Women's Health

Women's Health

From Harrison's Principles of Internal Medicine 17th Ed.

INTRODUCTION

The study of biologic differences between sexes has emerged as a distinct scientific discipline. A report from the Institute of Medicine (IOM) found that sex has a broad impact on biologic and disease processes and succinctly concluded: sex matters. The National Institutes of Health established the Office of Research on Women's Health in 1990 to develop an agenda for future research in the field. In parallel, women's health has become a distinct clinical discipline with a focus on disorders that are disproportionately represented in women. The integration of women's health into internal medicine and other specialties has been accompanied by novel approaches to health care delivery, including greater attention to patient education and involvement in disease prevention and medical decision-making.

The IOM report recommended the term sex difference to describe biologic processes that differ between males and females and gender difference for features related to social influences.
DISEASE RISK : REALITY AND PERCEPTION

The leading causes of death are the same in women and men: (1) heart disease, (2) cancer, and (3) cerebrovascular disease (Table 1; Fig. 1). The leading cause of cancer death, lung cancer, is the same in both sexes, with higher mortality rates than breast, colon, and prostate cancer combined. Breast cancer is the second leading cause of cancer death in women, but it causes about 60% fewer deaths than lung cancer. Men are substantially more likely to die from suicide, homicide, and accidents than women.

Table 1 Deaths and Percent of Total Deaths for the 15 Leading Causes of Death by Sex in the United States, 2003

Women Men Cause of Death Rank Deaths Total Deaths, % Rank Deaths Total Deaths, % Diseases of heart 1 348,994 28.0 1 336,095 28.0 Malignant neoplasms 2 268,912 21.6 2 287,990 24.0 Cerebrovascular diseases 3 96,263 7.7 4 61,426 5.1 Chronic lower respiratory diseases 4 65,668 5.3 5 60,714 5.1 Alzheimer's disease 5 45,122 3.6 10 18,335 1.5 Diabetes mellitus 6 38,781 3.1 6 35,438 2.9 Accidents 7 38,745 3.1 3 70,532 5.9 Influenza, pneumonia 8 36,385 2.9 7 28,778 2.4 Nephritis, nephrotic syndrome, nephrosis 9 21,972 1.8 9 20,481 1.7 Septicemia 10 19,082 1.5 12 14,987 1.2 Essential (primary) hypertension, hypertensive renal disease 11 13,727 1.1 15 8,213 0.7 Chronic liver disease, cirrhosis 12 9,591 0.8 11 17,912 1.5 Parkinson's disease 13 7,817 0.6 14 10,180 0.8 Intentional self-harm (suicide) 14 6,281 0.5 8 25,203 2.1 Assault (homicide) 15 3,850 0.3 13 13,882 1.2

Source: Data from Centers for Disease Control and Prevention: National Vital Statistics Reports, Vol. 54, No. 13, April 19, 2006, Table 12, http://www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_13.pdf.

Figure 1. Death rates per 100,000 population for 2003 by 5-year age groups in U.S. women. Note that the scale of the y-axis is increased by tenfold in the graph on the right compared to that on the left. Accidents and HIV/AIDS are the leading causes of death in young women 20–34 years of age. Accidents, breast cancer, and ischemic heart disease (IHD) are the leading causes of death in women 35–44 years of age. Breast cancer is the leading cause of death in women 45–49 years of age, and IHD becomes the leading cause of death in women beginning at 50 years of age. In older women, IHD remains the leading cause of death, cerebrovascular disease becomes the second leading cause of death, and lung cancer is the leading cause of cancer-related deaths. AD, Alzheimer's disease; Ca, cancer; CLRD, chronic lower respiratory disease; DM, diabetes mellitus. (Data adapted from Centers for Disease Control and Prevention,www.cdc.gov/nchs/data/statab/Mortfinal2003_worktable210r.pdf.)

Women's risk for many diseases increases at menopause, which occurs at a median age of 51.4 years. In the industrialized world, women spend one-third of their lives in the postmenopausal period. Estrogen levels fall abruptly at menopause, inducing a variety of physiologic and metabolic responses. Rates of cardiovascular disease increase and bone density begins to decrease rapidly after menopause. In the United States, women live on average about 5 years longer than men, with a life expectancy at birth in 2004 of 80.4 years, compared to 75.2 years in men. Elderly women outnumber elderly men, so that age-related conditions, such as hypertension, have a female preponderance. However, the difference in life expectancy between men and women has decreased an average of 0.1 year every year since 1980, and, if this convergence in mortality figures continues, it is projected that mortality rates will be similar by 2054.

Women's perception of disease risk is often inaccurate. Public awareness campaigns have resulted in almost 50% of U.S. women knowing that cardiovascular disease is the leading cause of death in women. Nevertheless, the condition they fear most is breast cancer, despite the fact that death rates from breast cancer have been falling since the 1990s. In any given decade of life, a woman's risk for breast cancer never exceeds 1 in 34. Although a woman's lifetime risk of developing breast cancer if she lives past 85 years is about 1 in 9, it is much more likely that she will die from cardiovascular disease than from breast cancer. In other words, many elderly women have breast cancer but die from other causes. Similarly, a minority of women are aware that lung cancer is the leading cause of cancer death in women. These misconceptions are unfortunate as they perpetuate inadequate attention to modifiable risk factors, such as dyslipidemia, hypertension, and cigarette smoking.

Physicians are also less likely to recognize women's risk for cardiovascular disease. A survey of physicians in 2004 found that women with intermediate risk for cardiovascular disease, according to Framingham risk score, were significantly more likely to be assigned to a lower risk category than men with similar risk profiles. Moreover, when presented with actors portraying patients with chest pain, physicians' estimates for probability of coronary heart disease (CHD) were significantly lower for women than for men and lower for black women than for white women. These perceptions on the part of both the patient and her physician lead to important differences in cardiac care.

Alzheimer's Disease

Alzheimer's disease (AD) affects approximately twice as many women as men. Because the risk for AD increases with age, part of this sex difference is accounted for by the fact that women live longer than men. However, additional factors likely contribute to the increased risk for AD in women, including sex differences in brain size, structure, and functional organization. There is emerging evidence for sex-specific differences in gene expression, not only for genes on the X and Y chromosomes but also for some autosomal genes. Estrogens have pleiotropic genomic and nongenomic effects on the central nervous system, including neurotrophic actions in key areas involved in cognition and memory. Women with AD have lower endogenous estrogen levels compared to women without AD. These observations have led to the hypothesis that estrogen is neuroprotective.

Some studies have suggested that estrogen administration improves cognitive function in nondemented postmenopausal women as well as in women with AD, and several observational studies have suggested that postmenopausal hormone therapy (PHT) may decrease the risk of AD. However, recent placebo-controlled trials have found no improvement in disease progression or cognitive function after up to 15 months of PHT in women with AD. Further, the Women's Health Initiative Memory Study (WHIMS), an ancillary study in the Women's Health Initiative (WHI), found no benefit compared to placebo of estrogen alone [combined continuous equine estrogen (CEE), 0.625 mg qd] or estrogen with progestin [CEE, 0.625 mg qd, and medroxyprogesterone acetate (MPA), 2.5 mg qd] on cognitive function or the development of dementia in women 65 years and older. Indeed, there was a significantly increased risk for both dementia and mild cognitive impairment in women receiving hormone therapy. The possible explanations for the discrepant results between the observational studies and the randomized clinical trials remain unclear.

Coronary Heart Disease

There are major sex differences in CHD, the leading cause of death in men and women in developed countries. CHD death rates have been falling in men over the past 30 years, but they have been increasing in women. Since 1984, more women than men have died of cardiovascular disease. Gonadal steroids have major effects on the cardiovascular system and lipid metabolism. Estrogen increases high-density lipoprotein (HDL) and lowers low-density lipoprotein (LDL), whereas androgens have the opposite effect. Estrogen has direct vasodilatory effects on the vascular endothelium, enhances insulin sensitivity, and has antioxidant properties. There is a striking increase in CHD after both natural and surgical menopause suggesting that endogenous estrogens are cardioprotective. Women also have longer QT intervals on electrocardiograms, which increases their susceptibility to certain arrhythmias. Animal studies suggest that the sex difference in QT interval duration is caused by sex steroid effects on cardiac repolarization, in part related to their effects on cardiac voltage-gated potassium channels; there is a lower density of the rapid component (I_Kr) of the delayed rectifier potassium current (I_K) in females.

CHD presents differently in women, who are usually 10–15 years older than their male counterparts and are more likely to have comorbidities such as hypertension, congestive heart failure, and diabetes mellitus (DM). In the Framingham study, angina was the most frequent initial symptom of CHD in women, whereas myocardial infarction was the most frequent initial presentation in men. Women more often have atypical symptoms, such as nausea, vomiting, indigestion, and upper back pain.

Women with myocardial infarction are more likely to present with cardiac arrest or cardiogenic shock, whereas men are more likely to present with ventricular tachycardia. Further, younger women with myocardial infarction are more likely to die than men of similar age, with women under 50 experiencing twice the mortality rate of men, even after adjustment for differences in disease severity and management. Indeed, the younger the woman, the greater the risk of death from myocardial infarction compared to men (Fig. 2).

Fig.2 Rates of death during hospitalization for myocardial infarction among women and men according to age. The overall mortality rate during hospitalization was 16.7% among women and 11.5% among men but was twice the rate in women <50>p(From V Vaccarino et al: N Engl J Med 341:217, 1999; with permission.) <.001).

Physicians are less likely to suspect heart disease in women with chest pain and less likely to perform diagnostic and therapeutic cardiac procedures in women. In addition, there are sex differences in the accuracy of certain diagnostic procedures. The exercise electrocardiogram has substantial false-positive as well as false-negative rates in women compared to men. Women are less likely to receive therapies such as angioplasty, thrombolytic therapy, coronary artery bypass grafts (CABGs), beta blockers, or aspirin. There are also sex differences in outcomes when women with CHD do receive therapeutic interventions. Women undergoing CABG surgery have more advanced disease, a higher perioperative mortality rate, less relief of angina, and less graft patency; however, 5- and 10-year survival rates are similar. Women undergoing percutaneous transluminal coronary angioplasty have lower rates of initial angiographic and clinical success than men, but they also have a lower rate of restenosis and a better long-term outcome. Women may benefit less and have more frequent serious bleeding complications from thrombolytic therapy than do men. Factors such as older age, more comorbid conditions, and more severe CHD in women at the time of events or procedures appear to account in part for the observed sex differences.

Elevated cholesterol levels, hypertension, smoking, obesity, low HDL cholesterol levels, DM, and lack of physical activity are important risk factors for CHD in both men and women. Total triglyceride levels are an independent risk factor for CHD in women but not in men. Low HDL cholesterol and DM are more important risk factors for CHD in women than in men. Smoking is an important risk factor for CHD in women—it accelerates atherosclerosis, exerts direct negative effects on cardiac function, and is associated with an earlier age of menopause. Cholesterol-lowering drugs are equally effective in men and women for primary and secondary prevention of CHD. However, because of perceptions that women are at lower risk for CHD, they receive fewer interventions for modifiable risk factors than do men. In contrast to men, randomized trials have shown that aspirin was not effective in the primary prevention of CHD in women; it did significantly reduce the risk of ischemic stroke. Secondary prevention in women with known CHD is also suboptimal. At baseline, only about 30% of women enrolled in the Heart and Estrogen/progestin Replacement Study (HERS), a secondary prevention trial in women with established CHD, were taking beta blockers, and only 45% received lipid-lowering medications.

The sex differences in CHD prevalence, beneficial biologic effects of estradiol on the cardiovascular system, and reduced risk for CHD in observational studies of women receiving PHT led to the widespread use of PHT for the prevention of CHD. However, the WHI, which studied more than 16,000 women on CEE plus MPA or placebo and more than 10,000 women with hysterectomy on CEE alone or placebo, did not demonstrate a benefit of PHT for the primary or secondary prevention of CHD. In addition, CEE plus MPA was associated with an increased risk for CHD, particularly in the first year of therapy, whereas CEE alone neither increased nor decreased CHD risk. There was no evidence for cardioprotective effects of estrogens in smaller randomized trials that used either oral or transdermal estradiol, arguing against the hypothesis that the type of estrogen or its route of administration accounted for the lack of CHD risk reduction. In the WHI, there was a suggestion of a reduction in CHD risk in women ages 50–59 at baseline who received CEE alone. This finding suggests that the time at which PHT is initiated is critical for cardioprotection and is consistent with the "timing hypothesis." According to this hypothesis, PHT has differential effects depending on the stage of atherosclerosis; adverse effects are seen with advanced, unstable lesions. This hypothesis is currently under investigation in randomized clinical trials.

Diabetes Mellitus

Women are more sensitive to insulin than men. Despite this, the prevalence of type 2 DM is similar in men and women. There is a sex difference in the relationship between endogenous androgen levels and DM risk: higher bioavailable testosterone levels are associated with increased risk in women, whereas lower bioavailable testosterone levels are associated with increased risk in men. Polycystic ovary syndrome and gestational DM—common conditions in premenopausal women—are associated with a significantly increased risk for type 2 DM. Premenopausal women with DM lose the cardioprotective effect of female sex and have identical rates of CHD to those in males. These women have impaired endothelial function and reduced coronary vasodilatory responses, which may predispose to cardiovascular complications. In individuals with DM, women have a greater risk for myocardial infarction than men. Women with DM are more likely to have left ventricular hypertrophy. In the WHI, CEE plus MPA significantly reduced the incidence of DM, whereas with CEE alone there was a trend only toward decreased DM incidence.

Hypertension

After age 60, hypertension is more common in U.S. women than in men, largely because of the high prevalence of hypertension in older age groups and the longer survival of women. Isolated systolic hypertension is present in 30% of women >60 years. Sex hormones affect blood pressure. Both normotensive and hypertensive women have higher blood pressure levels during the follicular phase than during the luteal phase. In the Nurses Health Study, the relative risk of hypertension was 1.8 in current users of oral contraceptives, but this risk is lower with the newer low-dose contraceptive preparations. PHT is not associated with hypertension. Among secondary causes of hypertension, there is a female preponderance of renal artery fibromuscular dysplasia.

The benefits of treatment for hypertension have been dramatic in both women and men. In a meta-analysis of the effects of hypertension treatment, the Individual Data Analysis of Antihypertensive Intervention Trial found a reduction of risk for stroke and for major cardiovascular events in women. The effectiveness of various antihypertensive drugs appears to be comparable in women and men; however, women may experience more side effects. For example, women are more likely to develop cough with angiotensin-converting enzyme inhibitors.

Autoimmune Disorders

Most autoimmune disorders occur more commonly in women than in men; these include autoimmune thyroid and liver diseases, lupus, rheumatoid arthritis (RA), scleroderma, multiple sclerosis (MS), and idiopathic thrombocytopenic purpura. However, there is no sex difference in the incidence of type 1 DM, and ankylosing spondylitis occurs more commonly in men. There are relatively few differences in bacterial disease infection rates in men and women. In general, sex differences in viral diseases can be accounted for by differences in behaviors, such as exposures or rates of immunization. Sex differences in both immune responses and adverse reactions to vaccines have been reported. For example, there is a female preponderance of postvaccination arthritis.

The mechanisms for these sex differences remain obscure. Adaptive immune responses are more robust in women than in men, which may be explained by the stimulatory actions of estrogens and the inhibitory actions of androgens on the cellular mediators of immunity. Consistent with an important role for gonadal hormones, there is variation in immune responses during the menstrual cycle, and the activity of certain autoimmune disorders is altered by castration or pregnancy (e.g., RA and MS may remit during pregnancy). Nevertheless, the majority of studies show that exogenous estrogens and progestins in the form of PHT or oral contraceptives do not alter autoimmune disease incidence or activity. Exposure to fetal antigens, including circulating fetal cells that persist in certain tissues, has been speculated to increase the risk of autoimmune responses. There is clearly an important genetic component to autoimmunity, as indicated by the familial clustering and HLA association of many such disorders. However, HLA types are not sexually dimorphic.

HIV Infection

Women account for almost 50% of the 40 million persons infected with HIV-1 worldwide. AIDS is an important cause of death in younger women (Fig. 1). Heterosexual contact with an at-risk partner is the fastest-growing transmission category, and women are more susceptible to HIV infection than men. This increased susceptibility is in part accounted for by an increased prevalence of sexually transmitted diseases in women. Some studies have suggested that hormonal contraceptives may increase the risk of HIV transmission. Progesterone has been shown to increase susceptibility to infection in nonhuman primate models of HIV. Women are also more likely to be infected by multiple variants of the virus than men. Women with HIV have more rapid decreases in their CD4 cell counts than men. Compared with men, HIV-infected women more frequently develop candidiasis, but Kaposi's sarcoma is less common than in men.

Other sexually transmitted diseases, such as chlamydial infection and gonorrhea, are important causes of infertility in women, and papilloma virus infection predisposes to cervical cancer.

Obesity

The prevalence of obesity is higher in women than in men. However, according to a recent study by the Agency for Healthcare Research and Quality, >80% of patients undergoing bariatric surgery are women. Pregnancy and menopause are risk factors for obesity. There are major sex differences in body fat distribution. Women characteristically have gluteal and femoral or gynoid pattern of fat distribution, whereas men typically have a central or android pattern. Gonadal steroids appear to be the major regulators of fat distribution through a number of direct effects on adipose tissue. Studies in humans also suggest that gonadal steroids play a role in modulating food intake and energy expenditure.

In men and women, upper-body obesity characterized by increased visceral fat is associated with an increased risk for cardiovascular disease and DM. In women, endogenous androgen levels are positively associated with upper-body obesity, and androgen administration increases visceral fat. In contrast, there is an inverse relationship between endogenous androgen levels and central obesity in men. Further, androgen administration decreases visceral fat in centrally obese men. The reasons for these sex differences in the relationship between visceral fat and androgens are unknown. Obesity increases a woman's risk for certain cancers, in particular postmenopausal breast and endometrial cancer, in part because adipose tissue provides an extragonadal source of estrogen through aromatization of circulating adrenal and ovarian androgens, especially the conversion of androstenedione to estrone. Obesity increases the risk of infertility, miscarriage, and complications of pregnancy.

Osteoporosis

Osteoporosis is about five times more common in postmenopausal women than in age-matched men, and osteoporotic hip fractures are a major cause of morbidity in elderly women. Men accumulate more bone mass and lose bone more slowly than women. Sex differences in bone mass are found as early as infancy. Calcium intake, vitamin D, and estrogen all play important roles in bone formation and bone loss. Particularly during adolescence, calcium intake is an important determinant of peak bone mass. Vitamin D deficiency is surprisingly common in elderly women, occurring in >40% of women living in northern latitudes. Receptors for estrogens and androgens have been identified in bone. Estrogen deficiency is associated with increased osteoclast activity and a decreased number of bone-forming units, leading to net bone loss. The aromatase enzyme, which converts androgens to estrogens, is also present in bone. Recent studies show that estrogen is an important determinant of bone mass in men (derived from the aromatization of androgens) as well as in women.

Pharmacology

On average, women have lower body weights, smaller organs, higher percent body fat, and lower total-body water than men. There are also important sex differences in drug action and metabolism that are not accounted for by these differences in body size and composition. Gonadal steroids alter the binding and metabolism of a number of drugs. Further, menstrual cycle phase and pregnancy can alter drug action. Two-thirds of cases of drug-induced torsades des pointes, a rare, life-threatening ventricular arrhythmia, occur in women because they have a longer, more vulnerable QT interval. These drugs, which include certain antihistamines, antibiotics, antiarrhythmics, and antipsychotics, can prolong cardiac repolarization by blocking cardiac voltage-gated potassium channels, particularly I_Kr. Women require lower doses of neuroleptics to control schizophrenia. Women awaken from anesthesia faster than men given the same doses of anesthetics. Women also take more medications than men, including over-the-counter formulations and supplements. The greater use of medications combined with these biologic differences may account for the reported higher frequency of adverse drug reactions in women than in men.

Psychological Disorders

Depression, anxiety, and affective and eating disorders (bulimia and anorexia nervosa) are more common in women than in men. Epidemiologic studies from both developed and developing nations consistently find major depression to be twice as common in women as in men, with the sex difference becoming evident in early adolescence. Depression occurs in 10% of women during pregnancy and in 10–15% of women during the postpartum period. There is a high likelihood of recurrence of postpartum depression with subsequent pregnancies. The incidence of major depression diminishes after age 45 years and does not increase with the onset of menopause. Depression in women appears to have a worse prognosis than in men; episodes last longer, and there is a lower rate of spontaneous remission. Schizophrenia and bipolar disorders occur at equal rates in men and women, although there may be sex differences in symptoms.

Both biologic and social factors account for the greater prevalence of depressive disorders in women. Men have higher levels of the neurotransmitter serotonin. Gonadal steroids also affect mood, and fluctuations during the menstrual cycle have been linked to symptoms of premenstrual syndrome. Sex hormones differentially affect the hypothalamic-pituitary-adrenal responses to stress. Testosterone appears to blunt cortisol responses to corticotropin-releasing hormone. Both low and high levels of estrogen can activate the hypothalamic-pituitary-adrenal axis.

Sleep Disorders

There are striking sex differences in sleep and its disorders. During sleep, women have an increased amount of slow-wave activity, differences in timing of delta activity, and an increase in the number of sleep spindles. Testosterone modulates neural control of breathing and upper airway mechanics. Men have a higher prevalence of sleep apnea. Testosterone administration to hypogonadal men as well as to women increases apneic episodes during sleep. Women with the hyperandrogenic disorder polycystic ovary syndrome have an increased prevalence of obstructive sleep apnea, and apneic episodes are positively correlated with their circulating testosterone levels. In contrast, progesterone accelerates breathing, and, in the past, progestins were used for treatment of sleep apnea.

Substance Abuse and Tobacco

Substance abuse is more common in men than in women. However, one-third of Americans who suffer from alcoholism are women. Women alcoholics are less likely to be diagnosed than men. A greater proportion of men than women seek help for alcohol and drug abuse. Men are more likely to go to an alcohol or drug treatment facility, while women tend to approach a primary care physician or mental health professional for help under the guise of a psychosocial problem. Late-life alcoholism is more common in women than men. On average, alcoholic women drink less than alcoholic men but exhibit the same degree of impairment. Blood alcohol levels are higher in women than in men after drinking equivalent amounts of alcohol, adjusted for body weight. This greater bioavailability of alcohol in women is due to both the smaller volume of distribution and the slower gastric metabolism of alcohol secondary to lower activity of gastric alcohol dehydrogenase than is the case in men. In addition, alcoholic women are more likely to abuse tranquilizers, sedatives, and amphetamines. Women alcoholics have a higher mortality rate than do nonalcoholic women and alcoholic men. Women also appear to develop alcoholic liver disease and other alcohol-related diseases with shorter drinking histories and lower levels of alcohol consumption. Alcohol abuse also poses special risks to a woman, adversely affecting fertility and the health of the baby (fetal alcohol syndrome). Even moderate alcohol use increases the risk of breast cancer, hypertension, and stroke in women.

More men than women smoke tobacco, but the prevalence of smoking is declining faster in men than in women. Smoking markedly increases the risk of cardiovascular disease in premenopausal women and is also associated with a decrease in the age of menopause. Women who smoke are more likely to develop chronic obstructive pulmonary disease and lung cancer than men and at lower levels of tobacco exposure.

Violence Against Women

Domestic violence is the most common cause of physical injury in women, exceeding the combined incidence of all other types of injury (such as from rape, mugging, and auto accidents). Sexual assault is one of the most common crimes against women. One in five adult women in the United States reports having experienced sexual assault during her lifetime. Adult women are much more likely to be raped by a spouse, ex-spouse, or acquaintance than by a stranger. Domestic violence may be an unrecognized feature of certain clinical presentations such as chronic abdominal pain, headaches, substance abuse, and eating disorders, in addition to more obvious manifestations such as trauma.

SUMMARY

Women's health is now a mature discipline, and the importance of sex differences in biologic processes is well-recognized. It is clear that understanding the mechanisms of these differences will have an impact on both women's and men's health. For example, estrogen is now recognized as an important regulator of bone density in men as well as in women. Elucidating the biology of sex hormone action has resulted in the design of drugs with tissue-specific hormone agonist and antagonist effects. These discoveries will make it feasible to selectively modulate the actions of sex hormones in both women and men to prevent and treat disease.

FURTHER READINGS Hsia J et al: Conjugated equine estrogens and coronary heart disease: The Women's Health Initiative. Arch Intern Med 166:357, 2006 [PMID: 16476878] Mendelsohn ME, Karas RH: Molecular and cellular basis of cardiovascular gender differences. Science 308:1583, 2005 [PMID: 15947175] Mosca L et al: National Study of Physician Awareness and Adherence to Cardiovascular Disease Prevention Guidelines. Circulation 111:499, 2005 [PMID: 15687140] Ridker PM et al: A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 352:1293, 2005 [PMID: 15753114] Special Section Women's Health. Science 308:1569, 2005 Turgeon JL et al: Hormone therapy: Physiological complexity belies therapeutic simplicity. Science 304:1269, 2004 [PMID: 15166356] Wizemann TM, Pardue M-L (eds): Exploring the Biological Contributions to Human Health: Does Sex Matter? Washington, DC, National Academy of Sciences, 2001