Postmenopausal Estrogen Therapy Research Articles

Concomitant medication use in postmenopausal women using estrogen therapy.

To determine whether long-term postmenopausal estrogen therapy is associated with use of other prescription medications. Using computer pharmacy records from 1969 to 1973 for members of the Kaiser Permanente Medical Care Program in San Francisco, we identified the 215 most commonly used prescription medications in the pharmacy database and recorded their use by 232 postmenopausal long-term estrogen users and by 222 postmenopausal age-matched nonusers. These medications were grouped into 39 therapeutic classes. Classes of medications used by estrogen users and nonusers were compared. A statistically significant difference in use was seen for 21 of the 39 medication classes; of these 21 classes, 20 (95%) were used more frequently and 1 less frequently by estrogen users. Differences between estrogen users and nonusers were greatest for thyroid hormone preparations (estrogen user/nonuser multivariate odds ratio = 25.6, 95% confidence interval 5.9-112) and antimigraine preparations (11 recipients among estrogen users, none among nonusers). Postmenopausal women using estrogen were more likely than nonusers to use additional medications. Greater use of certain prescription medications by estrogen users than by nonusers should be considered in studying the health effects of estrogen replacement therapy.

Estrogen and Neural Plasticity

Converging clinical evidence suggests that postmenopausal estrogen therapy in women is associated with improved cognition and a reduced incidence of Alzheimer's disease. In experimental work, investigators have found estrogen to promote changes in synaptic plasticity within the nervous system. In this article, we review both the clinical and the experimental literature, and consider mechanisms of action of estrogen on neurons and synaptic plasticity, and how they might protect against the cognitive impairments of old age.

Postmenopausal estrogen therapy and depressive symptoms in older women.

Evidence regarding the effect of postmenopausal estrogen therapy on mood is limited. To determine whether postmenopausal estrogen therapy is associated with fewer depressive symptoms in elderly women, we conducted a cross-sectional study of 6, 602 white women ages 71 years or older who were recruited from population-based listings in Baltimore, Md; Minneapolis, Minn; Portland, Ore; and the Monongahela Valley, Pa. Use of estrogen and progestin was determined by interview. Participants completed the Geriatric Depression Scale short form (GDS) and were considered depressed if they reported 6 or more of 15 possible symptoms of depression. A total of 6.3% (72/1,150) of current estrogen users, 7.2% (142/1,964) of past estrogen users, and 9.0% (313/3,488) of never users reported 6 or more symptoms of depression (P =.004). Current estrogen users had a decreased risk of reporting 6 or more depressive symptoms, compared with not current (past or never) users of estrogen (odds ratio [OR], 0.7; 95% CI, 0.5 to 0.9; P =.01], adjusted for living alone, bilateral oophorectomy, current smoking, physical activity, social network, self-perceived health, cognitive function, functional status, and antidepressant use. However, excluding women who use estrogen or progestin alone, we were unable to find an association between current use of combined estrogen plus progestin therapy and depressive symptoms (adjusted OR, 0.8; 95% CI, 0.5 to 1.4; P =.5). This cross-sectional study found that current use of unopposed estrogen was associated with a decreased risk of depressive symptoms in older women. Additional studies are needed to understand the effect of combined estrogen and progestin therapy on the prevalence of depressive symptoms in older women.

Oestrogens and dementia.

The decline in circulating oestrogen concentrations that occurs after the menopause has the potential to impact Alzheimer's disease and other forms of dementia. Relevant actions include neurotrophic and neuroprotective effects; effects on acetylcholine and other neurotransmitters; and effects on proteins implicated in Alzheimer's disease pathogenesis. Since 1990, 14 case-control and cohort studies have considered the relation between postmenopausal oestrogen therapy and Alzheimer's disease. Most, but not all, report that oestrogen therapy is associated with a reduced Alzheimer risk of approximately one-half. Almost no epidemiological data address the potential link between oestrogen and other forms of dementia. Several small interventional trials have considered whether oestrogen might improve cognitive function of women with Alzheimer's disease. Data, however, are limited, and there is no compelling evidence that the short-term use of oestrogen monotherapy has a substantial impact on dementia symptoms. In summary, the use of oestrogen to reduce Alzheimer risk is biologically credible, and the preponderance of epidemiological evidence suggests that oestrogen therapy is indeed protective. This potentially important role of oestrogens for the primary prevention of Alzheimer's disease remains to be verified through well-designed randomized controlled trials.

Hormones and heart disease in women: Heart and Estrogen/Progestin Replacement Study in perspective.

Despite the nearly universal finding from observational studies that postmenopausal estrogen therapy reduces the risk of CHD and the multiple plausible mechanisms by which estrogen might reduce the risk of CHD, hormone therapy had no benefit in the only large randomized clinical trial to date. Although it is possible that estrogen taken over the long term actually reduces CHD risk, it is not reasonable to begin the regimen used in HERS to prevent new or recurrent heart disease, given the observed excess early risk. Given the possible long term benefit, women who are already taking hormone replacement therapy may elect to remain on it. Women who are undecided should be asked to consider participation in clinical trials. The HERS has dramatically illustrated the need for them.

Oral-contraceptive use and risk of hip fracture: a case-control study

Epidemiological studies indicate a protective effect of postmenopausal oestrogen therapy on the risk of osteoporotic fractures. Whether premenopausal oestrogen exposure in the form of oral contraceptives also reduces the risk of osteoporotic fractures remains uncertain. We did a population-based case control study of hip fracture among Swedish postmenopausal women, 50-81 years of age, through mailed questionnaires and telephone interviews. Of those women who were eligible, 1327 (82.5%) cases and 3312 (81.6%) randomly selected controls responded. 130 (11.6%) cases and 562 (19.1%) controls reported ever-use of oral contraceptives. Ever-use of oral contraceptives was associated with a 25% reduction in hip fracture risk (odds ratio 0.75 [95% CI 0.59-0.96]). Women who had ever used a high-dose pill (equivalent to > or = 50 microg ethinylestradiol per tablet) had a 44% lower risk for hip fracture than never-users (0.56 [0.42-0.75]). No overall trend was observed with duration of oral-contraceptive use, or time since last use. However, when making comparisons with women who have never used oral contraceptives, the odds ratios for hip-fracture were 0.69 (0.51-0.94) for use after age 40, 0.82 (0.57-1.16) for use at ages 30-39, and 1.26 (0.76-2.09) for use before age 30. Our results imply that in postmenopausal women, oral-contraceptive use late in reproductive life may reduce the risk of hip fracture, although we recognise the limitations of the case-control method.

Postmenopausal Estrogen Therapy And Selected (Less-Often-Considered) Disease Outcomes

To review the association between postmenopausal estrogen therapy and chronic conditions not usually considered in risk-benefit reviews. Ten-year literature review (1989-1998) of case series and epidemiologic studies with risk estimates and 95% confidence intervals. Osteoarthritis and rheumatoid arthritis, the most extensively studied conditions, show no consistent association with hormone therapy. Two studies of systemic lupus erythematosus show a nearly three-fold increased risk apparent after 2 or more years of hormone therapy. Single studies suggest an increased risk of pancreatitis, asthma, and Raynaud's syndrome. Evidence for a reduced risk of diabetes mellitus is not compelling. Cataracts and migraine are either increased or decreased by hormone therapy. Among the associations considered here, only an increased risk of gallbladder disease and venous thromboembolic disease have been confirmed in clinical trials of hormone replacement therapy. Further studies are needed.

Beneficial Effects of Estrogen in Syndrome X of Postmenopausal Women

Background:There are many reports about the correlation between cardiovascular disorders and estrogen deficiency in postmenopausal women. The purpose of current study is to know that postmenopausal estrogen therapy may affect the lipid metabolism and endogenous fibrinolytic system and exercise tolerance. Method: We investigated the relation of estrogen treatment (srogen 0.625 mg/day to serum lipid levels, angiotensin converting enzyme activity, plasminogen activator inhibitor-1 and parameters of treadmill test in 22 post- menopausal women of normal coronary artery with abnormal exercise test complained with chest pain accompanied by postmenopausal symptoms. Results:Estrogen treatment significantly elevated the serum HDL- cholesterol level (42.8 to 50.1 mg/dl, p<0.05 and reduced the PAI-1 level (16.2 to 10.4 ng/dl, p<0.01 without considerable side effects. During the exercise test, the positivity appearance time and total exercise duration is significantly increased after estrogen treatment. Conclusion:The postmenopausal use of estrogen favorably changed the lipid level, fibrinolytic system and might improve the microcirculation which may protect against the ischemic heart disease risk without significant side effects. (Korean Circulation J 1999;29(3 :298-305

Androgen therapy in the aging male: assessing the effect on heart disease

Arterial diseases such as myocardial infarction and stroke are major causes of male morbidity and mortality. Steroid hormones have been linked to the process of atherosclerosis that often underlies these conditions, both through indirect mechanisms (such as lipoprotein metabolism) and direct mechanisms (such as vascular reactivity). Attempts to develop androgen therapies for the aging male are hindered by the perception of such steroids as being atherogenic. In part, this prejudice is based on the higher rates of arterial disease seen in young men compared to young women, together with the sporadic reports of premature vascular disease in athletes who abuse anabolic androgenic steroids. There are as yet no acceptable clinical trial or epidemiological data on arterial disease in men treated with androgens. The claim that male castration delays the onset of arterial disease is not based on fact. The metabolic risk profile in androgen users involves both positive and negative changes. ‘Risk factor’ studies must be interpreted with caution, given the recent demonstration of the failure of postmenopausal estrogen therapy to prevent heart disease. Studies in fat-fed primates have their limitations, as do studies of androgen therapy in women. In contrast, much of the positive vascular data involve studies of men with coronary heart disease. Overall, the existing evidence suggests that androgens are as likely to prevent arterial disease as they are to cause it. Consideration should be given to undertaking randomized, placebo-controlled trials using non-invasive methods of arterial assessment, such as carotid artery intima-media thickness.

Androgen effects on the central nervous system in the postmenopausal woman.

Interest in the effects of androgens on the central nervous system (CNS) in postmenopausal women dates back to at least fifty years. The mechanisms of action of androgens on the CNS are extremely complex and multi-faceted. Much data has been accumulated in recent years that suggest a beneficial role of androgens in several aspects of CNS function. These include positive effects on mood, cognition, memory, and libido. The information continues to be preliminary in nature and requires further investigations. There is evidence of altered androgen metabolism triggered by exogenous postmenopausal estrogen therapy. While promising, the current body of evidence does not yet support the routine addition of androgens to postmenopausal hormone therapy.

Postmenopausal hormone replacement therapy and autoantibodies against oxidized LDL

Objectives: Oxidative modification of low-density lipoprotein (oxLDL) has been suggested to play an important role in the pathogenesis of atherosclerosis, and autoantibodies against oxLDL have recently found to reflect this process. The antioxidant effect and inhibition of LDL oxidation may be one of the cardioprotective mechanisms of postmenopausal estrogen therapy. Methods: The effects of postmenopausal hormone replacement therapy (HRT) on the concentrations of serum lipids and oxLDL autoantibodies were studied in a population-based prospective 1-year study with 64 early postmenopausal women (mean age 52.2±0.4 (S.E.M.) years). The participants were randomized into two treatment groups: HRT-group: Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate alone or in combination with vitamin D 3, 300 IU/day+calcium lactate, 500 mg/day ( n=31) and the non-HRT-group: Calcium lactate, 500 mg/day alone or in combination with vitamin D 3, 300 IU/day ( n=33). The groups were well matched regarding age, body mass index and baseline serum lipid concentrations. Results: The serum concentrations of total cholesterol and LDL-cholesterol decreased in the HRT-group (4.1%, P=0.05 and 6.4%, P=0.03, respectively, paired t-test) but did not change in the non-HRT-group. No changes in the serum concentrations of HDL-cholesterol or triglycerides were observed. Additionally, no changes in oxLDL autoantibody concentrations were observed in either group. Conclusions: Although 1-year HRT lowered serum total- and LDL-cholesterol levels, it did not influence oxLDL antibody titers. On the basis of the present results we cannot question the possibility of there being beneficial effects of HRT on the oxidative modification of LDL. However, this effect is not reflected in the levels of oxLDL autoantibodies.

Estrogen therapy in postmenopausal women: effects on cognitive function and dementia.

Several studies have suggested that estrogen replacement therapy in postmenopausal women improves cognition, prevents development of dementia, and improves the severity of dementia, while other studies have not found a benefit of estrogen use. To determine whether postmenopausal estrogen therapy improves cognition, prevents development of dementia, or improves dementia severity. We performed a literature search of studies published from January 1966 through June 1997, using MEDLINE, manually searched bibliographies of articles identified, and consulted experts. Studies that evaluated biological mechanisms of estrogen's effect on the central nervous system and studies that addressed the effect of estrogen on cognitive function or on dementia. We reviewed studies for methods, sources of bias, and outcomes and performed a meta-analysis of the 10 studies of postmenopausal estrogen use and risk of dementia using standard meta-analytic methods. Biochemical and neurophysiologic studies suggest several mechanisms by which estrogen may affect cognition: promotion of cholinergic and serotonergic activity in specific brain regions, maintenance of neural circuitry, favorable lipoprotein alterations, and prevention of cerebral ischemia. Five observational studies and 8 trials have addressed the effect of estrogen on cognitive function in nondemented postmenopausal women. Cognition seems to improve in perimenopausal women, possibly because menopausal symptoms improve, but there is no clear benefit in asymptomatic women. Ten observational studies have measured the effect of postmenopausal estrogen use on risk of developing dementia. Meta-analysis of these studies suggests a 29% decreased risk of developing dementia among estrogen users, but the findings of the studies are heterogeneous. Four trials of estrogen therapy in women with Alzheimer disease have been conducted and have had primarily positive results, but most have been small, of short duration, non-randomized, and uncontrolled. There are plausible biological mechanisms by which estrogen might lead to improved cognition, reduced risk for dementia, or improvement in the severity of dementia. Studies conducted in women, however, have substantial methodologic problems and have produced conflicting results. Large placebo-controlled trials are required to address estrogen's role in prevention and treatment of Alzheimer disease and other dementias. Given the known risks of estrogen therapy, we do not recommend estrogen for the prevention or treatment of Alzheimer disease or other dementias until adequate trials have been completed.

Estrogen and Progestin Compared With Simvastatin for Hypercholesterolemia in Postmenopausal Women

Background Postmenopausal estrogen therapy has favorable effects on serum lipoproteins in women with normal serum lipid levels, but the effect of combined estrogen and progestin therapy on lipoproteins in women with hypercholesterolemia has not been determined, nor has it been directly compared with the effect of conventional lipid-lowering therapy. Methods In a randomized crossover trial, we studied 58 postmenopausal women with fasting serum total cholesterol levels greater than 250 mg per deciliter. Each woman received simvastatin (10 mg daily) for eight weeks and postmenopausal hormone therapy (up to 1.25 mg of conjugated equine estrogens daily, along with 5 mg of medroxyprogesterone acetate daily) for eight weeks, with an eight-week washout period between the two treatment phases. Results At base line, the mean (±SD) cholesterol values were as follows: total cholesterol, 305±39 mg per deciliter; high-density lipoprotein (HDL) cholesterol, 62±19 mg per deciliter; and low-density lipoprotein (LDL) chole...

Does postmenopausal estrogen administration increase the risk of breast cancer? Contributions of animal, biochemical, and clinical investigative studies to a resolution of the controversy.

Despite nearly six decades of epidemiological studies, meta-analyses, and reviews, there is still considerable controversy in the literature about the question, does postmenopausal estrogen administration increase the risk of breast cancer? In an effort to resolve the controversy, a number of animal, biochemical, and clinical investigative studies in this field have been reviewed. The following summary formulation is proposed: 1. Administration of estrogen is inherently capable of promoting the growth of breast cancer, and therefore of increasing the incidence of clinical breast cancer. 2. Human response to estrogen is like that of the low-cancer-incidence strains of mice studied by Lacassagne, in that large doses and prolonged administration are required to induce clinical breast cancer. 3. The blood levels of estradiol produced by the usual doses of postmenopausal estrogen are relatively low, equivalent to those of the follicular phase of the menstrual cycle. These levels may be near the threshold for producing breast-cancer-promoting effects; therefore, the tumor response will vary greatly in different populations, depending on genetic susceptibility factors: a. The prevalence of a family history of premenopausal breast cancer in a first-degree relative. b. The prevalence of abnormal BRCA1, BRCA2, and p53 genes. c. The prevalence of increased 16 alpha-hydroxylation of estradiol. d. The prevalence of smokers who are slow acetylators. 4. Consumption of alcohol (5 grams or more daily) along with the postmenopausal estrogen administration results in elevation of blood estradiol levels to values equivalent to those of the periovulatory peak of the menstrual cycle, which may be well above the threshold for producing breast-cancer-promoting effects in all women. The risk for cancer will therefore be uniformly increased in women who use alcohol and take estrogen. 5. Increased risk of breast cancer from postmenopausal estrogen administration can be eliminated by taking two synergistic steps: a. Eliminating alcohol consumption, or at least keeping it well below an average of 5 grams daily (equivalent to 2/3 ounce of whiskey or 3 ounces of wine). b. Diminishing the capacity to 16 alpha-hydroxylate estradiol, either through pharmacological agents such as indole-3-carbinol or through increased consumption of cruciferous vegetables. It is concluded that despite the inherent ability of postmenopausal estrogen therapy to increase the risk of breast cancer in theory, the increased risk can be eliminated in practice by minimizing or eliminating consumption of alcohol and ingesting pharmacological or dietary agents that reduce the 16 alpha-hydroxylation of estradiol.

Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease.

The goal of this study was to determine whether use of postmenopausal estrogen (Premarin®, Wyeth-Ayerst, Philadelphia, PA) in women with autosomal dominant polycystic kidney disease (ADPKD) increases liver, hepatic cyst, or kidney volume. We also determined whether clinical symptoms correlated with the volume of either the liver or kidneys. Eight women off estrogen (control, C) and 11 others on estrogen (Premarin®, E) were studied basally and after 1 year. The two groups were similar in age, weight, age at menarche, and gravida. Volumes of total liver, hepatic cysts, hepatic parenchyma, and total kidney were measured by a validated computed tomography (CT) technique. Estrogen treatment was associated with a selective increase in total liver volume (E vs. C: Δ = 7% +/- 12% vs. -2% +/- 8%, P < .03) and no change in kidney volume (E vs. C: Δ = 0% +/- 6% vs. -2% +/- 6%, P = NS). Symptoms were common, regardless of estrogen treatment (abdominal pain 60%, shortness of breath 40%, or both 35%). Patients with symptoms of abdominal pain and shortness of breath had significantly increased hepatic volumes (P < .03) but similar kidney volume compared with patients without symptoms. We conclude that estrogen treatment of postmenopausal ADPKD women is associated with selective liver enlargement and that abdominal symptoms in ADPKD patients may be because of extensive hepatic cystic disease. (Hepatology 1997 Nov;26(5):1282-6)

Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease.

The goal of this study was to determine whether use of postmenopausal estrogen (Premarin, Wyeth-Ayerst, Philadelphia, PA) in women with autosomal dominant polycystic kidney disease (ADPKD) increases liver, hepatic cyst, or kidney volume. We also determined whether clinical symptoms correlated with the volume of either the liver or kidneys. Eight women off estrogen (control, C) and 11 others on estrogen (Premarin, E) were studied basally and after 1 year. The two groups were similar in age, weight, age at menarche, and gravida. Volumes of total liver, hepatic cysts, hepatic parenchyma, and total kidney were measured by a validated computed tomography (CT) technique. Estrogen treatment was associated with a selective increase in total liver volume (E vs. C: delta = 7% +/- 12% vs. -2% +/- 8%, P < .03) and no change in kidney volume (E vs. C: delta = 0% +/- 6% vs. -2% +/- 6%, P = NS). Symptoms were common, regardless of estrogen treatment (abdominal pain 60%, shortness of breath 40%, or both 35%). Patients with symptoms of abdominal pain and shortness of breath had significantly increased hepatic volumes (P < .03) but similar kidney volume compared with patients without symptoms. We conclude that estrogen treatment of postmenopausal ADPKD women is associated with selective liver enlargement and that abdominal symptoms in ADPKD patients may be because of extensive hepatic cystic disease.

The effect of postmenopausal estrogen therapy on the risk of non-insulin-dependent diabetes mellitus.

This study examined the effect of postmenopausal estrogen replacement therapy on the incidence of non-insulin-dependent diabetes in women. Postmenopausal women aged 50 through 70 years (n=848) without diagnosed diabetes at baseline were followed for 10 to 15 years for incident diabestes. Over the average 11.5 year follow-ip, there were 105 new cases of diabetes. The age-adjusted relative-risk for development of diabetes was nonsignificantly lower for women with continuous estrogen replacement therapy use than for never users. After adjustment for major covariates, a nonsignificant linear trend with increasing duration of estrogen replacement therapy was reversed. This study suggests that previous results showing a reduced risk of diabetes in women using estrogen may have been due to selection bias regarding who is prescribed estrogen, confounding factors, or differential diagnostic efforts.

Timing of postmenopausal estrogen for optimal bone mineral density. The Rancho Bernardo Study.

To determine the effect of the timing of initiation and the duration of postmenopausal estrogen therapy on bone mineral density (BMD). Cross-sectional study. White, middle-class to upper middle-class community-dwelling women. A total of 740 women aged 60 to 98 years who participated in a study of osteoporosis. Questionnaire, validated medication use, and height and weight. Bone mineral density at the ultradistal radius and midshaft radius using single-photon absorptiometry (SPA) and at the hip and lumbar spine using dual-energy x-ray absorptiometry (DEXA). Of the 740 women, 69% had used oral estrogen after menopause and 30% were current users. Five groups of estrogen use were identified: never users, past users who started at menopause, past users who started after age 60 years, current users who started after age 60 years, and current users who started at menopause. At all 4 bone sites, current users who started at menopause had the highest BMD levels, which were significantly higher than never users or past users who started at menopause (with 10 years' duration of use). These differences persisted after controlling for all major risk factors for osteoporosis. Among current users, there was no significant difference in BMD levels at any site between those who started estrogen at menopause (with 20 years of use) and those who started after age 60 years (with 9 years of use). Estrogen initiated in the menopausal period and continued into late life is associated with the highest bone density. Nevertheless, estrogen begun after age 60 years and continued appears to offer nearly equal bone-conserving benefit.

Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women

Postmenopausal oestrogen therapy reduces the risk of osteoporosis and cardiovascular diseases but is associated with an increased risk of endometrial cancer. We have assessed the impact of a regimen of oestrogen with cyclic progestagen on risk of endometrial cancer for postmenopausal women. We did a population-based case-control study of women aged 45-74 years in western Washington State, USA. Cases were identified from a regional cancer registry as having histologically confirmed endometrial cancer during 1985-91. 832 (72%) of 1154 eligible cases completed interviews. Controls were identified by random digit dialling, screened for intact uterus, frequency matched for age and county, and randomly assigned a reference date within 1985-91. Interviews with 1114 (73%) of 1526 eligible controls were done. The women provided information about use of hormone replacement therapy, and reproductive and medical history before diagnosis date (cases) or reference date (controls). Relative to women who had never used hormones (for > 6 months), women who had taken unopposed oestrogen had a four-fold increase (95% CI 3.1-5.1) in risk of endometrial cancer. Women who used a combined therapy of oestrogen with cyclic progestagen (eg. medroxyprogesterone acetate) had a relative risk of 14 (1.0-1.9). Among women with fewer than 10 days of added progestagen per month, the relative risk was 3.1 (1.7-5.7). Whereas that for women with 10-21 days of added progestagen was 1.3 (0.8-2.2). The use of these combined regimens for 5 or more years was associated with risks of 3.7 (1.7-8.2) and 2.5 (1.1-5.5), respectively, relative to non-users of hormones. Postmenopausal women who use combined therapy of oestrogen with cyclic progestagen on a long-term basis have an increased risk of endometrial cancer compared with those who are not on hormone replacement, even when progestagen is added for 10 or more days per month. This increase is much smaller than that associated with unopposed oestrogen, but needs to be confirmed.

Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture.

It was a great privilege to be asked to give the 1995 Ancel Keys lecture, following five very distinguished colleagues [Geoffrey Rose, Henry Blackburn, Jeremiah Stamler, Fred Epstein, and William Kannel] and honoring Ancel Keys. It is difficult to imagine how little we would know about CHD without their contributions. The subject of my lecture, “Why are women so superior with regard to coronary heart disease?,” is surely one of the most interesting of all epidemiological questions. My intention is to illustrate methodological problems and review old and new provocative results, making inferences from a variety of disciplines. My focus is on the origin of the gender gap, not postmenopausal estrogen therapy. There will be no conclusions, only reconstruction. My lecture is outlined in Fig 1⇓. Figure 1. Lecture outline. ### Unhealthy Behaviors For years it was thought that the excess male mortality was explained by unhealthy behaviors that were more socially acceptable for men than women. These behaviors might include cigarette smoking, heavy alcohol use, eating more red meat and fewer fruits and vegetables, and exposure to physical hazards. The usual view was that differences in behavior were more important determinants of the higher male mortality than inherent sex differences in physiology.1 More recently, studies adjusting for unhealthy behaviors show that they contribute to but do not fully explain the increased risk of CHD in men.2 ### Work Outside the Home It was also a popular premise that men were harmed by the stresses of the workplace; women were apparently protected by being at home relaxing with the children and the washing up. As Bernard notes, “. . . the husband went forth each day to grapple with the cruel cold world and the wife remained in the ‘heart’ of the home, generating sweetness and light to bind the wounds inflicted on the husband and …