Selección de Resúmenes de Menopausia
Abril de 2007
Ann
Epidemiol. 2007 May;17(5):342-353.
Physical Activity
and Breast Cancer Risk Among Women in the
Slattery
ML, Edwards
S, Murtaugh MA, Sweeney
C, Herrick
J, Byers
T, Giuliano AR, Baumgartner
KB.
From
the Department of Medicine, University of Utah, Salt Lake City, UT (M.L.S.,
S.E., M.A.M., C.S., J.H.); University of Colorado School of Medicine, Denver
(T.B.); University of Arizona, Tucson (A.G. [currently at Moffitt Cancer
Center, Tampa, FL]); and Department of Internal Medicine and the Cancer
Research and Treatment Center Epidemiology and Cancer Prevention Program,
University of New Mexico Health Science Center, Albuquerque (K.B. [currently at
University of Louisville, KY]).
Physical
activity may influence breast cancer risk through multiple mechanisms and at
different periods in life. In this study we evaluate breast cancer risk
associated with total and vigorous physical activity at ages 15, 30, and 50
years and the referent year prior to diagnosis/selection. Participants were
non-Hispanic white (NHW) (1527 cases and 1601 control subjects) and
Hispanic/American Indian (HAI) (798 cases and 924 controls) women. Both total
and vigorous activity reduced risk of breast cancer in a dose-response manner.
Among premenopausal women, only high total metabolic equivalent of the task
(MET) hours of activity during the referent year was associated with reduced
breast cancer risk in NHW women (odds ratio [OR] 0.62; 95% confidence interval
[CI] 0.43, 0.91). Among postmenopausal women, physical activity had the
greatest influence among women not recently exposed to hormones. Among these
women, high total lifetime activity reduced risk of breast cancer for both NHW
(OR 0.60; 95% CI 0.36, 1.02; p trend 0.01) and HAI women (OR 0.52; 95% CI 0.23,
1.16; p trend 0.07). Additionally, high total MET hours of activity at age 30
years (OR 0.56; 95% CI 0.37, 0.85) and at age 15 years (OR 0.57; 95% CI 0.38,
0.88) reduced breast cancer risk among postmenopausal NHW women not recently
exposed to hormones. Among HAI women, more recent activity performed during the
referent year and at age 50 appeared to have the greatest influence on breast
cancer risk. Among postmenopausal NHW women. there was a significant interaction between physical
activity and hormone replacement therapy (p value, 0.01), while among
postmenopausal HAI women, physical activity interacted with body mass index (p
value, 0.04). These data suggest that physical activity is important in
reducing risk of breast cancer in both NHW and HAI women.
Curr
Opin Investig Drugs.
2007 Apr;8(4):293-8.
A new paradigm in the treatment of osteoporosis: Wnt
pathway proteins and their antagonists.
Chan A, van Bezooijen
RL, Lowik CW.
The
need to develop novel drugs that stimulate bone formation and thereby elevate
bone mass (anabolics), as opposed to preventing bone
loss (anti-resorptives), has opened new research
areas for therapeutic intervention in the treatment of osteoporosis. One of
these areas is the Wnt/beta-catenin
pathway that plays an important role in regulating osteoblast
proliferation and differentiation. Alterations in this pathway have been
associated with bone disorders characterized by either low or high bone mass.
However, as the Wnt/beta-catenin
pathway is a ubiquitous mechanism not just exclusively involved in bone
formation, targeting Wnts may be a challenge (eg, targeting Wnt activity may
induce cancer). Nevertheless, specific pharmacological targets to influence
bone formation have been identified in this pathway; these include the Wnt-lipoprotein receptor-related protein 5/6-frizzled
complex and Wnt antagonists such as sclerostin. Since sclerostin
expression is highly restricted to osteocytes, this
specific target may be ideal for anabolic drug therapy.
BMC Public Health. 2007 Apr 26;7(1):64 [Epub ahead of print]
Vitamin
D inadequacy in Belgian postmenopausal osteoporotic women.
Neuprez A, Bruyere O, Collette
J, Reginster JY.
ABSTRACT:
BACKGROUND: Inadequate serum vitamin D [25(OH)D]
concentrations are associated with secondary hyperparathyroidism, increased
bone turnover and bone loss, which increase fracture risk. The objective of
this study is to assess the prevalence of inadequate serum 25(OH)D concentrations in postmenopausal Belgian women. Opinions
with regard to the definition of vitamin D deficiency and adequate vitamin D
status vary widely and there are no clear international agreements on what
constitute adequate concentrations of vitamin D. METHODS: Assessment of
25-hydroxyvitamin D [25(OH)D] and parathyroid hormone was performed in 1195
Belgian postmenopausal women aged over 50 years. Main analysis has been
performed in the whole study population and according to the previous use of
vitamin D and calcium supplements. Four cut-offs of 25(OH)D
inadequacy were fixed : < 80 nmol/L, <75 nmol/L, < 50 nmol/L and <
30 nmol/L. RESULTS: Mean (SD) age of the patients was
76.9 (7.5) years, body mass index was 25.7 (4.5) kg/m;2. Concentrations of
25(OH)D were 52.5 (21.4) nmol/L.
In the whole study population, the prevalence of 25(OH)D
inadequacy was 91.3 %, 87.5 %, 43.1 % and 15.9% when considering cut-offs of
80, 75, 50 and 30 nmol/L, respectively. Women who
used vitamin D supplements, alone or combined with calcium supplements, had
higher concentrations of 25(OH)D than non-users.
Significant inverse correlations were found between age / serum PTH and serum
25(OH)D (r = -0.23 / r= -0.31) and also between age /
serum PTH and femoral neck BMD (r= -0.29 / r=-0.15). There is a significant
positive relation between age and PTH (r= 0.16), serum 25(OH)D
and femoral neck BMD (r= 0.07) (P < 0.05). Vitamin D concentrations varied
with the season of sampling but did not reach statistical significance
(P=0.09). CONCLUSIONS: This study points out a high prevalence of vitamin D
inadequacy in Belgian postmenopausal osteoporotic women, even among subjects
receiving vitamin D supplements.
J Clin Endocrinol
Metab. 2007 Apr 24; [Epub
ahead of print]
Growth Hormone Reduces Inflammation in Postmenopausal Women with
Abdominal Obesity: a 12-Month, Randomised, Placebo-Controlled
Trial.
Franco C, Andersson B, Lonn L, Bengtsson BA, Svensson J, Johannsson G.
Department
of Endocrinology, Department of Medicine, Department of Diagnostic Radiology, Sahlgrenska University Hospital, SE-413 45 Goteborg,
Sweden.
Context:
Abdominal obesity is associated with low GH secretion, elevated circulating
markers of inflammation, and increased risk of CVD. Objective: To study the
effect of GH treatment on inflammatory markers and
vascular adhesion molecules in postmenopausal women with abdominal obesity.
Design: Forty women aged 51-63 yrs received GH (0.67 mg/d) in a randomised, double-blind, placebo-controlled, 12-month
trial. Measurements of inflammatory markers: highly sensitive C-reactive
protein (CRP), interleukin-6 (IL-6) and amyloid polypeptideA (SAA) and markers of endothelial dysfunction:
soluble E-selectin (sE-selectin),
vascular adhesion molecule-1 (VCAM-1), intercellular molecule-1 (ICAM-1) and
matrix metalloproteinase (MMP)-9 were performed at baseline, after 6 and 12
months of treatment. Results: After 12 months, the mean
Int J Cancer. 2007 Apr 23; [Epub
ahead of print
Dietary patterns, the Alternate Healthy
Eating Index and plasma sex hormone concentrations in postmenopausal women.
Fung TT, Hu FB, Barbieri RL, Willett WC, Hankinson SE.
Department of Nutrition,
To
evaluate the association between overall diet and sex hormones concentrations,
we collected blood from 578 postmenopausal women ages 43 and 69 years in 1989
or 1990. Food intake was measured in 1990 via a food frequency questionnaire.
We calculated the Alternate Healthy Eating Index (AHEI), and dietary patterns
were identified by factor analysis. The cross-sectional association between
diet and estrogens, sex hormone binding globulin (SHBG) were evaluated with
linear regression and adjusted for energy and other potential confounders. We
found a higher AHEI score was associated with lower concentrations of estradiol, free estradiol, and
higher concentrations of SHBG. The prudent pattern, with higher intakes of
fruits, vegetables, and whole grains, was not associated with any sex hormones.
The Western pattern, which represents higher intakes of red and processed
meats, refined grains, sweets and desserts, was associated with a higher level
of estradiol and lower concentrations of SHBG.
Further adjustment for BMI attenuated these results except for free estradiol (5th vs. 1st quintile = 0.09 vs. 0.11 pg/mL, p for trend = 0.03). In addition, the AHEI was
inversely associated with estradiol among those with
BMI > 25, and Western pattern with SHBG among those with BMI < 25. In
conclusion, we observed inverse associations between the AHEI score and several
estrogens, and it was positively associated with
plasma levels of SHBG. In contrast, the Western pattern was positively
associated with estrogen levels and inversely with SHBG. However, these
associations appeared to be largely accounted for by BMI.
Scand J
Clin Lab Invest. 2007;67(3):257-63
High C-reactive protein levels are associated with oral hormonal
menopausal therapy but not with intrauterine levonorgestrel
and transdermal estradiol.
Blumenfeld Z, Boulman N, Leiba R, Siegler E, Shachar S, Linn R, Levy Y.
Reproductive Endocrinology, Department of OB/GYN.
Objective . Oral hormone
replacement therapy (HRT) has been linked to increased cardiovascular (CVD)
morbidity. HRT causes a sustained increase in C-reactive protein (CRP), an
excellent marker of subclinical inflammation and CVD. The aim of the study was
to support our hypothesis that CRP, which is synthesized in the liver, is not
increased in association with transdermal/intrauterine
HRT. Material and methods . A case-control study was
performed in which CRP measurements in women receiving levonorgestrel
intrauterine system combined with transdermal estradiol (LNG/TDE, n = 27) were followed for 9 months or
longer. CRP concentrations in these women were compared with those of either
oral HRT users (n = 20) or controls (n = 19). Results .
No significant differences were found in CRP concentrations between the LGN/TDE
and control groups (1.8+/-1.2 and 1.8+/-1.8 mg/L, respectively). However, CRP
was significantly increased in the oral HRT group (5.5+/-2.9 mg/L, p<0.001).
Conclusions . CRP is significantly increased by oral
HRT but not by the LNG/TDE combination after 9 months of treatment. This trend
may explain the preponderance of some menopausal women on HRT being at
increased risk for the development of CVD. Therefore, the use of LNG/TDE is
acceptable for relief of severe climacteric symptoms possibly not imposing an
increased CVD risk documented upon oral HRT.
Gynecol Endocrinol. 2007 Feb;23(2):99-104
Effects of postmenopausal hormone replacement
therapy on body fat composition.
Yuksel H, Odabasi AR, Demircan S, Koseoglu K, Kizilkaya K, Onur E.
Department of Obstetrics and Gynecology,
Aim. To evaluate the
effects of different types, regimens and administration routes of hormone
replacement therapy (HRT) on body fat composition indices in postmenopausal
women at increased risk of anthropometry-related cardiovascular disease (CVD). Methods. Fifty-nine postmenopausal women (aged 41-57 years,
mean +/- standard deviation: 49.9 +/- 3.8 years) with body mass index (BMI)
>/=25 kg/m(2) participated in this 6-month,
prospective, randomized single-blind study. Subjects were assigned into three
groups and received transdermal estradiol
(E(2))/norethisterone acetate (NETA) (50 mug E(2)
daily for 14 days followed by 50 mug E(2)/0.25 mug NETA daily for 14 days; transdermal group, n = 19), transdermal
continuous E(2)/oral medroxyprogesterone acetate
(MPA) (50 mug E(2)/5 mg MPA daily; transdermal/oral
group, n = 19) or oral continuous E(2)/NETA (1 mg E(2)/0.5 mg NETA daily; oral
group, n = 21). Anthropometric indices (body weight, height, and hip and waist
circumferences) were measured, and BMI and waist-to-hip ratio (WHR) were
calculated, before and after treatment. Also, the thickness of subcutaneous
abdominal fat was measured by ultrasound. Depending on waist circumference
(WC), the subjects were divided into two risk groups: increased-risk group with
WC <88 cm (n = 32) and high-risk group with WC >/=88 cm (n = 27). Also,
the effects of HRT were evaluated separately in subjects with median subcutaneous
fat of <33 mm (n = 29) and those with median subcutaneous fat of >/=33 mm
(n = 30). Results. Overall, all three types of HRT
caused a significant decrease in both WC and subcutaneous fat (p < 0.001),
and also in WHR (p < 0.05). There was no significant difference in baseline
(p > 0.05) and final values (p > 0.05) between HRT groups. In each group,
all types of HRT significantly decreased WC and subcutaneous fat (transdermal group: p < 0.001 and p < 0.05; transdermal/oral group: p < 0.001 and p < 0.01; oral group:
p < 0.001 and p < 0.001, respectively), while body weight, BMI and WHR
changed only insignificantly (p > 0.05). In the increased-risk group, body
weight increased significantly (p < 0.05) while WC and subcutaneous fat
decreased significantly (p < 0.001 and p < 0.001). As for the high-risk
group, there was a significant decrease in WC and subcutaneous fat (p <
0.001, p < 0.001) while the remaining parameters did not change
significantly. However, BMI showed a tendency to increase in the increased-risk
group, while there was a decrease in all measurements in the high-risk group.
Regardless of the drugs used and baseline subcutaneous fat, WC and subcutaneous
fat decreased significantly at the end of the treatment (subcutaneous fat
<33 mm: p < 0.001 and p < 0.01; subcutaneous fat >/=33 mm: p <
0.001 and p < 0.001, respectively). Conclusions.
The three different types of HRT have comparable effects on central fat tissue
in women at increased risk of anthropometry-related CVD. Indeed, the three
combinations of HRT reduced fat tissue in the central part of the body.
However, the overall effect of HRT was more marked in women with WC >/=88 cm
and subcutaneous fat >/=33 cm. Whether HRT increases body weight depends on
the body composition indices of individuals before treatment.
Climacteric. 2007 Apr;10(2):155-63
Testosterone addition during menopausal hormone therapy: effects on
mammographic breast density.
Hofling M, Lundstrom E, Azavedo E, Svane G, Hirschberg AL, von Schoultz
B.
Departments of Obstetrics and Gynecology.
Objective
To study the effect on mammographic breast density of
testosterone addition during combined estrogen/progestogen
therapy in postmenopausal women. Methods A prospective,
randomized, double-blind, placebo-controlled trial. A total of 99 women were
given 2 mg 17beta-estradiol and 1 mg norethisterone
acetate in combination with either a testosterone patch (300
mug/24 h) or a placebo patch. Mammographic breast density at baseline
and after 6 months was assessed by visual classification scales and by
digitized quantification. A standardized questionnaire was used to quantify
subjective breast symptoms. Results Visual classifications showed an increase
in mammographic density in 18-30% of the women, with no significant differences
between the treatment groups. The mean increase of the area of dense breast
during treatment according to digitized assessment was 7.4% in the placebo
group and 5.4% in the testosterone group. Breast symptoms showed a positive
association with the increase in density (r(s) = 0.34; p < 0.01). Symptoms
were most pronounced at 2 months of treatment. Density, both at baseline (r(s)
= -0.35; p < 0.01) and change during treatment (r(s) = -0.28; p < 0.01)
showed a negative association with free testosterone levels. Conclusion The addition of testosterone does not appear to influence
mammographic breast density in women concurrently treated with a common oral
estrogen/progestogen regimen for a period of 6
months.
Climacteric. 2007 Apr;10(2):147-54
The influence of smoking on uterine
bleeding during sequential oral hormone therapy.
Bjarnason NH, Byrjalsen I, Jorgensen HL, Christiansen C.
Center for Clinical & Basic Research. Ballerup.
Objective
To study the influence of smoking on uterine bleeding
patterns during sequentially administered oral hormone therapy (HT). Methods Using a post-hoc strategy, we included four sequential oral
HT groups from two studies. The therapies consisted of estradiol
from days 1 to 28 (estradiol or estradiol
valerate) and progestogen (levonorgestrel or gestodene) on
days 17-28. A total of 111 healthy, early postmenopausal women (38 smokers and
73 non-smokers) followed for 2 years were included in the analyses. Uterine
bleeding data were collected from bleeding calendars. Results On the regimen containing
levonorgestrel, smoking women had a cyclical bleeding
significantly earlier than non-smoking women (about 2 days' difference).
Moreover, smoking women had significantly longer bleeding than non-smoking
women (about 1 day in difference). This was in contrast to the three regimens
containing gestodene, where smoking seemed to have
far less influence on uterine bleeding. Conclusions On a regimen containing levonorgestrel, smokers exhibit an
earlier and longer uterine bleeding than do non-smokers. This is in contrast to
regimens containing gestodene, where smoking women
are less likely to differ from non-smoking women with regard to bleeding. This
indicates that smoking influences progestogen
metabolism, and that this influence may vary with different progestogens.
Further studies are needed.
Climacteric. 2007 Apr;10(2):120-31
Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom
relief.
Panay N, Ylikorkala O, Archer DF, Gut R, Lang E.
Objective
To evaluate the efficacy of two ultra-low-dose
17beta-estradiol plus norethisterone acetate (NETA)
treatment regimens for relieving menopausal symptoms. Design A total of 577
postmenopausal women were enrolled, in three treatment groups in a
double-blind, randomized, placebo-controlled study of 0.5 mg 17beta-estradiol +
0.1 mg NETA or 0.5 mg 17beta-estradiol + 0.25 mg NETA or placebo. Participants
returned at weeks 4, 8, 12 and 24 for climacteric complaint evaluation based on
a daily diary vasomotor symptom record. Patients were assessed by the Greene
Climacteric Scale and urogenital symptoms were also
evaluated. Results Treatment with ultra-low-dose 0.5 mg 17beta-estradiol + 0.1
mg NETA (0.1 Group) or 0.5 mg 17beta-estradiol + 0.25 mg NETA (0.25 Group)
effectively reduced the severity and number of hot flushes within the initial
weeks of therapy. Compared to placebo, a rapid, statistically significant
decrease in the frequency and severity of hot flushes was achieved by week 3,
followed by further improvement which continued throughout the study. There
were no statistically significant differences between the active treatment
arms. Conclusions The data show that both ultra-low-dose regimens are effective
in reducing the severity and number of hot flushes compared to placebo, with
good safety profiles.
Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2007 May;14(3):301-28
Effects of hormone replacement therapy and aging on cognition: evidence
for executive dysfunction.
The
present study was designed to explore whether the frontal lobe hypothesis of
cognitive aging may be extended to describe the cognitive effects associated
with estrogen use in postmenopausal women. Postmenopausal
estrogen-only users, estrogen + progesterone users, and non-users (60-80 years
old), as well as young, regularly cycling women (18-30 years old) completed an
item and source memory task. Since source memory is thought to rely more
on executive processes than item memory, we hypothesized that aging and
estrogen effects would be greater for source memory than for item memory.
Neuropsychological tests explored whether the effects of aging and estrogen use
were revealed on other tests of frontal lobe function. Results from the
experimental task revealed greater aging and estrogen effects for source memory
than for item memory, and neuropsychological results revealed aging and
estrogen effects on a subset of tests of executive function. Women on estrogen
+ progesterone therapy did not outperform non-users, suggesting that the
addition of progesterone to hormone therapy may mitigate the benefits induced
by estrogen use alone. Overall, findings support the hypothesis that estrogen
use may temper age-related cognitive decline by helping to maintain functions subserved by the frontal lobes.
Acta Oncol. 2007;46(2):133-45.
Long-term follow-up of the randomized
Stockholm Breast Cancer Study
Group.
Department of Oncology,
The
Stockholm Breast Cancer Study Group conducted a randomized trial during 1976
through 1990 comparing adjuvant tamoxifen versus
control. A total of 2,738 postmenopausal women with invasive, early stage
disease were randomised between tamoxifen
for 2 or 5 years, or no adjuvant endocrine therapy.
Among high-risk patients the treatment was given against a background of either
postoperative, locoregional radiation or CMF-type
chemotherapy. The median follow up was 18 years (range 11-25 years). There was
a statistically significant (p =0.001) interaction between ER status and tamoxifen with no treatment benefit among receptor
negatives. PgR-status had little additional
predictive value. Among ER-positive patients tamoxifen
reduced locoregional recurrences by 48%, contralateral breast cancers by 54%, distant metastases by
28%, and all events by 24% (p <0.001). On the other hand, there was a
substantial increase of endometrial cancer associated with tamoxifen.
There was no effect of tamoxifen on intercurrent mortality whereas breast cancer deaths were
reduced by 31% (p <0.001) and overall mortality by 15% (p =0.01). Tamoxifen produced long-term benefits among estrogen
receptor positive patients in terms of breast cancer-related events, but also
an increased incidence of endometrial cancer. Despite long-term follow-up we
observed no benefit with tamoxifen in terms of
cardiovascular mortality.
Breast
Cancer Res Treat. 2007 Apr 24; [Epub ahead of print
Decline in breast cancer incidence after
decrease in utilisation of hormone replacement
therapy.
Hormone
replacement therapy (HRT) has been implicated as a risk factor for breast
cancer and the use of HRT has decreased substantially in general population
over the last years. Recently, there are first indications that breast cancer
incidence has started declining. We examined recent breast cancer incidence and
actual data on HRT utilisation in
Menopause
Int. 2007 Mar;13(1):44-5.
Management of premature menopause.
Writing
Group for the British Menopause Society Council.
There
has been some confusion among women and health professionals since the
publication of the Women's Health Initiative and Million Women studies about
the management of premature ovarian failure (POF). Both studies were undertaken
in women aged 50 and over, and cannot be extrapolated to their younger
counterparts, who would normally be producing their endogenous estrogen, since
they have functioning ovaries. Estrogen-based replacement therapy is the main
stay of treatment for women with POF and is recommended at least until the
average age of natural menopause (52 years in the
Semana del 17 al 23 de Abril 2007
Menopause. 2007 Apr
13; [Epub ahead of print]
The role of local vaginal estrogen for
treatment of vaginal atrophy in postmenopausal women: 2007 position statement
of The North American Menopause Society.
OBJECTIVE:: To create an evidence-based position
statement published by The North American Menopause Society (NAMS) on the role
of local vaginal estrogen therapy (ET) for the treatment of vaginal atrophy in
postmenopausal women. DESIGN::
N Engl J Med. 2007 Apr 19;356(16):1670-4
The decrease in
breast-cancer incidence in 2003 in the
Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA.
Department of Biostatistics,
An initial analysis of data from the National Cancer
Institute's Surveillance, Epidemiology, and End Results (SEER) registries shows
that the age-adjusted incidence rate of breast cancer in women in the United
States fell sharply (by 6.7%) in 2003, as compared with the rate in 2002. Data
from 2004 showed a leveling off relative to the 2003 rate, with little
additional decrease. Regression analysis showed that the decrease began in
mid-2002 and had begun to level off by mid-2003. A comparison of incidence
rates in 2001 with those in 2004 (omitting the years in which the incidence was
changing) showed that the decrease in annual age-adjusted incidence was 8.6%
(95% confidence interval [CI], 6.8 to 10.4). The decrease was evident only in
women who were 50 years of age or older and was more evident in cancers that
were estrogen-receptor-positive than in those that were
estrogen-receptor-negative. The decrease in breast-cancer incidence seems to be
temporally related to the first report of the Women's Health Initiative and the
ensuing drop in the use of hormone-replacement therapy among postmenopausal
women in the
Cancer Causes Control. 2007 Apr
16; [Epub ahead of print]
Alcohol consumption, cigarette smoking, and
endometrial cancer risk: results from the
Loerbroks A, Schouten LJ, Goldbohm RA, van den Brandt PA.
Department of Epidemiology, Nutrition and Toxicology
Research Institute Maastricht (NUTRIM), Maastricht University, PO Box 616, 6200
MD, Maastricht, The Netherlands, lj.schouten@epid.unimaas.nl.
OBJECTIVE: To examine the association between alcohol
consumption, cigarette smoking, and endometrial cancer. METHODS: In 1986, the
Netherlands Cohort Study was initiated. A self-administered questionnaire on
dietary habits and other cancer risk factors was completed by 62,573 women.
Follow-up for cancer was established by record linkage to the Netherlands
Cancer Registry. RESULTS: After 11.3-years of follow-up, 280 incident
endometrial cancer cases were available for analyses. In multivariate analysis,
the rate ratio (RR) for alcohol users versus non-users was 1.06 (95% Confidence
Interval (95% CI) = 0.78-1.43). There were neither dose-dependent trends nor
associations with different types of beverages. The RR for former and current
smokers versus never-smokers was 0.83 (95% CI = 0.58-1.20) and 0.59 (95% CI =
0.40-0.88), respectively. These estimates did not change significantly when
body mass index (BMI) and age at menopause were added to the models.
CONCLUSIONS: There is no association between alcohol consumption and endometrial
cancer. Current smoking is associated with a reduced risk of endometrial
cancer. This association is neither mediated by BMI nor by age at menopause.
Menopause. 2007 Apr
13; [Epub ahead of print]
Estrogen effects on arteries vary with
stage of reproductive life and extent of subclinical atherosclerosis
progression.
From the Comparative Medicine
Clinical
ABSTRACT: The past several years have been marked by
confusion and controversy concerning whether estrogens are cardioprotective.
The issue is of utmost public health importance because coronary heart disease
(CHD) remains the leading cause of death among postmenopausal women.
Fortunately, a unifying hypothesis has emerged that reproductive stage is a
major determinant of the effect of estrogens on atherosclerosis progression,
complications, and plaque vulnerability. PREMENOPAUSAL YEARS::
Premenopausal atherosclerosis progression seems to be an important determinant
of postmenopausal atherosclerosis and thus the risk for CHD. Clearly, plasma
lipids/lipoproteins influence this progression; however, estradiol
deficiency seems to be the major modulator. Both monkeys and women with
premenopausal estrogen deficiency develop premature atherosclerosis, an effect
that can be prevented in both species by estrogen-containing oral
contraceptives. PERIMENOPAUSAL/EARLY POSTMENOPAUSAL YEARS::
During this stage, there are robust estrogen benefits. Monkeys given estrogens
immediately after surgical menopause have a 70% inhibition in coronary
atherosclerosis progression. Estrogen treatment prevented progression of
atherosclerosis of women in the Estrogen in the Prevention of Atherosclerosis
Trial. A meta-analysis of women younger than 60 years given hormone therapy had
reduced total mortality (relative risk = 0.61, 95% CI: 0.39-0.95). LATE
POSTMENOPAUSAL YEARS:: This stage is one in which
there are no or possible deleterious estrogen effects. Monkeys lose CHD
benefits of estrogens when treatment is delayed. The increase in CHD events
associated with initiating hormone therapy 10 or more years after menopause
seems to be related to up-regulation of the plaque inflammatory processes and
plaque instability and may be down-regulated by statin
pretreatment.
Bone. 2007 May;40(5 Suppl 1):S5-8. Epub 2007 Feb 17
Strontium ranelate:
New insights into its dual mode of action.
INSERM U606 and University
Paris 7, Lariboisiere Hospital,
2 rue Ambroise Pare, 75475 Paris cedex 10, France.
Strontium ranelate is a
newly developed drug that acts as an effective antiosteoporotic
therapy in postmenopausal women with osteoporosis. In contrast to other
available treatments for osteoporosis, strontium ranelate
induces opposite effects on bone resorption and
formation. Preclinical studies showed that this dual effect results in
increased bone mass and improved bone microarchitecture
and strength in intact rodents, and in prevention of bone loss in osteopenic animals. Histomorphometric
analysis of unpaired iliac crest bone biopsies in postmenopausal osteoporotic
patients treated with strontium ranelate for 3 years
showed that the drug increased bone formation, assessed by both the
mineralization rate and osteoblast surface, and
tended to decrease the osteoclast surface, compared
with the placebo group. Three-dimensional micro-computed tomography analysis of
the bone biopsies consistently showed a higher number of trabeculae,
decreased trabecular separation, and an increase in
cortical thickness, which provides evidence for a better trabecular
and cortical bone microarchitecture in treated
patients compared with the placebo group. Some mechanisms that underlie the
beneficial effects of strontium ranelate on bone
metabolism and strength have now been identified. In vitro analyses showed that
strontium activates the calcium-sensing receptor. We, however, showed that
strontium ranelate activates cell replication and
downstream ERK1/2 signaling in osteoblasts from
calcium-sensing receptor-null mice, indicating that, in addition to the
calcium-sensing receptor, another receptor could mediate the effect of
strontium ranelate on osteoblastic
cell replication. Other in vitro studies showed that strontium ranelate can activate the osteogenic
differentiation of bone marrow stromal cells by
activating cyclo-oxygenase 2 (COX-2)-mediated
prostaglandin E(2) production. Finally, recent data
indicate that strontium ranelate can upregulate osteoprotegerin (OPG)
and decrease receptor activator of nuclear factor kappa B (RANK) ligand expression in human osteoblastic
cells, suggesting that strontium ranelate may reduce
bone resorption by modulating the RANK/RANK-ligand/OPG system, which is essential for osteoclastogenesis. These recent data provide new insights
into the mechanism of action of strontium ranelate
and give biochemical support to cell physiology which explain
the opposite effects of strontium ranelate on bone
formation and resorption.
Clin Endocrinol (Oxf). 2007 Apr
15
Menopausal hormone therapy and gallbladder
disease: the Study of Health in
Schwarz S, Volzke H, Baumeister SE, Hampe J, Doren M.
Charite- Universitatsmedizin
Objective Several studies suggest that oral menopausal
hormone therapy (MHT) is associated with an increased risk of gallbladder
disease. It has been hypothesized that nonoral MHT
may reduce the risk of cholelithiasis. The objective
of the present study was to analyse the association
between (1) use of life-time MHT (ever use) and gallbladder disease and (2) nonoral use of MHT and gallbladder disease. Design
Cross-sectional study using population-based data from the Study of Health in
Pomerania (SHIP). Population The study population included 994 postmenopausal
women, aged 40-79 years. The subgroup of current oral and nonoral
MHT users comprised 139 women. Methods and measurements Sociodemographic,
medical and reproductive characteristics were based on computer-assisted
personal interviews, and selected laboratory parameters were analysed. Gallbladder disease was defined by either a prior
history of cholecystectomy or the presence of current
sonographically diagnosed gallstones. Data analyses
consisted of descriptive, bivariable and
multivariable procedures. We performed Poisson regression with Huber/White
standard errors to investigate the association between ever use, current nonoral use of MHT and gallbladder disease. Results We found no significant association between ever use of MHT
and gallbladder disease and sonographically diagnosed
gallstones in fully adjusted analyses. Women who used MHT had a significantly
higher risk for cholecystectomy compared to nonusers.
There was no association between nonoral use of MHT
and gallbladder disease. Conclusions Our analyses do
not lend support to the hypothesis that use of MHT is associated with
gallbladder disease.
J Clin Endocrinol Metab. 2007 Apr
17; [Epub ahead of print
Addition of monofluorophosphate to estrogen therapy in postmenopausal
osteoporosis - a randomized controlled trial.
Reid IR, Cundy T, Grey AB, Horne A, Clearwater J, Ames R, Orr-Walker BJ, Wu F, Evans MC, Gamble GD, King A.
Department of Medicine, University of Auckland,
Auckland, New Zealand; Pathology Laboratory, Middlemore
Hospital, Auckland, New Zealand.
Introduction: Treatment of osteoporosis with high-dose
fluoride alone does not reduce fracture risk. We hypothesized that the
anti-fracture efficacy of fluoride could be optimized by its use in low doses
combined with an antiresorptive agent. Experimental
Subjects: 80 women with postmenopausal osteoporosis who had been taking
estrogen for >/=1 year. Methods: Subjects were randomized to receive monofluorophosphate (fluoride content of 20 mg/day) or
placebo over 4 years in a double-blind trial. Results and Discussion: There
were progressive increases in lumbar spine bone density (BMD) over the duration
of the study (MFP 22%, placebo 6%, P<0.0001). In the trabecular
bone of L3, these increases were even greater (MFP 49%, placebo 2.5%,
P<0.0001). In the proximal femur there were smaller but significant
treatment effects (P=0.015). Total body scans and their subregions
also showed significantly greater increases in the MFP group. Bone formation
markers increased significantly in the MFP group at year 1. Hyperosteoidosis
was present in biopsies from 5 of 7 MFP subjects, with osteomalacia
in 2 of 7. The hazards ratio for vertebral fractures was 0.20 (95% confidence
interval 0.05-1.30) and the incidence rate ratio was 0.12 (95% confidence
interval, 0.06-0.23, P<0.01). The hazards ratio for non-vertebral fractures
was 3.3 (95% CI 0.8-12.0). We conclude that fluoride 20 mg/day produces
substantial increases in BMD, but still interferes with bone mineralization.
This indicates that most previous studies with this ion have used toxic doses,
and that much lower doses should be assessed to find a safe dose window for the
use of this powerful anabolic agent.
Rev Endocr Metab Disord. 2007 Apr
14; [Epub ahead of print
SERMs for the
treatment and prevention of breast cancer.
Swaby
RF, Sharma
CG, Jordan
VC.
Tamoxifen and raloxifene are both selective estrogen receptor modulators
(SERMs). The medicines can block estrogen mediated breast cancer growth and
development but will also maintain bone density in postmenopausal women and
lower circulating cholesterol. Tamoxifen has remained
the antihormonal therapy of choice for the treatment
of ER positive breast cancer for the last 30 years. However, although adjuvant tamoxifen produces profound increases in disease-free and
overall survival in patients with ER positive breast cancer, concerns about
drug resistance, blood clots and endometrial cancer have resulted in a change
to the use of aromatase inhibitors for the treatment
of postmenopausal women. Nevertheless, tamoxifen
remains the antihormonal treatment of choice for
premenopausal women with ER positive breast cancer and for risk reduction in
premenopausal women who are at high risk for developing breast cancer. The risk
of endometrial cancer and thromboembolic disorders
during tamoxifen therapy is not elevated in
premenopausal women. It is important to note that aromatase
inhibitors or raloxifene should not be used in
premenopausal women. Raloxifene is used to prevent
osteoporosis in postmenopausal women and, unlike tamoxifen,
does not increase the risk of endometrial cancer. However, raloxifene
does reduce breast cancer risk by 50-70% in both low risk and high risk
postmenopausal women. Comparisons of raloxifene with tamoxifen show equal efficacy as a chemopreventive
for breast cancer but there is a reduction in thromboembolic
disorders, fewer endometrial cancers, hysterectomies, cataracts and cataract
surgeries in women taking raloxifene. Overall, SERMs
continue to fulfill their promise as appropriate medicines that target specific
populations for the treatment and prevention of breast cancer.
Endocrinology. 2007 Apr
19; [Epub ahead of print]
The endogenous estradiol
metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in
female ApoE-deficient mice.
Bourghardt J, Bergstrom G, Krettek A, Sjoberg S, Boren J, Tivesten A.
The Wallenberg Laboratory for Cardiovascular Research,
Sahlgrenska Academy at Goteborg University, Sahlgrenska University Hospital, SE-413 45 Goteborg,
Sweden.
Estradiol, the major
endogenous estrogen, reduces experimental atherosclerosis and metabolizes to
2-methoxyestradiol in vascular cells. Currently undergoing evaluation in
clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation
independently of the classical estrogen receptors. This study examined whether
2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse
model of atherosclerosis, were ovariectomized and
treated through slow release pellets with placebo; 17beta-estradiol (6 microg/day); or 2-methoxyestradiol (6.66 microg/day (ME low) or 66.6 microg/day
(ME high)). After 90 days, body weight gain decreased and uterine weight
increased in the ME high but not in the ME low group. En face analysis showed
that the fractional area of the aorta covered by atherosclerotic lesions
decreased in the ME high (52%) but not in the ME low group. Total serum
cholesterol levels decreased in the high and low dose ME groups (19%, P <
0.05 and 21%, P = 0.062, respectively). Estradiol
treatment reduced the fractional atherosclerotic lesion area (85%) and
decreased cholesterol levels (42%). In conclusion, our study shows for the
first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in
vivo. The anti-atherogenic activity of an estradiol metabolite lacking estrogen receptor activating
capacity may argue that trials on cardiovascular effects of hormone replacement
therapy should use estradiol rather than other
estrogens. Future research should define the role of 2-methoxyestradiol as a
mediator of the anti-atherosclerotic actions of estradiol.
Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular
disease endpoints in ongoing clinical trials is of great interest.
J Natl Med Assoc. 2007 Apr;99(4):412-8
History of
fractures as predictor of subsequent hip and nonhip
fractures among older Mexican Americans.
Ojo F, Al Snih S, Ray LA, Raji MA, Markides KS.
Osteoporosis Clinic in the Division of Geriatrics,
Internal Medicine Department, Sealy Center on Aging, The University of Texas
Medical Branch, Galveston 77555-0460, USA. folojo@utmb.edu
OBJECTIVE: To examine the association between previous
fracture and risk of new hip and nonhip fractures
over a seven-year period among older Mexican Americans. METHOD: Data used are
from the Hispanic Established Population for the Epidemiological Study of the
Elderly (H-EPESE) (1993-2001). Measures included history of previous fracture
(hip fracture only, a nonhip fracture, hip and nonhip fractures, and no fractures), sociodemographic
factors, smoking status, medical conditions (arthritis, diabetes, stroke and
cancer), activities of daily living disability, and high depressive symptoms.
Cox proportional regression model was used to estimate the seven-year incidence
of fractures. RESULTS: Of the 2,589 subjects, 42 reported a hip fracture, 328
reported a nonhip fracture, and 2,219 did not report
a fracture at baseline. After controlling for all covariates, the hazard ratio
(HR) of new hip fracture at seven-year follow-up was 6.48 (95% CI: 3.26-12.97)
for subjects with only hip fracture at baseline and 1.96 (95% CI: 1.22-3.16)
for subjects with nonhip fracture at baseline. The HR
of new nonhip fracture was 1.90 (95% CI: 0.96-3.77)
for subjects with only hip fracture at baseline and 2.62 (95% CI: 1.95-3.52)
for subjects with nonhip fracture at baseline.
CONCLUSIONS: A previous history of fractures in older Mexican Americans is the
strongest predictor of recurrent fractures at hip and nonhip
sites, independent of other health measures. Our findings of recurrent
fractures suggest the need for more aggressive detection and adequate treatment
of osteoporosis- and fall-related factors in this population.
PLoS ONE. 2007 Apr 18;2:e377
Established risk factors account for most
of the racial differences in cardiovascular disease mortality.
Henderson SO, Haiman CA, Wilkens LR, Kolonel LN, Wan P, Pike MC.
Department of Preventive
Medicine,
BACKGROUND: Cardiovascular disease (CVD) mortality
varies across racial and ethnic groups in the
Carcinogenesis. 2007 Apr
17; [Epub ahead of print
Diabetes and risk
of breast cancer in Asian-American women.
Wu AH, Yu MC, Tseng CC, Stanczyk FZ, Pike MC.
Affiliations of authors: A.H.Wu,
C.C. Tseng, M.C. Pike, Department of Preventive Medicine; F.Z. Stanczyk, Department of Obstetrics and Gynecology,
University of Southern California Keck School of Medicine, Los Angeles,
California 90089. M.C. Yu, The
The role of diabetes in the etiology of breast cancer
in Asian-Americans is not known. We investigated the relation between diabetes
and breast cancer risk in a population-based case-control study in
BMC Public Health. 2007 Apr
17;7(1):56 [Epub ahead of
print
Changes of the prescription of hormone
therapy in menopausal women: An observational study in
Huang WF, Tsai YW, Hsiao FY, Liu WC.
ABSTRACT: BACKGROUND: The prescribing of hormone
therapy to menopausal women has been changed since the publication of 2002 Womens Health Initiative (WHI) report. This study evaluates
the impact of WHI study results on the prescription of menopausal hormone
therapy (MHT) to treat menopause-related symptoms in
Am J Med
Sci. 2007 Apr;333(4):208-214
Interrelationship Between
Insulin Resistance and Menopause on the Metabolic Syndrome and Its Individual
Component Among Nondiabetic Women in the Kinmen Study.
Lin KC, Tsai ST, Kuo SC, Tsay SL, Chou P.
From the Department of Nursing, National Taipei
College of Nursing, Taipei, Taiwan (kcl, slt); the Department of Medicine, Veterans General
Hospital-Taipei, Taipei, Taiwan (stt); Graduate
Institute of Nurse-Midwifery, National Taipei College of Nursing, Taipei,
Taiwan (sck); and Community Medicine Research Center,
Institute of Public Health, National Yang-Ming University, Taipei, Taiwan (pc).
BACKGROUND:: The literature
to date is not clear as to whether any interactive effect exists between
insulin resistance and menopause on the metabolic syndrome and its individual
components. We explored this issue in 4107 homogeneous, nondiabetic
Chinese women in the Kinmen Study. METHODS:: Overnight fasting blood samples were drawn for glucose,
insulin, lipid, and other biochemical measurements. Demographic and clinical
variables including body mass index, waist circumference, and blood pressure
were measured and documented during face-to-face interviews with structured questionnaires.
Menstrual history was used to define menopause as the absence of menses for 12
consecutive months. RESULTS:: Approximately 16% of
premenopausal women (390/2423) were insulin-resistant. After
adjustment for age, body mass index, lifestyle, and diet, both menopause and
insulin resistance were independently and significantly correlated with
metabolic syndrome. For each component of the metabolic syndrome,
besides the main effect, the interaction (insulin resistance x menopause) had
significant correlation with systolic blood pressure, diastolic blood pressure,
and waist circumference. CONCLUSIONS:: Both insulin
resistance and menopause have significant effects on metabolic syndrome
independent of age and obesity. In premenopausal and nondiabetic
women, various degrees of insulin resistance exist. The synergistic
contribution of insulin resistance and menopause to components of the metabolic
syndrome were observed with systolic blood pressure, diastolic blood pressure,
and waist circumference.
This requires
further study.
Calcif Tissue
Int. 2007 Apr 13; [Epub ahead of print]
Relationship
between Vascular Calcification and Bone Mineral Density in the Old-Order Amish.
Shen H, Bielak LF, Streeten EA, Ryan KA, Rumberger JA, Sheedy PF 2nd, Shuldiner AR, Peyser PA, Mitchell BD.
Division of Endocrinology, Diabetes, and Nutrition, Department of
Medicine, University of Maryland, 660 W. Redwood Street, Room 492, Baltimore,
MD, 21201, USA, bmitchel@medicine.umaryland.edu.
Vascular calcification and osteoporosis are common age-related processes
that are influenced by both genetic and nongenetic
factors. Whether common genes underlie these processes is not known. We
measured coronary artery calcification (CAC), aortic calcification (AC), and
bone mineral density (BMD) in 682 men and women from large Old-Order Amish
families. We assessed the heritabilities of these
traits and then evaluated, using variance decomposition procedures, whether
variation in the traits was influenced by a common set of genes (i.e., pleiotropy). Significant heritabilities
were detected for BMD of the femoral neck and spine (0.65, 0.63) and CAC and AC
(0.43, 0.42). Mean BMD did not differ significantly across quartiles of either
CAC or AC in either sex. In neither the total group nor any single subgroup
(men, women, postmenopausal women) did any of the
genetic or environmental correlations between BMD and vascular calcification
achieve statistical significance. However, subjects with a history of cardiovascular
disease (CVD) events had significantly lower BMD at the femoral neck compared
to subjects who reported no prior history of CVD (age-, sex-, body mass index-,
and family structure-adjusted P = 0.003). We detected no evidence for shared
genes affecting the joint distribution of bone and vascular calcification.
However, our results do reveal a lower BMD in subjects with a prior history of
CVD in the Old-Order Amish.
Endocr Rev. 2007 Apr 12; [Epub ahead of print]
Novel
perspectives for progesterone in HRT, with special reference to the nervous
system.
Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F, El-Etr M, Akwa Y, Rajkowski K, Baulieu EE.
INSERM UMR 788 and University Paris-Sud 11,
80, rue du General Leclerc, 94276
The utility and safety of postmenopausal hormone replacement therapy
(HRT) has recently been put into question by large clinical trials. Their
outcome has been extensively commented upon, but discussions have mainly been
limited to the effects of estrogens. In fact, progestagens
are generally only considered with respect to their usefulness in preventing
estrogen stimulation of uterine hyperplasia and malignancy. In addition,
various risks have been attributed to progestagens,
and their omission from HRT has been considered, but this may be to
underestimate their potential benefits and therapeutic promises. A major reason
for the controversial reputation of progestagens is
that they are generally considered as a single class. Moreover, the term
progesterone is often used as a generic one for the different types of both
natural and synthetic progestagens. This is not
appropriate, as natural progesterone has properties very distinct from the
synthetic progestins. Within the nervous system, the neuroprotective and promyelinating
effects of progesterone are promising not only for preventing, but also for
reversing, age-dependent changes and dysfunctions. There is indeed strong
evidence that the aging nervous system remains at least to some extent
sensitive to these beneficial effects of progesterone. The actions of
progesterone in peripheral target tissues including breast, blood vessels and
bones are less well understood, but there is evidence for its beneficial
effects. The variety of signaling mechanisms of progesterone offers exciting
possibilities for the development of more selective, efficient and safe progestagens. The recognition that progesterone is
synthesized by neurons and glial cells requires a
re-evaluation of hormonal aging.
Int J Gynecol Cancer. 2007 Apr 8;
The
relation between age, time since menopause, and endometrial cancer in women
with postmenopausal bleeding.
van Doorn HC, Opmeer BC, Jitze Duk M, Kruitwagen RF, Dijkhuizen FP, Mol BW.
Department of Obstetrics and Gynaecology,
University Medical Centre
The objective is to assess among women with postmenopausal bleeding the
relationship of age and time since menopause on one hand and the presence of
endometrial cancer and atypical hyperplasia on the other hand. In a multicenter
prospective cohort study, 614 women presenting with postmenopausal bleeding
were included. Women underwent transvaginal sonography and, in cases where the endometrial thickness
was >4 mm, endometrial sampling. Splines were used
to assess the association between each of the continuous variables and
(pre)malignancy of the endometrium. Subsequently, univariate and multivariate analysis were performed. The
average age for women without (pre)malignancy was 61.7 years (SD 9.8). As
malignant and premalignant cases were found to have similar age, these
subgroups were merged in the analyses. Age was an independent predictor of
(pre)malignancy. In women younger than 55 years, the odds ratio was 1.9 (95%
CI: 1.1-3.3) for each year under 55 years of age and 1.03 (95% CI: 1.00-1.06)
for each year over 55 years of age. The risk of (pre)malignancy of the endometrium was 4.9% in women less than 3 years
postmenopausal versus 19.7% in women more than 20 years postmenopausal.
However, in a multivariate analysis only age contributed to the prediction of risk.
This study demonstrates that, in postmenopausal women with vaginal bleeding,
the risk of (pre)malignancy of the endometrium is low
in women under 50 years of age, increases considerably until 55 years of age,
and rises only modestly with further advancing age. Future studies should
explore whether these findings can be incorporated in the diagnostic work-up of
women with postmenopausal bleeding.
Drug Metab Dispos. 2007 Apr 9; [Epub ahead of print]
Selective tissue
distribution of tibolone metabolites in mature ovariectomized female cynomolgus
monkeys after multiple doses of tibolone.
Verheul HA, van Iersel ML, Delbressine LP, Kloosterboer HJ.Organon.
Tibolone is a
selective tissue estrogenic activity regulator (STEAR). In postmenopausal
women, it acts as an estrogen on brain, vagina and bone, but not on endometrium and breast. Despite ample supporting in vitro
data for tissue selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we
analyzed tibolone and metabolites in plasma and
tissues from six ovariectomized cynomolgus
monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied
at 1, 1.25, 2.25, 4, 6 and 24 hours after the final dose. The plasma and tissue
levels of active, non-sulfated (tibolone,
3alpha-hydroxytibolone, 3beta-hydroxytibolone, Delta(4)-tibolone), mono-sulfated
(3alpha-sulfate,17beta-hydroxytibolone, 3beta-sulfate,17beta-hydroxytibolone)
and di-sulfated (3alpha,17beta-di-sulfated-tibolone,
3beta,17betaS-di-sulfated-tibolone) metabolites were measured by validated gas
chromatography with mass spectrometry and liquid chromatography with tandem
mass spectrometry. Detection limits were 0.1-0.5 ng/mL (plasma) and 0.5-2 ng/g
(tissues). In brain tissues, estrogenic 3alpha-hydroxytibolone was predominant
with 3-8 times higher levels than in plasma; levels of sulfated metabolites
were low. In vaginal tissues, major non-sulfated metabolites were
3alpha-hydroxytibolone and the androgenic/progestagenic
Delta(4)-tibolone; di-sulfated metabolites were predominant. Remarkably high
levels of mono-sulfated metabolites were found in the proximal vagina. In endometrium, myometrium and mammary
glands, levels of 3-hydroxymetabolites were low and those of sulfated
metabolites high (about 98% di-sulfated). Delta(4)-tibolone/3-hydroxytibolone ratios were 2-3 in endometrium, about equal in breast and proximal vagina, and
0.1 in plasma and brain. It is concluded that tibolone
metabolites show a unique tissue-specific distribution pattern explaining the
tissue effects in monkeys and the clinical effects in postmenopausal women.
Cancer Epidemiol
Biomarkers Prev. 2007 Apr;16(4):740-6
Age at
Menarche and Menopause and Breast Cancer Risk in the International BRCA1/2
Carrier Cohort Study.
Chang-Claude J, Andrieu N, Rookus M, Brohet R, Antoniou AC, Peock S, Davidson R, Izatt L, Cole T, Nogues C, Luporsi E, Huiart L, Hoogerbrugge N, Van Leeuwen FE, Osorio A, Eyfjord J, Radice P, Goldgar DE, Easton DF.
Division of Cancer Epidemiology,
BACKGROUND: Early menarche and late menopause are important risk factors
for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2
carriers are unknown. METHODS: We assessed breast cancer risk in a large series
of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2 Carrier
Cohort Study. Rate ratios were estimated using a weighted Cox-regression
approach. RESULTS: Breast cancer risk was not significantly related to age at
menopause {hazard ratio [HR] for menopause below age 35 years, 0.60 [95%
confidence interval (95% CI), 0.25-1.44]; 35 to 40 years, 1.15 [0.65-2.04]; 45
to 54 years, 1.02 [0.65-1.60]; >/=55 years, 1.12 [0.12-5.02], as compared
with premenopausal women}. However, there was some suggestion of a reduction in
risk after menopause in BRCA2 carriers. There was some evidence of a protective
effect of oophorectomy (HR, 0.56; 95% CI, 0.29-1.09)
and a significant trend of decreasing risk with increasing time since oophorectomy, but no apparent effect of natural menopause.
There was no association between age at menarche and breast cancer risk, nor
any apparent association with the estimated total duration of breast mitotic
activity. CONCLUSIONS: These results are consistent with other observations
suggesting a protective effect of oophorectomy,
similar in relative effect to that in the general population. The absence of an
effect of age at natural menopause is, however, not consistent with findings in
the general population and may reflect the different natural history of the
disease in carriers.
Maturitas
Relationship
between adolescent amenorrhea and climacteric osteoporosis
Tamás Csermely, László Halvax, Miklós Vizer, István
Drozgyik, Péter Tamás, Péter Göcze,
István Szabó, Sára Jeges and András Szilágyi
Department of Obstetrics and Gynecology, University of Pécs, Faculty of Medicine, H-7624 Pécs, Édesanyák útja 17, Hungary; Department of Biostatistics and Health Informatics of Faculty of Health Sciences, University of Pécs, Hungary.
Objectives: The
relationship between climacteric osteoporosis and disturbances in menstrual
cycle during adolescence was examined. Methods: Seven
hundred and seventy-one questionnaires were shared out among women visiting the
outpatient department for climacteric complaints for the first time between
2001 and 2004. Questions revealed the age, age at menarche and menopause, the
regularity or irregularity of menstrual cycle during adolescence and adult
ages. The bone mineral density was examined using the Dual Energy X-ray Absorptiometry (DEXA) method on the lumbar spine. Results: Six hundred and thirty-five of the 771 questionnaires
were suitable for analysis. Osteoporosis was observed in 30.1% of the cases.
Age, age at the menarche or at the menopause did not alter in the subgroups
with or without osteoporosis. The incidence and severity of osteoporosis were
significantly higher in patients reporting secondary amenorrhea during
adolescent ages (42.1%; average BMD of the lumbar spine 71.6 ą 3.9),
as compared to the patients with normal cycle (30.4%; average BMD of the lumbar
spine 84.8 ą 7.8). No correlation between the occurrence of
osteoporosis and the frequency of menstrual cycle during adulthood was
observed. Conclusions: Secondary amenorrhea during the
years of adolescence might play a role in the development of more severe
osteoporosis in menopause.
Maturitas Volume 56, Issue 4,
Use of hormone
replacement therapy (HRT) among women aged 4564 years in the German
EPIC-cohorts
Gabriele
Nagel, Petra H Lahmann, Mandy Schulz, Heiner Boeing and Jakob Linseisen.
Division of Clinical Epidemiology, German
Cancer Research Centre,
Objective: To describe the prevalence and to assess type
and indicators of hormone replacement therapy (HRT) use in the two German
EPIC-cohorts. Methods: Approximately 30,000 women
predominantly aged 3565 years were recruited in EPIC-Heidelberg and
EPIC-Potsdam between 1994 and 1998. Information on diet and lifestyle, medical
history and use of hormone therapy was collected at recruitment. Prevalence and
type of HRT-regime was described and logistic regression models used to examine
correlates of HRT-use. Results: Among women aged 4564
years, 37.9% in
Maturitas.2007.02.011. Available online
Breast cancer: Are oestrogen metabolites carcinogenic?
Alfred O.
Mueck,
and Harald Seeger
University Women's
The World Health Organization (WHO) classified oestrogens
as carcinogenic in humans. One of the main arguments has been that oestrogens not only can promote cancers but also may
initiate mutations caused by certain oestrogen
metabolites. Indeed there is evidence that they can have biological properties
even at very low concentrations which can exceed manifold those of their parent
substance. Highly sophisticated laboratory methods will allow us to understand oestrogenic effects as a net effect of the corresponding
metabolite pattern. Current research focuses on the possible carcinogenic
properties of 4-hydroxyoestrogens and 16-alpha-hydroxyoestrone, but also on the
anticancerogenic effects particularly of
2-methoxyoestradiol. Thus, potential toxic secondary metabolites like
4-quinones can be eliminated, e.g. by methylation.
2-methoxyoestradiol is a potent antiproliferative and
antiangiogenic metabolite, and is currently tested in
patients with refractory metastatic breast cancer. Observational trials have
demonstrated that the ratio of 2- to 16-alpha-hydroxyoestrone is decreased in
women with breast cancer. We have been able to demonstrate that oestradiol metabolism during HRT can be influenced by
administration route, possibly also by certain progestogens.
In in vitro and animal experiments certain oestrogen metabolites indeed can act as carcinogens.
However, since for the formation of these metabolites the appearance of very
special conditions is a prerequisite and also various protective mechanisms are
present, this might only contribute to breast carcinogenesis in very rare
cases. However, the clinical relevance remains unclear and it appears to be
important to ascertain this issue.
Maturitas. Article in Press.
Available
online
WHI risks: Any
relevance to menopause management?
Henry G.
Burger
Prince Henry's Institute & Jean Hailes
Foundation For Women's Health,
Two randomised controlled trials of hormone
therapy (HT) were conducted within the US Women's Health Initiative. Both were
chronic disease prevention trials, undertaken to determine whether HT reduced
cardiovascular risk and increased breast cancer risk. Because the majority of
subjects in both trials were asymptomatic and many years postmenopausal, and
because substantial numbers had received HT prior to recruitment to the trials,
care must be taken in drawing conclusions that the observed risks are
applicable to women for whom HT is conventionally prescribed. Each of the
reported risks must be examined critically to determine its likely
applicability to symptomatic women treated for two to three years to relieve symptoms,
but sometimes for substantially longer periods. Further, the risks reported in
each of the two trials must be considered separately. Concerning cardiovascular
disease, many subjects in the trials were at increased baseline risk because of
their age, body mass index, smoking status, blood pressure and years since
menopause, in contrast to the usual situation for symptomatic perimenopausal women. Therefore the reported overall
cardiovascular risks in WHI, in both treatment arms, should be regarded as irrelevant
to menopause management. In contrast, breast cancer risk is relevant, providing
that proper note is taken of the fact that there was no increased risk after
five years of combined hormone therapy in non-prior HT users and there was a
tendency to a decreased risk in oestrogen only
treated individuals. Other risks are analysed
similarly.
Semana del 3 al 9 de Abril 2007
JAMA. 2007 Apr 4;297(13):1465-77.
Postmenopausal
hormone therapy and risk of cardiovascular disease by age and years since
menopause.
Rossouw JE, Prentice
RL, Manson
JE, Wu
L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis
KL, Stefanick ML.
Women's Health Initiative
Branch, National Heart, Lung, and Blood Institute,
CONTEXT: The timing of initiation of hormone therapy
may influence its effect on cardiovascular disease. OBJECTIVE: To explore
whether the effects of hormone therapy on risk of cardiovascular disease vary
by age or years since menopause began. DESIGN, SETTING, AND PARTICIPANTS:
Secondary analysis of the Women's Health Initiative (WHI) randomized controlled
trials of hormone therapy in which 10,739 postmenopausal women who had
undergone a hysterectomy were randomized to conjugated equine estrogens (CEE)
or placebo and 16,608 postmenopausal women who had not had a hysterectomy were
randomized to CEE plus medroxyprogesterone acetate
(CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study
from 40
MedGenMed.
2006;8(3):40.
Should symptomatic menopausal women be
offered hormone therapy?
Lobo
RA, Belisle S, Creasman WT, Frankel
NR, Goodman
NF, Hall
JE, Ivey
SL, Kingsberg S, Langer
R, Lehman
R, McArthur
DB, Montgomery-Rice
V, Notelovitz M, Packin GS, Rebar
RW, Rousseau
M, Schenken RS, Schneider
DL, Sherif K, Wysocki S.
Many physicians remain uncertain about prescribing
hormone therapy for symptomatic women at the onset of menopause. The American
Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of
healthcare providers to discuss the efficacy and risks of hormone therapy for
symptomatic women, and to determine whether it would be appropriate to treat
women at the onset of menopause who were complaining of menopausal symptoms.
MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate
that hormone therapy, administered via oral, transdermal,
or vaginal routes, is the most effective treatment for vasomotor symptoms.
Topical vaginal formulations of hormone therapy should be preferred when
prescribing solely for the treatment of symptoms of vulvar
and vaginal atrophy. Data from the Women's Health Initiative indicate that the
overall attributable risk of invasive breast cancer in women receiving estrogen
plus progestin was 8 more cases per 10,000 women-years. No increased risk for
invasive breast cancer was detected for women who never used hormone therapy in
the past or for those receiving estrogen only. Hormone therapy is not effective
for the treatment of cardiovascular disease and that the risk of cardiovascular
disease with hormone therapy is principally in older women who are considerably
postmenopause. CONCLUSIONS: Healthy symptomatic women
should be offered the option of hormone therapy for menopausal symptoms.
Symptom relief with hormone therapy for many younger women (at the onset of
menopause) with menopausal symptoms outweighs the risks and may provide an
overall improvement in quality of life. Hormone therapy should be
individualized for symptomatic women. This involves tailoring the regimen and
dose to individual needs.
FASEB J. 2007 Apr 5; [Epub
ahead of print]
Disruption of androgen receptor signaling
by synthetic progestins may increase risk of
developing breast cancer.
Birrell SN, Butler
LM, Harris
JM, Buchanan
G, Tilley
WD.
*Dame Roma Mitchell Cancer Research Laboratories, The
University of Adelaide, Hanson Institute, Adelaide, South Australia, Australia;
andSchool of Life Science, Queensland University of
Technology, Brisbane, Queensland, Australia.
There is now considerable evidence that using a
combination of synthetic progestins and estrogens in
hormone replacement therapy (HRT) increases the risk of breast cancer compared
with estrogen alone. Furthermore, the World Health Organization has recently cited
combination contraceptives, which contain synthetic progestins,
as potentially carcinogenic to humans, particularly for increased breast cancer
risk. Given the above observations and the current trend toward progestin-only
contraception, it is important that we have a comprehensive understanding of
how progestins act in the millions of women worldwide
who regularly take these medications. While synthetic progestins,
such as medroxyprogesterone acetate (MPA), which are
currently used in both HRT and oral contraceptives
were designed to act exclusively through the progesterone receptor, it is clear
from both clinical and experimental settings that their effects may be
mediated, in part, by binding to the androgen receptor (AR). Disruption of
androgen action by synthetic progestins may have
serious deleterious side effects in the breast, where the balance between
estrogen signaling and androgen signaling plays a critical role in breast
homeostasis. Here, we review the role of androgen signaling in the normal
breast and in breast cancer and present new data demonstrating that androgen
receptor function can be perturbed by low doses of MPA, similar to doses
achieved in serum of women taking HRT. We propose that the observed excess of
breast malignancies associated with combined HRT may be explained, in part, by
synthetic progestins such as MPA acting as endocrine
disruptors to negate the protective effects of androgen signaling in the
breast. Understanding the role of androgen signaling in the breast and how this
is modulated by synthetic progestins is necessary to
determine how combined HRT alters breast cancer risk, and to inform the
development of optimal preventive and treatment strategies for this disease.
Bone. 2007 Mar
1; [Epub ahead of print]
Effects of statins
on bone mineral density: A meta-analysis of clinical studies.
Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY.
AP-HP, Laboratoire de Pharmacologie, Hopital
Avicenne, 125 route de Stalingrad, 93009-Bobigny, France et Universite
Paris-XIII, France.
CONTEXT: Statins inhibit
HMG-CoA reductase,
preventing synthesis of mevalonate but also of isoprenoids, which affect osteoclast
activity. Amino-bisphosphonates share this effect. In
vitro and in vivo, statins show convincing anabolic
and anti-resorptive bone effects. However, in a
clinical meta-analysis (MA), they did not prevent hip fractures. OBJECTIVE AND
DESIGN: Our meta-analysis studied the impact of statins
on bone mineral density (BMD) at various sites and compared the effects of lipophilic and more hydrophilic statins.
DATA SOURCES: Our PubMed and Embase
queries using two keywords (statins, BMD) were
updated to October 2006. DATA COLLECTION: Two readers independently collected
BMDs from studies. DATA SYNTHESIS: Twenty-one studies, mostly observational
(three randomized controlled trials and one pseudo-randomized study), were
assessed. Two studies were excluded (no control groups). Three studies could
not be analyzed. The sixteen studies analyzed mainly included postmenopausal osteopenic women (2971 patients under statins).
Statins significantly increased BMD at total hip (TH)
and femoral neck (FN). Effect sizes (ESs) were modest: 0.21 at TH (95%
confidence interval [CI]: 0.16-0.25) and 0.20 at FN (CI: 0.08-0.28). Among
women, statins acted similarly (ES: 0.20 for TH and
0.18 for FN; CI: 0.14-0.25 and 0.06-0.31 respectively); lipophilic
statins (simvastatin, lovastatin) almost entirely caused this effect, at both TH
(ES: 0.20; CI: 0.15-0.26) and FN (ES: 0.22; CI: 0.06-0.37). CONCLUSION: Our
findings of modest but statistically significant beneficial effects of statins on hip BMD should promote large double-blind
randomized controlled trials on their bone effects, in view of their major
beneficial cardiovascular effects with excellent safety profile.
Br J Cancer. 2007 Apr
9;96(7):1139-46.
Meat consumption
and risk of breast cancer in the
Taylor
EF, Burley
VJ, Greenwood
DC, Cade
JE.
1Nutritional Epidemiology
Group, 30-32 Hyde Terrace,
We performed a survival analysis to assess the effect
of meat consumption and meat type on the risk of breast cancer in the UK
Women's Cohort Study. Between 1995 and 1998 a cohort of 35 372 women was
recruited, aged between 35 and 69 years with a wide range of dietary intakes,
assessed by a 217-item food frequency questionnaire. Hazard ratios (HRs) were
estimated using Cox regression adjusted for known confounders. High consumption
of total meat compared with none was associated with premenopausal breast
cancer, HR= 1.20 (95% CI: 0.86-1.68), and high non-processed meat intake
compared with none, HR=1.20 (95% CI: 0.86-1.68). Larger effect sizes were found
in postmenopausal women for all meat types, with significant associations with
total, processed and red meat consumption. Processed meat showed the strongest
HR= 1.64 (95% CI: 1.14-2.37) for high consumption compared with none. Women,
both pre- and postmenopausal, who consumed the most meat
had the highest risk of breast cancer.
Eur J Cancer
Prev. 2007 Jun;16(3):232-242.
Hormonal interventions to prevent hormonal
cancers: breast and prostate cancers.
Basic Prevention Science Research Group National
Cancer Institute, Division of Cancer Prevention,
In 1998, the concept of breast cancer prevention
became a reality with the approval of tamoxifen to
reduce the risk of developing breast cancer in women at increased risk for the
disease. This approval was based on decades of research on selective estrogen
receptor modulators providing an understanding of the role of the estrogen
receptor in breast cell growth, and an appreciation of the carcinogenic
process. Although results from the Breast Cancer Prevention Trial demonstrated
a 49% reduction in breast cancer in women at increased risk, there were
associated toxicities related to the estrogenic effects of tamoxifen;
that is, deep vein thrombosis, pulmonary embolism, and endometrial cancer. In
an effort to improve its benefit-risk profile, tamoxifen
is now being compared with raloxifene, a selective
estrogen receptor modulator approved for the treatment and prevention of
osteoporosis. This equivalency prevention Study of Tamoxifen
and Raloxifene completed accrual of 19 747 high-risk
postmenopausal women in November 2004. Meanwhile, another class of
estrogen-directed drugs, the aromatase inhibitors,
have shown efficacy in breast cancer adjuvant trials, spawning a number of
prevention trials that have recently been initiated. As with breast cancer the
hormonal contribution to prostate carcinogenesis was the basis for the Prostate
Cancer Prevention Trial which showed that finasteride,
an androgen antagonist, reduces the incidence of prostate cancer compared to
placebo.
Menopause. 2007 Mar
23; [Epub ahead of print]
Mammographic
density in a multiethnic cohort.
Habel LA, Capra
AM, Oestreicher N, Greendale
GA, Cauley JA, Bromberger J, Crandall
CJ, Gold
EB, Modugno F, Salane M, Quesenberry C, Sternfeld B.
Division of Research, Kaiser Permanente, Oakland, CA;
David Geffen School of Medicine at UCLA, Los Angeles, CA; University of
Pittsburgh, Pittsburgh, Pittsburgh, PA; University of California, Davis, CA;
and MSW Consulting, Bloomfield Hills, MI.
OBJECTIVES:: To compare
mammographic density among premenopausal and early perimenopausal
women from four racial/ethnic groups and to examine density and acculturation
among Japanese and Chinese women. DESIGN:: The study
included 391 white, 60 African American, 171 Japanese, and 179 Chinese
participants in the Study of Women's Health Across the Nation, a multisite
study of
Clin Orthop Relat Res. 2007 Mar 29; [Epub ahead of print]
Prior Fractures Are Common in Patients With Subsequent Hip Fractures.
Edwards
BJ, Bunta AD, Simonelli
C, Bolander
M, Fitzpatrick
LA.
Treating osteoporosisin
patients with prior fractures potentially results in a 50% reduction of risk of
future fractures. We retrospectively reviewed 632 patients with incident hip
fractures to evaluate (1) the prevalence of prior fractures in incident hip
fractures, (2) whether prior fractures led to an increase in the treatment of
osteoporosis, and (3) the cost utility of osteoporosis treatment after a prior
fracture. The patients were treated at three hospitals from January 2000 to
June 2001 and 514 (80%) were women. A minimal trauma fracture was defined as a
fracture resulting from a fall while standing or walking or falling from a
height less than 4 feet. Two hundred eighty-two patients (45%) with incident
hip fractures described a prior minimal trauma fracture. Osteoporosis was
diagnosed in 43 (13%) women and three (5%) men. In 107 cases (17%), the
incident hip fracture was the second hip fracture. A prior minimal trauma
fracture did not increase treatment for osteoporosis. Presuming a 50% reduction
in fracture risk with medications, treating the 282 patients with prior minimal
trauma fracture would have resulted in a savings of $3.5 million.Level
of Evidence: Level III, therapeutic Study. See the Guidelines for Authors for a
complete description of levels of evidence.
Med Sci Sports Exerc. 2007 Apr;39(4):587-92.
Exercise training-induced changes in
coagulation factors in older adults.
Lockard MM, Gopinathannair R, Paton CM, Phares DA, Hagberg JM.
Department of Kinesiology,
The coagulation cascade plays a critical role in the
development of cardiovascular disease (CVD). Elevated plasma prothrombin fragment 1 + 2 (F1 + 2) and factor VIII antigen
(FVIII:Ag) levels have been
associated with a hypercoagulable state, enhancing
the risk for vascular thrombotic events. Aerobic training is known to reduce
CVD risk, and an improved coagulation profile may contribute to this reduction.
PURPOSE:: To analyze the effect of 6 months of
standardized aerobic exercise training on resting F1 + 2 and FVIII:Ag levels in men and postmenopausal women aged 50-75
while accounting for several possibly confounding factors. MATERIALS AND
METHODS:: Sedentary men (N = 16) and women (N = 31) underwent supervised
aerobic training 3 d.wk for 6 months while
maintaining the American Heart Association step 1 diet. Baseline and final
testing included measurement of F1 + 2, FVIII:Ag, plasma lipoprotein-lipid levels, body
composition, and V O2max. RESULTS:: When adjusted for baseline values and
changes in diastolic blood pressure with training, F1 + 2 was found to decrease
significantly with exercise training from 1.493 +/- 0.058 to 1.422 +/- 0.059 nM (P = 0.014). FVIII:Ag levels
were found to increase significantly with training when adjusted for baseline
values, from 152.5 +/- 6.7% of standard at baseline to 156.0 +/- 6.1% of
standard at final testing (P = 0.005). Training-induced changes in coagulation
markers were independent of changes in blood lipids, aerobic capacity, and body
composition. CONCLUSIONS:: These results indicate that
endurance training has a significant impact on the coagulation cascade,
reducing coagulation activity in the common pathway and thrombin formation at
rest while increasing the activation potential of the intrinsic pathway.
Menopause. 2007 Mar
19; [Epub ahead of print]
Development and
preliminary validation of the Menopause Symptoms Treatment Satisfaction
Questionnaire (MS-TSQ).
Hill
CD, Fehnel SE, Bobula JD, Yu H, McLeod LD.
OBJECTIVE:: The Menopause
Symptoms Treatment Satisfaction Questionnaire, an eight-item questionnaire with
a 4-week recall period, was developed to assess women's satisfaction with
treatment for symptoms associated with menopause. We describe the development
and initial testing of the scale. DESIGN:: Following
standard instrument-development procedures, focus groups were conducted with
menopausal women experiencing hot flushes to generate potential constructs.
Multiple items were drafted to address each construct. An iterative process of
cognitive testing, item revision, and item reduction was followed to identify
the most appropriate items and optimal response scales. The psychometric
validation of the questionnaire used data collected through a multicenter,
randomized, double-blind, placebo-controlled study including 543 postmenopausal
women. Psychometric analyses were conducted to explore potential item reduction
and to address questionnaire scaling and scoring. Internal consistency
reliability, construct validity, and discriminant
validity of the new scale were also examined. RESULTS::
The questionnaire includes items addressing the control of daytime and
nighttime hot flushes; effects of treatment on sleep, mood, libido, and
cognition; medication tolerability; and overall satisfaction. Correlation
analyses indicated that the items are related to each other without being
overly redundant and that the item set is best described using a one-factor
model. The subsequent scale score demonstrated sound internal consistency
reliability, strong construct validity, and good discriminant
validity. CONCLUSIONS:: The results of the development
and initial validation are favorable. It is expected that the questionnaire
will prove to be a worthwhile tool for assessing women's satisfaction with
treatment for menopausal symptoms.
Obstet Gynecol.
2007 Apr;109(4):823-30.
Ineffectiveness of sertraline
for treatment of menopausal hot flushes: a randomized controlled trial.
Grady
D, Cohen
B, Tice
J, Kristof M, Olyaie A, Sawaya GF.
University of California, San Francisco; and San Francisco VA Medical Center, San Francisco, California.
OBJECTIVE: To estimate the effect of the selective
serotonin reuptake inhibitor sertraline on hot flush
frequency and severity in perimenopausal and
postmenopausal women. METHODS: We performed a randomized, blinded,
placebo-controlled trial in women aged 40 to 60 years with 14 or more hot
flushes per week (N=99). Women were randomly assigned initially to daily oral sertraline (50 mg) or identical placebo for 2 weeks. If no
substantial side effects were noted, the dose was increased to two tablets
daily (100 mg sertraline or placebo) and continued
for an additional 4 weeks. Hot flush frequency and severity were recorded on a
daily diary. Hot flush score was calculated as frequency multiplied by
severity. Participants also completed questionnaires addressing quality of
life, menopausal symptoms, sleep quality, sexual function, mood, and side
effects. RESULTS: After 6 weeks of treatment, hot flush frequency decreased
similarly in both the placebo (38%) and sertraline
(39%) groups (P=.94). Mean hot flush scores also decreased similarly in both
groups (41% and 42%, respectively, P=.86). Compared with placebo, women in the sertraline group were more likely to report
gastrointestinal complaints, dry mouth, and dizziness. Treatment with sertraline also resulted in greater worsening of scores on
the Medical Outcomes Study (MOS) Short Form 36 standardized physical component
and the global Female Sexual Function Index. Results were similar in women at
least 80% adherent to study medication. CONCLUSION: Treatment with sertraline did not improve hot flush frequency or severity
in generally healthy perimenopausal and
postmenopausal women, but was associated with bothersome side effects.
JAMA. 2007 Feb 28;297(8):842-57.
Mortality in randomized trials of
antioxidant supplements for primary and secondary prevention: systematic review
and meta-analysis.
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C.
The Cochrane Hepato-Biliary
Group, Copenhagen Trial Unit, Center for Clinical Intervention Research, Copenhagen
University Hospital, Rigshospitalet, Copenhagen,
Denmark. goranb@junis.ni.ac.yu
CONTEXT: Antioxidant supplements are used
for prevention of several diseases. OBJECTIVE: To assess the effect of
antioxidant supplements on mortality in randomized primary and secondary
prevention trials. DATA SOURCES AND TRIAL SELECTION: We searched electronic
databases and bibliographies published by October 2005. All randomized trials
involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid),
vitamin E, and selenium either singly or combined vs
placebo or vs no intervention were included in our
analysis. Randomization, blinding, and follow-up were considered markers of
bias in the included trials. The effect of antioxidant supplements on all-cause
mortality was analyzed with random-effects meta-analyses and reported as
relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was
used to assess the effect of covariates across the trials. DATA EXTRACTION: We
included 68 randomized trials with 232 606 participants (385 publications).
DATA SYNTHESIS: When all low- and high-bias risk trials of antioxidant
supplements were pooled together there was no significant effect on mortality (RR,
1.02; 95% CI, 0.98-1.06). Multivariate meta-regression analyses showed that
low-bias risk trials (RR, 1.16; 95% CI, 1.05-1.29) and selenium (RR, 0.998; 95%
CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias
trials with 180 938 participants, the antioxidant supplements significantly
increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In
low-bias risk trials, after exclusion of selenium trials, beta carotene (RR,
1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin
E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased
mortality. Vitamin C and selenium had no significant effect on
mortality. CONCLUSIONS: Treatment with beta carotene, vitamin A, and vitamin E
may increase mortality. The potential roles of vitamin C and selenium on
mortality need further study.