Oral contraceptive use is not associated with increased breast
Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and
the risk of breast cancer. N Engl J Med 2002;346:2025-2032.
Neither current nor former use
of combined estrogen plus progestin oral contraceptives (OCs) is associated with increased risk for breast cancer in women,
according to the results of this population-based, case-control study. Investigators interviewed 4,575 women with breast cancer
and 4,682 women without breast cancer. Women were aged 35 to 64; 77% of the case subjects and 79% of the controls had used
some type of OC. Compared with never users, the relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for current OC users
and 0.9 (95% CI,0.8-1.0) for former users. The relative risk did not increase consistently with longer periods of OC use,
higher doses of estrogen, type of progestin used, or age at first use. Also, women with a family history of breast cancer
did not have an increased risk from OC use.
Level II-2 evidence
Comment. Oral contraceptives are the most widely used reversible method of contraception
used by US women (approximately 78% of participants in this large study were ever users). They provide consistent users with
convenient, effective, and reversible birth control. Furthermore, use of OCs is associated with important noncontraceptive
health benefits, ranging from lighter less painful more regular menses to prevention of endometrial and ovarian cancers. Perhaps
the biggest concern that women, and their clinicians, have regarding OCs is that their use might increase breast cancer risk.
This large, NIH-sponsored, CDC-conducted, study provides a high level of reassurance that OC users, regardless of age, formulation
type, duration of use, or family history, will not increase their breast cancer risk.
Andrew M. Kaunitz, MD
Professor and Assistant Chairman
of Obstetrics and Gynecology
University of Florida Health Science Center
Director of Menopause and Bone Density Services
The News making JAMA published studies about risk factors: Overall risk was minor. They did
not consider such factors as gallbladder disease, diabetes, cognitive
function, and quality of life. CEE plus MPA (hormones administered) does increase
the risk of incident breast cancer and to quantify the degree of risk. Eight
more breast cancers, 5 fewer colo-rectal cancers, and 6 fewer hip fractures. Moreover, the results hold only for the
unique combination of estrogen and MPA--JK
Low doses of
vaginal estradiol cream treat urogenital atrophy with no adverse endometrial effects
Santen RJ, Pinkerton JV, Conaway M, et al. Treatment of urogenital atrophy
with low-dose estradiol: preliminary results. Menopause 2002;9:179-187.
A vaginal cream estradiol dose as low as 10 µg is effective for treating
urogenital atrophy and does not cause endometrial hyperplasia or increased estradiol levels, according to the preliminary
findings from this single-blind, single-arm study. The study is designed to determine the effects of low doses of vaginal
estrogen on symptoms of urogenital atrophy, vaginal pH, and vaginal and urethral cytology. Women receive vaginal estradiol
daily for 3 weeks then twice weekly for another 9 weeks. Of the first 7 women who received the 10-µg dose, all were responders
vaginal and urethral cytology improved, vaginal pH decreased, and endometrium remained atrophic. Later stages of this study
will look at doses as small as 1.25 µg.
Level II-1 evidence
This study indicates that ultra-low doses of vaginal estradiol do not stimulate the endometrium, at least over the short term.
Estradiol vaginal cream improved the vaginal and urethral cytology and decreased vaginal pH, but the endometrium remained
atrophic. Caution should be expressed, but these results will probably be true over the long term, especially since vaginal
estradiol is better absorbed than through more normal mucosa.
R. Don Gambrell, Jr. MD
Clinical Professor of Endocrinology
and Obstetrics and Gynecology
Medical College of Ge
Oral estrogen replacement therapy slows progression of atherosclerosis
Hodis HN, Mack WJ, Lobo RA, et al, for the Estrogen in Prevention of
Atherosclerosis Trial (EPAT) Research Group. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled
trial. Ann Intern Med 2001(Dec 4);135:939-953.
Healthy postmenopausal women who take oral estrogen replacement therapy
(ERT) with 17-beta estradiol have a slower rate of progression of subclinical atherosclerosis than women taking placebo, according
to results from this randomized, double-blind, placebo-controlled trial. A total of 222 postmenopausal women without pre-existing
cardiovascular disease received either ERT (1 mg/day unopposed oral 17-beta estradiol) or placebo. Participants had low-density
lipoprotein (LDL) cholesterol levels of 130 mg/dl (3.37 mmol/L) or higher. All women received dietary counseling. A lipid-lowering
agent was prescribed if LDL levels exceeded 160 mg/day (4.15 mmol/L); 57% of the estradiol group and 66% of the placebo group
received these medications. During the 2-year trial, the average rate of progression of subclinical atherosclerosis (as measured
by B-mode ultrasound of the common carotid artery) was significantly lower in ERT recipients than in placebo recipients (P
= 0.046). Average rates of progression did not differ between women who were assigned estradiol and placebo recipients who
were assigned lipid-lowering medications. Estrogen therapy had no additional effect on the progression of atherosclerosis
in women receiving lipid-lowering therapy.
The positive results of this randomized clinical trial in healthy women taking unopposed oral 17-beta estradiol with the endpoint
of carotid intima-media thickness stand in direct opposition to other recent HRT trials in women with cardiovascular disease
or CHD risk factors. Differences in womens cardiovascular health at baseline, age, years since menopause, type of estrogen,
and presence or absence of progestogen may all contribute to the differences in trial results. Importantly, this trial (EPAT)
also found no added benefit of combined estrogen and lipid-lowering therapy on the progression of subclinical atherosclerosis.
The positive findings of EPAT provides another important piece of the evolving puzzle of the relationship between estrogen
and cardiovascular disease in women, and they underscore the importance of continuing the WHI and WISDOM trials to assess
the effect of estrogen on clinical outcomes such as heart attack and stroke in healthy women.
Cynthia A. Stuenkel, MD
Clinical Professor of Medicine
University of California, San Diego
San Diego, CA
24 (2): 133-151
Copyright © 2003 by The Endocrine Society
Estrogen and Cognitive Functioning in Women
Barbara B. Sherwin
Department of Psychology, McGill University, Montreal, Quebec, Canada H3A 1B1
Correspondence: Address all correspondence and requests for
reprints to: Barbara B. Sherwin, Ph.D., James McGill Professor, Department of Psychology and Department of Obstetrics/Gynecology,
1205 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A
1B1. E-mail: firstname.lastname@example.org
Research in basic neuroscience has provided biological plausibility for the
hypothesis that estrogen replacement therapy (ERT) would protect against cognitive aging in healthy women. The weight of the evidence from randomized controlled trials of estrogen and cognition
in women shows that this hormone preferentially protects verbal memory in postmenopausal women, whereas
findings from observational studies are less consistent and show a more diffuse effect of estrogen on
a range of cognitive functions. There is fairly consistent evidence from epidemiological
studies that ERT significantly reduces the risk of Alzheimer’s disease (AD) in women. On
the other hand, findings from controlled treatment trials of women diagnosed with probable AD failed to
show that physiological doses of ERT ameliorate existing deficits in cognitive functioning and/or prevent further
deterioration in memory that inevitably occurs in these women over time.
Finally, an accumulating body of evidence is beginning to suggest that the
immediate postmenopausal period may constitute a critical window for treatment with ERT that maximizes its potential
to protect against cognitive decline with aging and/or to reduce the risk of AD.
Both ERT and HRT improve skin-aging measures
Sator P-G, Schmidt JB, Sator MO, Huber JC, Hönigsmann H. The influence
of hormone replacement therapy on skin ageing: a pilot study. Maturitas 2001;39:43-55.
Estrogen replacement therapy, either with or without a progestogen,
had a significant beneficial effect on skin aging in postmenopausal women, according to this study from Austria. A total of
24 women (mean age, 54.9 years) who had not received estrogen or hormone replacement therapy for at least 6 months were randomly
assigned to one of four groups: transdermal estrogen alone, transdermal estrogen plus a progestogen (vaginal suppository),
oral estrogen plus a progestogen (vaginal suppository), or an unblinded control group receiving no therapy. Skin measurements
were taken monthly for skin surface lipids, epidermal skin moisture, skin elasticity, and skin thickness. After the 6-month
treatment regimen, mean levels of epidermal skin moisture, skin elasticity, and skin thickness were significantly improved
in all treatment groups compared with the control group. The surface lipid measure was significantly improved for both combined
estrogen plus progestogen therapy groups compared with the controls.
This article presents a comprehensive survey of clinical, subjective, and physical measures of the effect of ERT and HRT on
skin aging. Although limited in statistical power by both design and the small number of participants, this study demonstrates
a convincing clinical benefit to the skin from the three different regimens. The portion of the effect due to enhanced collagen
probably parallels the effect of estrogen on bone density, as type I collagen is the predominant collagen in both skin and
bone. From a clinical standpoint, womens subjective reaction to aging skin can be a powerful stimulus to initiate or continue
ERT/HRT. The benefits of a fuller dermis and less dryness can be directly touted as clear advantages of treatment.
Laurence J. Meyer, PhD, MD
Associate Professor, Dermatology
and Internal Medicine
University of Utah Health Sciences Center
Salt Lake City, UT
HRT moderates blood pressure gains in postmenopausal women
Scuteri A, Bos AJG, Brant LJ, et al. Hormone replacement therapy and
longitudinal changes in blood pressure in postmenopausal women. Ann Intern Med 2001(Aug 21);135:229-238.
Postmenopausal women taking hormone replacement therapy (estrogen plus
a progestin; HRT) have less of an increase in systolic blood pressure (BP) over time than women not taking HRT, according
to the Baltimore Longitudinal Study of Aging, an observational study that began recruiting participants in 1978. Cardiovascular
risk factors are among the measurements taken at baseline and every 2 years thereafter. For this report, data were analyzed
for 226 normotensive, postmenopausal women (mean age 64) with an average follow-up of 5.7 years (range 2 to 18 years); 77
were HRT users and 149 used neither drug. After adjustment for confounding factors, the average systolic BP increase was statistically
smaller in HRT users than in nonusers: 1.6 mm Hg (range 1.3-1.9 mm Hg) versus 8.9 mm Hg (range 8.6-9.2 mm Hg), respectively.
Diastolic BP was not statistically different between the two groups.
Interpretation of this study is challenging due to the rolling enrollment into this prospective cohort study and the complex
statistical modeling that is required to analyze such data. Nevertheless, the results are consistent with the growing body
of evidence indicating that HRT acts as a vasodilator that may attenuate age-related increases in systolic BP. Whether this
effect will translate into a cardiovascular benefit with respect to clinical cardiovascular events has not yet been established.
David M. Herrington, MD
Associate Professor of Medicine/Cardiology
Forest University School of Medicine
Studies have demonstrated that BP in midlife women increases with age, especially after age 55. With hypertension being a
major risk factor for development of CHD, identification of any factors that might affect the level of BP merits aggressive
consideration. This study, although observational, suggests that women using HRT may experience a lower incidence of elevation
in systolic BP than nonusers. Of significant importance is the finding that HRT use may have a positive effect on BP over
time by limiting the usual systolic elevations that occur with age, even considering the extraneous factors of body mass index,
lipids, smoking status, and physical activity.
Diane Todd Pace, PhD, APRN, BC
Family Nurse Practitioner/Researcher
Medical Center of Memphis
Longer-term HRT use significantly reduces the risk of recurrent coronary events
Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and
secondary prevention of coronary events in the Nurses Health Study. Ann Intern Med 2001(July);135:1-8.
The risk for recurrent major coronary events seems to increase among
users of short-term hormone replacement therapy (HRT, either with or without a progestogen) who have established coronary
heart disease (CHD) but appears to decrease with longer-term use, according to data from the Nurses Health Study. This prospective,
observational cohort study sought to determine a time trend in the risk for recurrent heart disease among postmenopausal women
with CHD. A total of 2,489 postmenopausal women with previous myocardial infarction (MI) or documented atherosclerosis were
evaluated. Investigators observed a significant trend toward decreasing risk for recurrent major CHD events with longer duration
of HRT use. Short-term and current users of HRT had an adjusted relative risk of 1.25 (95% CI, 0.78-2.00) compared with never
users. For longer-term users (at least 2 years), the risk was significantly lower than in never users (RR, 0.38; 95% CI, 0.22-0.66).
Overall, with up to 20 years of follow-up, the relative risk for a recurrent CHD event among current HRT users was 0.65 (95%
This latest report from the Nurses Health Study responds to an issue raised by the HERS trial whether short-term use of HRT
can, in some women, increase the risk of recurrent CHD events. In this data set, there was a nonsignificant trend toward increased
risk in short-term users of HRT. However, in women who used HRT for two or more years, the risk was significantly reduced.
This trend echoes the retrospective analysis of the Puget Sound Group Health Cooperative, which showed a short-term increased
risk and a longer-term reduced risk of recurrent CHD events. In the aggregate, these data continue to raise concerns about
an early increase in risk of CHD events in women with established disease. But in longer-term users, benefit may accrue over
David M. Herrington, MD
Associate Professor of Medicine/Cardiology
Forest University School of Medicine
Science's STKE | 25 June 2002
Estrogen Actions in the Brain
Ling Wang1, Sandra
Andersson1, Margaret Warner2, and Jan-Åke Gustafsson1,2*
1Department of Medical Nutrition, Karolinska Institute, NOVUM, S-141 86 Huddinge, Sweden.
of Biosciences, Karolinska Institute, NOVUM, S-141 86 Huddinge, Sweden.
Summary: Understanding of the mechanisms of estrogen action in the brain has always been poor. Neurons in several
brain regions do not harbor estrogen receptor (ER ) and yet are estrogen responsive. It was formerly
thought that these responses represented indirect actions of estrogen. It is now evident that these neurons express ERß and
that estrogen receptors have diverse actions in the central nervous system. By clear delineation of the cellular expression
and function of the two estrogen receptors, it is likely that, in the future, selective ER and ERß ligands will be developed and used for
treatment of depression and behavioral disorders and may be useful in preventing degenerative diseases, such as Alzheimer's
and Parkinson's disease.
author. E-mail: email@example.com
ABSTRACTS JAMA December 5, 2000--vol. 284 No. 21
OF INTERNAL MEDICINE
Replacement Therapy and Peripheral
Disease: The Rotterdafli Study
Background: As the number of elderly women increases in Western society, peripheral arterial disease (PAD) is likely to become
an increasing problem. Hormone replacement therapy, suggested to protect against
coronary atherosclerosis, might also inhibit the development of PAD.
Methods: The association between hormone replacement therapy and the presence of PAD was studied in a population-based
study consisting of 2196 naturally menopausal women aged 55 to 80 years living in a suburban area of Rotterdam, the Netherlands.
Peripheral arterial disease was defined as an ankle/arm systolic blood pressure index (ratio of the systolic blood pressure
at the ankle to the systolic blood pressure at the arm) lower than 0.9.
Hormone replacement therapy for 1 year or longer was associated with a 52%
decreased risk of PAD (odds ratio, 0.48 [95% confidence interval, 0.24-0.851), while no association was found for therapy
duration shorter than 1 year (odds ratio, 0.97 [95% confidence interval, 0.58-1.63) after adjustment for age, smoking, and
socioeconomic status. Additional adjustment for body mass index, age at menopause, total cholesterol and high-density lipoprotein
cholesterol, alcohol intake, and frequency of visits to health care facilities did not change the results.
Conclusion: The findings of this population-based study suggest that hormone replacement therapy given for a year or more is associated
with a decreased risk of PAD among postmenopausal women.
(20001 602498-2502) Iris C. D. Westendorp et
at. Reprints: Jacqueline C. M. Witteman, Department of Epidemiology and Biostatistics, Erasmus University Medical School
Rotterdam, PC Boa 1738, 3000 DR, Rotterdam, the Netherlands (e-mail: firstname.lastname@example.org).
A meta-analysis of hormone replacement therapy
and colon cancer in women (Structured abstract)
NHS Centre for Reviews and Dissemination
N. A meta-analysis of hormone replacement therapy and colon cancer in women. Cancer Epidemiology, Biomarkers
and Prevention. 1998. 7(8). 653-659.
This record is a structured
abstract written by CRD reviewers. The original has met a set of quality criteria. Since September 1996 abstracts have been
sent to authors for comment. Additional factual information is incorporated into the record. Noted as (A:....).
To investigate the association
between hormone replacement therapy (HRT) and colon cancer.
SPECIFIC INTERVENTIONS INCLUDED IN THE REVIEW
Use of menopausal hormones.
Only one type of exposure by study was assessed. However, where studies only provided combined estimate of the effects of
different hormonal derivatives (e.g. oral contraceptives and HRT, or hormone substitution therapy of any kind) these interventions
PARTICIPANTS INCLUDED IN THE REVIEW
Women, age not stated (assumed
OUTCOMES ASSESSED IN THE REVIEW
Incidence of colorectal
tumours, specifically colon cancer.
STUDY DESIGNS OF EVALUATIONS INCLUDED IN THE REVIEW
Case control, cohort and
randomised clinical trials (RCTs).
WHAT SOURCES WERE SEARCHED TO IDENTIFY PRIMARY STUDIES?
MEDLINE and Cancerlit were
searched (dates not stated). Key words included: colorectal neoplasm or colonic neoplasm or gastrointestinal neoplasm or rectal
neoplasm, and oestrogen replacement therapy or estrogens or contraceptives, oral. Reference lists from the internet sites
Cancernet and Oncolink and from published studies and a previous meta-analysis were searched (see Other Publications of Related
Only studies published
in French or English up to December 1996 were included. Unpublished studies were excluded.
CRITERIA ON WHICH THE VALIDITY (OR QUALITY) OF STUDIES WAS ASSESSED
No formal validity assessment
was conducted but a sensitivity analysis was conducted in which studies were grouped according to design, year of publication,
and the degree of adjustment for confounding.
HOW WERE THE INCLUSION CRITERIA APPLIED?
The authors do not state
how the papers were selected for review, or how many of the authors performed the selection.
HOW WERE JUDGEMENTS OF VALIDITY (OR QUALITY) MADE?
The authors do not state
how the papers were assessed for validity, or how many of the authors performed the validity assessment.
HOW WERE THE DATA EXTRACTED FROM PRIMARY STUDIES?
The authors do not state
how the data were extracted for the review, or how many of the authors performed the data extraction.
NUMBER OF STUDIES INCLUDED
19 studies: 8 cohort studies
(although one of these appears to be a randomised clinical trial) and 11 case-control studies.
HOW WERE THE STUDIES COMBINED?
A fixed effects model was
used to combine summary estimates of relative risks (RR). However, as evidence of heterogeneity was found Der Simonian and
Laird's random effects model(see Other Publications of Related Interest) was fitted to all subsets of studies. For case-control
studies odds ratios were used to approximate the RR. Three aspects of exposure to HRT were assessed: ever versus never use
(both jointly and separately for right and left colon), recency of use comparing current and past users and duration of use
contrasting users of more than 5 years with users of shorter duration.
HOW WERE THE DIFFERENCES BETWEEN STUDIES INVESTIGATED?
Heterogeneity was assessed
using a Chi-squared test. Specific exclusions or subsets of studies were used to identify significant sources of heterogeneity
and to assess methodological or other factors responsible for any observed heterogeneity.
Ever use versus never use
of HRT (n=19 studies).
There was substantial heterogeneity
across studies, this remained for subsets of studies defined by design, year of publication and adjustment for confounding
(p ranged from greater than 0.001 for all studies to 0.36 for studies published before 1990). The summary RR obtained using
a fixed effects meta-analysis was 0.82 (0.76, 0.89) indicating a protective effect of the use of HRT on colorectal cancer.
The summary RR from the random effects model was 0.81 (95% CI: 0.70, 0.93). Summary measures of effect varied little across
subgroups (fixed effects RRs ranged from 0.76 for studies which controlled for confounding to 0.93 for studies published before
Current verus past use
of HRT - n= 6 studies.
Studies of current use
showed evidence of heterogeneity (p=0.07), studies of past use appeared to be fairly homogeneous (p=0.48). The summary estimate
of the RR obtained for current use was 0.65 (95% CI: 0.54 to 0.79) this was less than that for past use (RR=0.78, 95% CI:
0.69, 0.88). Estimates for sub-groups within these categories (cohort studies only, case-control studies only and studies
published after 1990) were similar to the overall estimates.
Long (greater than or equal
to 5 years) versus short-term (greater than 5 years) use of HRT.
Both sub-sets of studies
showed evidence of heterogeneity (p=0.04 for those of short-term use and p=0.02 for long-term use). The summary estimate of
the RR obtained for short-term use was 0.84 (95% CI: 0.73, 0.97), this was greater than that for long-term use (RR=0.69, 95%
CI: 0.58, 0.82). All RR estimates for the subgroup (cohort studies only, case-control studies only and studies published after
1990) analyses were greater for studies of short-term duration compared to those of long-term duration when the estimates
for similar sub-groups were compared.
WAS ANY COST INFORMATION REPORTED?
The results suggest a small
but significant protective effect of the use of HRT on colon cancer. The finding of a dose-response with a greater effect
for longer duration of treatment is consistent with this finding.
A reasonable review of
the area. The literature search could have been improved by searching further databases and including unpublished studies
and those published in languages other than English and French, limiting the search on these factors may have resulted in
some important studies being missed. No details were provided on the participants included in the review limiting the applicability
of results. No formal validity assessment was carried out, however some methodological features of the studies were investigated
in the sensitivity analysis (study design and control of confounding). Study details and results of the analysis were clearly
presented. In view of the substantial heterogeneity between studies included in the main review a meta-analysis should not
have been attempted. Instead a meta-regression, in which possible sources of heterogeneity are controlled for, or a qualitative
analysis should have been presented. In view of these limitations, not a great deal of confidence can be placed in the author's
WHAT ARE THE IMPLICATIONS OF THE REVIEW?
Author stated that women
are unlikely to start HRT to reduce their risk of colon cancer, but establishing this chemo-preventive property of menopausal
hormones could help put into perspective the small increase in breast cancer risk reported in many studies as well as other
important health outcomes, such as cardiovascular disease, osteoporosis, and quality of life, in the decision to use or not
use these products. Additional studies are needed to estimate summary effects with more precision to better discriminate between
categories of users, and to establish a causal relationship.
OTHER PUBLICATIONS OF RELATED INTEREST
1. DerSimonian R, Laird
N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. 2. MacLennan SC, MacLennan AH, Ryan P. Colorectal
cancer and oestrogen replacement therapy. A meta-analysis of epidemiologic studies. Medical Journal of Australia 1995;162:491-3.
Ms. N Hebert-Croteau, Direction
de la Sante Publique de Montreal-Centre, 4835 Avenue Christophe-Colomb, Montreal, PQ H2J 3G8, Canada. E-mail:email@example.com
Copyright: University of
indexing assigned by NLM: Colonic Neoplasms [prevention & control]; Estrogen Replacement Therapy [statistics & numerical data]; Adult; Age Distribution; Aged; Canada [epidemiology]; Case-Control Studies; Cohort Studies; Colonic Neoplasms [epidemiology]; Confidence Intervals; Incidence; Middle Age; Randomized Controlled Trials; Risk Factors