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
Department of Obstetrics and Gynecology
University of Florida Health Science Center
Menopause and Bone Density Services
Medicus Diagnostic Center
IN HEART DISEASE FOUND
By Joseph M. Kowalski, M.D.
Director of Investigational Interventions
Cardiovascular Institute of the South
A new epidemiological study suggests that the heart benefits of estrogen
supplements for post menopausal women continue quite late in life.
The study by the University of Pittsburgh Medical School found a 30 percent reduction in heart disease
in white women age 65 to 74 who take estrogen supplements. The findings reinforce previous government research that revealed
a 25 percent reduction in heart disease among women age 45 to 64 who took estrogen supplements.
Women rarely experience heart attacks before menopause. Researchers believe that estrogen offers some
protection against the blood vessel blockage that causes heart attacks and strokes. Studies suggest that estrogen increases
the "good" high-density lipoprotein (HDL) and lowers the "bad" low-density lipoprotein (LDL) in the blood, thus slowing the
rate at which plaque builds up in the arteries.
Another recent report that strongly suggested a connection between estrogen levels and lower rates
of heart attack came out of ongoing research at Harvard Medical School. The analysis of 32,000 nurses for four years in the
Nurses Cohort Study showed that those taking estrogen appeared to have one half the risk of heart attack of those not taking
The Harvard study also showed that women who go through early menopause (before age 40) have a significantly
higher risk of heart disease. The study and its findings link the ovaries and its hormones --- estrogen and progesterone ---
to heart health.
According to an article in the New England Journal of Medicine co-authored by investigators at Harvard
Medical School and its affiliated Brigham and Women's Hospital, "...post menopausal women who take estrogen generally have
lower rates of cardiovascular disease than women of similar age who do not take estrogen."
In the 1970s, when estrogen was first prescribed as a birth control measure for women, researchers
feared elevated doses of estrogen would put women at higher risk for stroke and high blood pressure. Studies in the past 35
years have not confirmed those fears. Instead, they persist in showing that estrogen supplements for post-menopausal women
provide a prolongation of the natural protection from heart disease they enjoyed in their child-bearing years. Nevertheless, women enjoying the heart disease-resisting benefits of
estrogen are in a minority. Only 15 to 30 percent of post-menopausal women in this country now take estrogen supplements --
in part because of concerns that it may be linked to an increase in the incidence of some cancers.
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 women’s 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
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).
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
David M. Herrington, MD
Associate Professor of Medicine/Cardiology
Forest University School of Medicine
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, women’s 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
The problem with many of the later studies is that they used a prostaglandin which blocked the therapeutic effect
of estrogen upon neuron.
Estrogen replacement therapy and risk of Alzheimer disease
Archives of Internal Medicine, Vol.
156 No. 19, October 28, 1996
A. Paganini-Hill and V. W. Henderson
Department of Preventive Medicine, University of Southern California
School of Medicine, Los Angeles, USA.
BACKGROUND: With Alzheimer disease emerging as a major public health problem, the identification of factors
that might prevent this disease are important. Estrogen loss associated with menopause may contribute to the
development of Alzheimer disease. OBJECTIVE: To evaluate the effects of different estrogen preparations,
varying dosages of estrogen, and duration of estrogen replacement therapy on the risk of Alzheimer disease in
postmenopausal women. STUDY DESIGN AND METHODS: A case-control study nested within a prospective cohort study
of residents of Leisure World Laguna Hills, a retirement community in Southern California. The cohort comprised 8877 women who were first mailed a health survey in 1981. Of
the 3760 female cohort members who died between 1981 and 1995, 248 women with Alzheimer disease or other
dementia diagnoses likely to represent Alzheimer disease (senile dementia, dementia, or senility) mentioned on
the death certificate were identified. Five controls were individually matched to each case according
to year of death and year of birth (+/- 1 year). RESULTS: The risk of Alzheimer disease and related dementia was
significantly reduced in estrogen users compared with nonusers (odds ratio, 0.65; 95% confidence interval,
0.49-0.88). The risk was reduced for both oral and nonoral (i.e., injections and/or creams) routes of administration.
The risk decreased significantly with both increasing dosages (P = .01) and increasing duration (P = .01)
of oral therapy with conjugated equine estrogen, the most commonly used estrogen preparation. Within each dose
category, the risk decreased with increasing duration of therapy, with the lowest observed risk in long-term
users who received high doses (odds ratio, 0.48; 95% confidence interval, 0.19-1.17). CONCLUSION: This study
suggests that estrogen replacement therapy may be useful for preventing or delaying the onset of Alzheimer
disease in postmenopausal women.