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Oral contraceptive use is not associated with increased breast cancer risk

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
Department of Obstetrics and Gynecology
University of Florida Health Science Center
Director of Menopause and Bone Density Services
Medicus Diagnostic Center
Jacksonville, FL


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 g 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-g 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 g.

Level II-1 evidence

Comment. 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.

Comment. 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
Endocrinology and Metabolism
University of California, San Diego
San Diego, CA


Endocrine Reviews 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, McGill University, 1205 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A 1B1. E-mail: bsherwin@ego.psych.mcgill.ca

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, Hnigsmann 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.

Comment. 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.

Comment. 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
Wake Forest University School of Medicine
Winston-Salem, NC

Comment. 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
Regional Medical Center of Memphis
Memphis, TN


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% CI, 0.45-0.95).

Comment. 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 time.

David M. Herrington, MD
Associate Professor of Medicine/Cardiology
Wake Forest University School of Medicine
Winston-Salem, NC

Science's STKE | 25 June 2002

Estrogen Actions in the Brain

Ling Wang1, Sandra Andersson1, Margaret Warner2, and Jan-ke Gustafsson1,2*

1Department of Medical Nutrition, Karolinska Institute, NOVUM, S-141 86 Huddinge, Sweden.
2Department 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 ER 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 ER 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.

*Corresponding author. E-mail: jan-ake.gustafsson@mednut.ki.se



ABSTRACTS     JAMA  December 5, 2000--vol. 284 No. 21


Hormone Replacement Therapy and Peripheral

Arterial 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.

Results:          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:  witteman@epib.fgg.eur.nl).


A meta-analysis of hormone replacement therapy and colon cancer in women (Structured abstract)

NHS Centre for Reviews and Dissemination


Original article:

Hebert-Croteau 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.








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 were included.




Women, age not stated (assumed menopausal).




Incidence of colorectal tumours, specifically colon cancer.




Case control, cohort and randomised clinical trials (RCTs).




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 Interest).

Only studies published in French or English up to December 1996 were included. Unpublished studies were excluded.




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.




The authors do not state how the papers were selected for review, or how many of the authors performed the selection.




The authors do not state how the papers were assessed for validity, or how many of the authors performed the validity assessment.




The authors do not state how the data were extracted for the review, or how many of the authors performed the data extraction.




19 studies: 8 cohort studies (although one of these appears to be a randomised clinical trial) and 11 case-control studies.




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.




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 1990).

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.








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 conclusions.




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.




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:ncroteau@santepub-mtl.qc.ca








Copyright: University of York, 2000.




Subject 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



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