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.
 

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

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.
 

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.
 

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, 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.

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.
 

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.
 

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.
 

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.
 

Science's STKE | 25 June 2002

Estrogen Actions in the Brain

Ling Wang¹, Sandra Andersson¹, Margaret Warner², and Jan-Åke Gustafsson^1,2*

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 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.