Women's Health-audio

Womens Health: 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 that sex matters. The National Institutes of Health established the Office of Research on Womens Health in 1990 to develop an agenda for future research in the field. In parallel, womens health has become a distinct clinical discipline with a focus on disorders that occur disproportionately in women. The integration of womens 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. Disorders highlighted here are reviewed in detail in other chapters.

Disease Risk: Reality and Perception

The leading causes of death are the same in women and men: (1) heart disease, (2) cancer (Table 6-1; Fig. 6-1). The leading cause of cancer death, lung cancer, is the same in both sexes. Breast cancer is the second leading cause of cancer death in women, but it causes about 60% fewer deaths than does lung cancer. Men are substantially more likely to die from suicide, homicide, and accidents than are women.

Table 6-1 Deaths and Percentage of Total Deaths for the Leading Causes of Death by Sex in the United States in 2006

Cause of Death	“	Female	“	“	Male	“
“	Rank	Deaths	Deaths,%	Rank	Deaths	Deaths,%
Diseases of heart	1	315,930	25.8	1	315,706	26.3
Malignantneoplasms	2	269,819	22.0	2	290,069	24.1
Cerebrovascular diseases	3	82,595	6.7	5	54,524	4.5
Cronic lower respiratory diseases	4	65,323	5.3	4	59,260	4.9
Alzheimers disease	5	51,281	4.2	9	21,151	1.8
Accidents (unintentional injuries)	6	42,658	3.5	3	78,941	6.6
Diabetes mellitus	7	36,443	3.0	6	36,006	3.0
Pneumonia	8	30,189	2.5	8	25,288	2.1
Renal failure	9	22,229	1.8	10	21,115	1.8
Septicemia	10	18,712	1.5	12	15,522	1.3
Essential hypertension and hypertensive renal disease	11	14,440	1.2	16	9,415	0.8
Other diseases of respiratory system	12	13,916	1.1	14	13,728	1.1
Chronic liver disease and cirrhosis	13	9,689	0.8	11	17,866	1.5
Parkinsons disease	14	8,266	0.7	15	11,300	0.9
Pneumonitis due to solids and liquids	15	7,971	0.7	17	8,916	0.7
Intentional self-harm (suicide)	17	6,992	0.6	7	26,308	2.2
Assault (homicide)	24	3,856	0.3	13	14,717	1.2
Note that the scale of the y axis is increased in the graph on the right compared with 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 35–49 years of age. IHD becomes the leading cause of death in women beginning at age 50 years. 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. At age 85 years and beyond, AD becomes the third leading cause of death. AD, Alzheimers disease; Ca, cancer; CLRD, chronic lower respiratory disease; DM, diabetes mellitus.

Womens 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 2007 of 80.4 years compared with 75.3 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.

Womens perception of disease risk is often inaccurate (Fig. 6-2). Public awareness campaigns have resulted in almost 60% 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 specific decade of life, a womans risk for breast cancer never exceeds 1 in 34. Although a womans 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. Physicians are also less likely to recognize womens risk for cardiovascular disease. These misconceptions are unfortunate as they perpetuate inadequate attention to modifiable risk factors such as dyslipidemia, hypertension, and cigarette smoking.
Data for obesity were not available for 1997 and 2000. Significantly more women cited heart disease/heart attack as the greatest health problem for women in 2006 compared with previous survey years. Breast cancer remained the most commonly identified greatest health risk in all survey years.

Sex Differences in Health and Disease

Alzheimers Disease

Alzheimers 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. 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. However, HT placebo-controlled trials have found no improvement in disease progression or cognitive function in women with AD. Further, the Womens Health Initiative Memory Study (WHIMS), an ancillary study in the Womens Health Initiative (WHI), found no benefit compared with 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. 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.

Cardiovascular Disease

There are major sex differences in cardiovascular disease, the leading cause of death in men and women in developed countries. 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 as well as anti-inflammatory properties. There is a striking increase in coronary heart disease (CHD) 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. Animal studies suggest that the sex difference in the duration of the QT interval is caused by the effects of sex steroids on cardiac repolarization, in part related to their effects on cardiac voltage-gated potassium channels; there is a lower density of the rapid component (IKr) of the delayed rectifier potassium current (IK) 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 common initial symptom of CHD in women, whereas myocardial infarction was the most common 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 are men of similar age. However, this mortality gap has decreased substantially in recent years because younger women have experienced greater improvements in survival after myocardial infarction than men (Fig. 6-3). The improvement in survival is due largely to a reduction in comorbidities, suggesting a greater attention to modifiable risk factors in women.
Women younger than age 65 years had substantially greater mortality than men of similar age in 1994–95. Mortality rates declined markedly for both sexes across all age groups in 2004–06 compared with 1994–95. However, there was a more striking decrease in mortality in women younger than age 75 years compared with men of similar age. The mortality rate reduction was largest in women less than age 55 years (52.9%) and lowest in men of similar age (33.3%).

Nevertheless, 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 with men. 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 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 compared with 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 showed 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 HT led to the widespread use of HT 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 HT 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. Both CEE plus MPA and CEE alone were associated with an increased risk for ischemic stroke. 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 who initiated HT closer to menopause. This finding suggests that the time at which HT is initiated is critical for cardioprotection and is consistent with the “timing hypothesis.” According to this hypothesis, HT has differential effects, depending on the stage of atherosclerosis; adverse effects are seen with advanced, unstable lesions. This hypothesis is under investigation in randomized clinical trials, for example, the Kronos Early Estrogen Prevention Study (KEEPS). It is noteworthy that there is no reduction in the risk for ischemic stroke when HT is initiated closer to menopause. HT is discussed further in.

Diabetes Mellitus

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 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 rates of CHD identical to those in males. These women have impaired endothelial function and reduced coronary vasodilatory responses, which may predispose to cardiovascular complications. Among individuals with DM, women have a greater risk for myocardial infarction than do 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 only a trend 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. 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.

Autoimmune Disorders

Most autoimmune disorders occur more commonly in women than in men; they 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 between 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; 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 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 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. 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. 6-1). Heterosexual contact with an at-risk partner is the fastest-growing transmission category, and women are more susceptible to HIV infection than are men. This increased susceptibility is accounted for in part 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 are 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 Kaposis 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.

Obesity

The prevalence of obesity is higher in women than in men. Further, >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. 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 womans 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 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.

Pharmacology

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. 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 IKr. Women require lower doses of neuroleptics to control schizophrenia. Women awaken from anesthesia faster than do 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 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. 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, 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 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.

error: Content is protected !!

NEWNMCLE

NEWNMCLE