(See also Chap. 423) 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 probably 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. There are sex differences in the severity of AD with women experiencing greater deficits in cognition.
Women with AD have lower endogenous estrogen levels than do 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 (HT) may decrease the risk of AD. The Women’s Health Initiative Memory Study (WHIMS), an ancillary study in the Women’s Health Initiative (WHI) in women aged ≥65 years, found significantly increased risk for both dementia and mild cognitive impairment in women receiving estrogen alone (combined continuous equine estrogen [CEE], 0.625 mg daily) or estrogen with progestin (CEE, 0.625 mg daily, and medroxyprogesterone acetate [MPA], 2.5 mg daily) compared to placebo. However, the Kronos Early Estrogen Prevention Study (KEEPS), a randomized clinical trial of early initiation of HT after menopause that compared CEE 0.45 mg daily, 50 μg of weekly transdermal estradiol (both estrogen arms included cyclic oral micronized progesterone 200 mg daily for 12 days each month), or placebo, found no adverse effects of HT on cognitive function. In summary, there is no evidence from placebo-controlled trials that HT improves cognitive function.
(See also Chap. 267) There are major sex differences in CVD, the leading cause of death in men and women in developed countries. However, there are also major gender differences because of perceptions by both women and their health care providers that women are at lower risk for CVD. As a result of these misconceptions, women are less likely to seek medical help when they experience symptoms of CVD. Health care providers are less likely to suspect CVD, so women receive fewer interventions for modifiable risk factors as well as fewer acute interventions than do men. Women and their health care providers are also less aware that prodromal symptoms of cardiac disease differ in women compared to men. Women are less likely than men to present with chest pain and more likely to present with fatigue, shortness of breath, indigestion/nausea, and anxiety.
Sex 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 and anti-inflammatory properties. There is a striking increase in CVD after both natural and surgical menopause, suggesting that endogenous estrogens are cardioprotective. Women also have longer QT intervals on electrocardiograms, and this increases their susceptibility to certain arrhythmias.
CVD 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 common initial symptom of CVD in women, whereas myocardial infarction (MI) was the most common initial presentation in men. Women more often have atypical symptoms such as fatigue, anxiety, nausea, indigestion, and upper back pain. Although awareness that heart disease is the leading cause of death in women has nearly doubled over the last 15 years, women remain less aware that its symptoms are often atypical, and they are less likely to contact 9-1-1 when they experience such symptoms. The recent availability of a high-specificity troponin assay with sex-specific cutoffs has increased diagnostic accuracy for MI in women but not in men.
Deaths from CVD have decreased markedly in men since 1980, whereas CVD deaths only began to decrease substantially in women beginning in 2000. Women with MI 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 MI are more likely to die than are men of similar age. However, this mortality gap has decreased in recent years because younger women have experienced greater improvements in survival after MI than men (Fig. 391-3). The improvement in survival is due largely to a reduction in comorbidities, suggesting a greater attention to modifiable risk factors in women. Nevertheless, 1 year after MI, 26% of women aged >45 years will die compared to 19% of men. Within 5 years of the first MI, 47% of women compared to 36% of men will die.
Hospital mortality rates in men and women for acute myocardial infarction (MI) in 1994–1995 compared with 2004–2006. Women aged <65 years had substantially greater mortality than men of similar age in 1994–1995. Mortality rates declined markedly for both sexes across all age groups in 2004–2006 compared with 1994–1995. However, there was a more striking decrease in mortality in women aged <75 years compared with men of similar age. The mortality rate reduction was largest in women <55 years (52.9%) and lowest in men of similar age (33.3%). (Data adapted from V Vaccarino et al: Arch Intern Med 169:1767, 2009.)
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. Women are less likely to receive therapies such as angioplasty, thrombolytic therapy, coronary artery bypass grafts (CABGs), beta blockers, and aspirin. There are also sex differences in outcomes when women with CVD 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 compared with men. Factors such as older age, more comorbid conditions, smaller body size, and more severe CVD in women at the time of events or procedures 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 CVD in both men and women. Total triglyceride levels are an independent risk factor for CVD in women but not in men. Low HDL cholesterol and DM are more important risk factors for CVD in women than in men. Smoking is an important risk factor for CVD in women—it accelerates atherosclerosis, exerts direct negative effects on cardiac function, and is associated with an earlier age of menopause. Several disorders affect women exclusively, including pregnancy-associated hypertension, preeclampsia, gestational DM, polycystic ovary syndrome, or predominantly, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cholesterol-lowering drugs are equally effective in men and women for primary and secondary prevention of CVD. In contrast to men, randomized trials showed that aspirin was not effective in the primary prevention of CVD in women; it did significantly reduce the risk of ischemic stroke.
The sex differences in CVD prevalence, beneficial biologic effects of estrogen on the cardiovascular system, and reduced risk for CVD in observational studies led to the hypothesis that HT was cardioprotective. However, the WHI, which studied >16,000 women on CEE plus MPA or placebo and >10,000 women with hysterectomy on CEE alone or placebo, did not demonstrate a benefit of HT for the primary or secondary prevention of CVD. In addition, CEE plus MPA was associated with an increased risk for CVD, particularly in the first year of therapy, whereas CEE alone neither increased nor decreased CVD risk. Both CEE plus MPA and CEE alone were associated with an increased risk for ischemic stroke.
In the WHI, there was a suggestion of a reduction in CVD risk in women who initiated HT closer to menopause. This finding suggests that the time at which HT is initiated is critical for cardioprotection. According to this “timing” hypothesis, HT has differential effects, depending on the stage of atherosclerosis; adverse effects are seen with advanced, unstable lesions. This hypothesis was supported by data from the Danish Osteoporosis Prevention Study (DOPS), an open-label randomized trial of triphasic oral estradiol compared with no treatment in recently menopausal or perimenopausal women (a cyclic oral synthetic progestin, norethisterone acetate, was added in women who had a uterus), that found significantly reduced mortality and CVD after 10 years of HT. However, DOPS was designed to investigate HT for the primary prevention of osteoporotic bone fractures, and CVD outcomes were not prespecified endpoints.
KEEPS was designed to directly test the “timing” hypothesis. Seven hundred twenty-seven recently menopausal women aged 42–58 years (mean 52.7 years) were randomized to oral CEE (lower dose than WHI), transdermal estradiol, or placebo for 4 years; both estrogen arms included oral cyclical micronized progesterone (see above section on AD for dosing details). There were no significant beneficial or deleterious effects on the progression of atherosclerosis by computed tomography assessment of coronary artery calcification in either HT arm. Adverse events including stroke, MI, venous thromboembolism, and breast cancer were not increased in the HT arms compared with the placebo arm. There were improvements in hot flashes, night sweats, mood, sexual function, and bone density in the HT arms. This relatively small study does not suggest that early HT administration reduces atherosclerosis. However, the study suggests that short-term HT may be safely administered for symptom relief in recently menopausal women. HT is discussed further in Chap. 388.
(See also Chap. 396) Women are more sensitive to insulin than men are. 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, preeclampsia, pregnancy-associated hypertension, and gestational DM—common conditions in premenopausal women—are associated with a significantly increased risk for type 2 DM. Among individuals with DM, women have a greater risk for MI than do men. Women with DM have a sixfold greater risk of dying of CVD compared to women without DM.
Premenopausal women with DM lose the cardioprotective effect of female sex and have rates of CVD identical to those in males. These women have impaired endothelial function and reduced coronary vasodilatory responses, which may predispose to cardiovascular complications. Women with DM are more likely to have left ventricular hypertrophy. Women with DM receive less aggressive treatment for modifiable CVD risk factors than men with DM. In the WHI, CEE plus MPA significantly reduced the incidence of DM, whereas with CEE alone, there was only a trend toward decreased DM incidence.
(See also Chap. 271) 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 old. 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. HT 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. 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.
(See also Chap. 348) Most autoimmune disorders occur more commonly in women than in men; they include autoimmune thyroid and liver diseases, SLE, 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. Women may be more resistant to bacterial infections than men. Sex differences in both immune responses and adverse reactions to vaccines have been reported. For example, there is a female preponderance of postvaccination arthritis.
Adaptive immune responses are more robust in women than in men; this 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 sex 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 HT 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. X chromosome genes also contribute to sex differences in immunity. Indeed, nonrandom X chromosome inactivation may be a risk factor for autoimmune diseases.
(See also Chap. 197) Women accounted for almost 19% of the ~40,000 new HIV diagnoses in the United States in 2015. Of these newly diagnosed women, 61% were African American, 19% were Caucasian, and 15% were Hispanic. Annual HIV diagnoses declined by 20% among women from 2010 to 2014. Nevertheless, AIDS remains an important cause of death in younger women, particularly African-American women aged 25–44 years. Heterosexual contact with an at-risk partner is the fastest-growing transmission category, and women are more susceptible to HIV infection during vaginal sex than men. This increased susceptibility is accounted for in part by an increased prevalence of sexually transmitted diseases, i.e., gonorrhea and syphilis, 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 do men. Compared with men, HIV-infected women more frequently develop candidiasis, but Kaposi’s sarcoma is less common than it is in men. Women have more adverse reactions, such as lipodystrophy, dyslipidemia, and rash, with antiretroviral therapy than do men. This observation is explained in part by sex differences in the pharmacokinetics of certain antiretroviral drugs, resulting in higher plasma concentrations in women.
(See also Chap. 395) The prevalence of both obesity (body mass index [BMI] ≥30 kg/m2) and abdominal obesity (waist circumference ≥88 cm in women) is higher in U.S. women than in men. Between 2005 and 2014, the prevalence of obesity (BMI ≥30 kg/m2) and class 3 obesity (BMI ≥40 kg/m2) increased significantly in women but not in men. In 2014, the prevalence of obesity was 40.4% and class 3 obesity 9.9% for women, and 35.0% and class 3 obesity 5.5% for men. The prevalence of abdominal obesity increased over this time period in both sexes. More than 80% of patients who undergo 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. Women have more subcutaneous fat than men. In women, endogenous androgen levels are positively associated with abdominal obesity, and androgen administration increases visceral fat. In contrast, there is an inverse relationship between endogenous androgen levels and abdominal obesity in men. Further, androgen administration decreases visceral fat in these obese men. The reasons for these sex differences in the relationship between visceral fat and androgens are unknown. Studies in humans also suggest that sex steroids play a role in modulating food intake and energy expenditure.
In men and women, abdominal obesity characterized by increased visceral fat is associated with an increased risk for CVD and DM. 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.
(See also Chap. 404) 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 do 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. Estrogen is an important determinant of bone mass in men (derived from the aromatization of androgens) as well as in women.
On average, women have lower body weights, smaller organs, a higher percentage of 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. Sex steroids alter the binding and metabolism of a number of drugs. Further, menstrual cycle phase and pregnancy can alter drug action. 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.
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. Women require lower doses of neuroleptics to control schizophrenia. Women awaken from anesthesia faster than do men given the same doses of anesthetics. In 2013, the Food and Drug Administration recommended that doses of the drug zolpidem be lowered for women because of slower drug clearance than in men.
(See also Chap. 444) 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 the age of 45 years and does not increase with the onset of menopause. Depression in women appears to have a worse prognosis than does depression 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. Sex 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.
(See also Chap. 27) 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
(See also Chaps. 445 and 448) 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, whereas 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 in 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 this sex difference continues to decrease. Women have a much larger burden of smoking-related disease. Smoking markedly increases the risk of CVD 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. Postmenopausal women who smoke have lower bone density than women who never smoked. Smoking during pregnancy increases the risk of preterm deliveries and low birth weight infants.
More than one in three women in the United States have experienced rape, physical violence, and/or stalking by an intimate partner. Adult women are much more likely to be raped by a spouse, ex-spouse, or acquaintance than by a stranger. Domestic or intimate partner violence is a leading cause of death among young women. Domestic violence may be an unrecognized feature of certain clinical presentations, such as chronic abdominal pain, headaches, and eating disorders, in addition to more obvious manifestations such as trauma. Intimate partner violence is an important risk factor for depression, substance abuse, and suicide in women. Screening instruments can accurately identify women experiencing intimate partner violence. Such screening by health care providers is acceptable to women in settings ensuring adequate privacy and safety.