Selección de Resúmenes de Menopausia
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. Links
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
Dr. Juan Enrique Blümel
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 ± 3.9), as compared to the patients with normal
cycle (30.4%; average BMD of the lumbar spine 84.8 ± 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 45–64 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 35–65 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 45–64
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
Dr. Juan Enrique Blümel
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.