the menstrual
cycle
Phipps W.R.; Martini M.C.; Lampe J.W.; Slavin J.L.; Kurzer
M.S.
Department of Obstetrics-Gynecology, Rochester University
Medical Center, Box 668, 601 Elmwood Avenue, Rochester, NY
14642 USA
J. Clin. Endocrinol. Metab. (USA), 1993, 77/5
(1215-1219)
Lignans are a group of phytochemicals shown to have weakly
estrogenic and antiestrogenic properties. Two specific
lignans, enterodiol and enterolactone, are absorbed after
formation in the intestinal tract from plant precursors
particularly abundant in fiber-rich food and are excreted in
the urine. We evaluated the effect of the ingestion of flax
seed powder, known to produce high concentrations of urinary
lignans, on the menstrual cycle in 18 normally cycling women,
using a balanced randomized cross-over design. Each subject
consumed her usual omnivorous, low fiber (control) diet for 3
cycles and her usual diet supplemented with flax seed for
another 3 cycles. The second and third flax cycles were
compared to the second and third control cycles. Three
anovulatory cycles occurred during the 36 control cycles,
compared to none during the 36 flax seed cycles. Compared to
the ovulatory control cycles, the ovulatory flax cycles were
consistently associated with longer luteal phase (LP) lengths
(mean plus or minus SEM, 12.6 plus or minus 0.4 vs. 11.4 plus
or minus 0.4 days; P = 0.002). There were no significant
differences between flax and control cycles for concentrations
of either estradiol or estrone during the early follicular
phase, midfollicular phase, or LP. Although flax seed
ingestion had no significant effect on LP progesterone
concentrations, the LP progesterone/estradiol ratios were
significantly higher during the flax cycles. Midfollicular
phase testosterone concentrations were slightly higher during
flax cycles. Flax seed ingestion had no effect on early
follicular phase concentrations of DHEA-S, PRL, or sex
hormone-binding globulin. Our data suggest a significant
specific role for lignans in the relationship between diet and
sex steroid action, and possibly between diet and the risk of
breast and other hormonally dependent cancers.
Estrogen and nerve growth factor-related systems in
brain. Effects on basal forebrain cholinergic neurons and
implications for learning and memory processes and aging
Gibbs R.B.; Jones K.J.; Moorjani B.; Luine V.
Department Pharmacy and Therapeutics, University of
Pittsburgh, School of Pharmacy, Pittsburgh, PA 15261 USA
Ann. New York Acad. Sci. (USA), 1994, 743/-
(165-199)
Estrogen replacement can significantly affect the
expression of ChAT and NGF receptors in specific basal
forebrain cholinergic neurons. The time-course of the effects
is consistent with a direct up-regulation of ChAT followed by
either direct or indirect down-regulation of p75(NGFR) and
trkA NGF receptors, possibly due to increased cholinergic
activity in the hippocampal formation and cortex and a
decrease in hippocampal levels of NGF. Current evidence
suggests ChAT, p75(NGFR) trkA, and NGF all play a role in
regulating cholinergic function in the hippocampal formation
and cortex. In addition, all have been implicated in the
maintenance of normal learning and memory processes as well as
in changes in cognitive function associated with aging and
with neurodegenerative disease. It is possible that estrogen
may affect cognitive function via effects on NGF-related
systems and basal forebrain cholinergic neurons. Effects of
estrogen on cognitive function have been reported, as has some
preliminary evidence for beneficial effects of estrogen in
decreasing the prevalence of and reducing some cognitive
deficits associated with Alzheimer's disease. Whether these
effects are related to effects on NGF-related systems or basal
forebrain cholinergic neurons is currently unknown. Indirect
evidence suggests that estrogen interacts with NGF-related
systems and that changes in circulating levels of estrogen can
contribute to age-related changes in hippocampal levels of
NGF. These findings have important implications for
consideration of estrogen replacement therapy in pre- and
post-menopausal women. Further studies examining effects of
different regimens of estrogen replacement as well as estrogen
combined with progesterone on NGF and basal forebrain
cholinergic neurons in young and aged animals are required.
Prospective studies correlating aging and estrogen replacement
with numbers of basal forebrain cholinergic neurons and
hippocampal and cortical levels of NGF also need to be
performed to better assess the potential benefits of estrogen
replacement in reducing age- and disease-related cognitive
decline.
Postmenopausal estrogen replacement: A long-term
cohort study
Lafferty F.W.; Fiske M.E.
University Suburban Health Center, 1611 South Green Road,
Cleveland, OH 44121 USA
Am. J. Med. (USA), 1994, 97/1 (66-77)
To assess the long-term effects of estrogen replacement
therapy (ERT) in 157 postmenopausal women, a prospective,
nonrandomized, cohort study was conducted from 1964 to 1989.
ERT consisted of 0.625 mg of conjugated equine estrogen daily
for the first 25 days of each month without oral progesterone
from 1964 to 1984. From 1984 to 1989 5 mg of
medroxyprogesterone was added from day 14 to 25 of every sixth
month in subjects with an intact uterus. The mean loss of
height was significantly less among the ERT subjects after age
65 years and remained at 0.08 cm/year from age 56 to 80 years,
whereas the loss of height accelerated among the control
subjects to 0.19 cm/year from age 66 to 70, to 0.22 cm/year
from age 71 to 75, and to 0.30 cm/year from age 76 to 80. The
mean cortical bone density at the distal third of the radius
was significantly greater among the ERT subjects compared to
the control subjects with the difference representing a 12.0%
higher bone density with ERT.
Impact of the menopause on the epidemiology and
risk factors of coronary artery heart disease in women
Gorodeski G.I.
Department of Obstetrics/Gynecology, University MacDonald
Womens Hospital, 2074 Abington Road, Cleveland, OH 44106
USA
Exp. Gerontol. (USA), 1994, 29/3-4 (357-375)
Cardiovascular disease is the leading cause of morbidity
and mortality in women, and coronary artery heart disease
(CHD) is the largest single component of fatal cardiovascular
disease. Gender-related differences are observed in the
symptomatology, natural course and outcome, and in the
management of the acute coronary event. More women, compared
to men, have angina as their first manifestation of CHD, and
they are less likely to have serious stenosis. Women undergo
less invasive diagnostic procedures, but have an overall
prognosis that is worse than that of men. Rates of CHD in
women increase after the fifth-sixth decades of life,
suggesting that young women have a protective factor that is
lost after the fifth decade. Because most women become
menopausal during this age range, it is speculated that the
protective factor may the female hormone, estrogen. This
conclusion is supported by results of epidemiological studies
indicating an increased risk of CHD in women with early-onset
menopause and a reduced risk in postmenopausal women treated
with estrogen replacement therapy. The impact of the
menopausal transition on other CHD risk factors is still not
fully understood. Reduced estrogen levels resulting from the
menopausal transition have been implicated in adverse effects
on obesity and fat distribution, plasma lipid profile, and
rheological properties of plasma and platelet function.
Postmenopausal estrogen deficiency may also aggravate
preexisting diabetes mellitus and hypertension, and have an
overall negative effect on the reaction to stress. These data
suggest that estrogen deficiency can directly and indirectly
promote CHD in women. More research is needed to clarify and
differentiate menopause-related from aging-related effects on
the risk of CHD women.
Hormone therapy and endometrium cancer
Bergeron C.
Reprod Hum. Horm. (France), 1994, 7/4 (137-139)
Endometrial carcinomas are hormone-dependent by the
presence of estrogen and progesterone receptors in the
neoplastic proliferation. Treatment with estrogen alone is
associated with an increase risk of endometrial carcinoma but
those carcinomas are discovered at an early stage and have an
excellent prognosis. Estrogen replacement therapy following
treatment for stage I endometrial carcinoma is no more a
contraindication and is associated with a better prognosis by
the benefit on bone and cardiovascular system. Progestogens
suppress the risk of endometrial carcinoma by their
antiestrogenic effect and lead to a secretory or atrophic
endometrium. They may be used as adjuvant therapy in advanced
endometrial carcinomas which have retained progesterone
receptors in the neoplastic proliferation. Tamoxifen may have
an estrogenic effect on the endometrial mucosa but the
increase risk for development of endometrial carcinoma with
tamoxifen (20 mg/j) remains hypothetical. Tamoxifen is mostly
associated with an atrophic mucosa or with cystic and atrophic
polyps.
Progestin replacement in the menopause: Effects on
the endometrium and serum lipids
Williams D.B.; Moley K.H.
Curr. Opin. Obstet. Gynecol. (USA), 1994, 6/3
(284-292)
The benefits of estrogen replacement therapy (ERT) in the
menopause have been well demonstrated and are of significant
importance, particularly with regard to prevention of
osteoporosis and reduction in cardiovascular morbidity and
mortality. The addition of a progestin to ERT is advocated in
patients with a uterus to minimize the risk of endometrial
hyperplasia and cancer. Although progestins can have adverse
effects on serum lipids, it is unclear whether or not these
effects negate the cardioprotective effects of estrogen.
Progestins are an important part of hormone replacement
therapy (HRT) regimen in patients with an intact uterus. The
minimum dose and duration should be given to offset potential
adverse effects on serum lipids while affording adequate
protection of the endometrium. Both continuous and sequential
progestin regimens appear to be efficacious. The newer
progestins may offer increased flexibility in minimizing
progestin side-effects while protecting the endometrium. Other
regimens, such as less than monthly progestin administration,
may offer another alternative to achieve these goals. Future
studies in these areas are warranted.
Effects of hormone replacement therapy on
lipoprotein(a) and lipids in postmenopausal women
Chee Jeong Kim; Hak Chul Jang; Dong Hee Cho; Yong Ki
Min
Internal Medicine, Cheil General Hospital, 1-23
Mookchung-Dong, Chung-Ku, Seoul 100-380 South Korea
Arterioscler. Thromb. (USA), 1994, 14/2
(275-281)
High concentrations of lipoprotein(a) (Lp(a)), an
independent risk factor for atherosclerosis, cannot be managed
by the usual lipid-lowering agents. It has been suggested that
Lp(a) levels are related to female sex hormones. Estrogen
replacement therapy makes the lipid profiles favorable for
delaying atherosclerosis in postmenopausal women. The effects
of the combination therapy of estrogen and progesterone on
lipids are controversial. This study was designed to evaluate
the effect of female sex hormones on the concentration of
Lp(a) and to clarify the influence of progesterone on the
effect of estrogen in postmenopausal women. Postmenopausal
women (n=184) were divided into four groups: control; 0.625 mg
conjugated equine estrogen (CEE) plus 10 mg
medroxy-progesterone acetate (MPA); 0.625 mg CEE plus 5 mg
MPA; and 0.625 mg CEE only. Medication for 2 months lowered
the concentrations of Lp(a) by 20% in all treated groups. The
decrease was more pronounced in subjects with a relatively
higher basal Lp(a) concentration. Estrogen replacement therapy
raised the concentration of high-density lipoprotein
cholesterol and decreased low-density lipoprotein cholesterol
without changing total cholesterol. The combination therapy of
estrogen and progesterone abolished the effect of estrogen on
high-density lipoprotein cholesterol. Hormone replacement
therapy lowered Lp(a) levels in postmenopausal women. The
effect was prominent in subjects with high basal Lp(a) levels.
This decrease may be one of the mechanisms of the
cardioprotective effects of estrogen. The cardioprotective
effect of estrogen cannot be applied to the combination
therapy due to the adverse effect of progesterone on
high-density lipoprotein cholesterol.
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