Joan and Sanford Weill Medical College of Cornell University, New York, New York 10021
Address correspondence and requests for reprints to: Phyllis August, M.D., Division of Hypertension, New York Presbyterian Hospital, Weill Medical College of Cornell University, 520 East 70th Street, Room ST-420, New York, New York.
In recent years, considerable attention has been given to gender differences in epidemiology, pathophysiology, and treatment of human disease. The focus of much of the literature addressing gender differences in cardiovascular disease has been on the unique presentation of disease in women, differences in natural history, and gaps in our knowledge regarding gender-based therapy. Indeed, recent reviews of hypertension in women have emphasized the fact that hypertension is more common in older women compared with men, and although large clinical trials have not always included sufficient numbers of women, available data support an equally aggressive approach to treatment in men and women (1, 2).
Men have been well represented in the studies regarding the prevalence of hypertension in the population, the natural history of hypertension and the relationship to cardiovascular and cerebrovascular disease, and the benefits of treatment; thus, much of what we know about hypertension is about hypertension in men. Then why a review of hypertension with emphasis on male gender? As in women, there are unique issues with respect to the epidemiology, risk, and treatment of hypertension in men, which will be discussed in this review.
Epidemiology
The Third National Health and Nutrition Examination survey (NHANES III) reported higher overall mean arterial pressure in normotensive and hypertensive men compared with women (3). In all ethnic groups, men have higher mean systolic and diastolic blood pressure compared with women, and through middle age hypertension is more prevalent in men compared with women. The Community Hypertension Evaluation clinic program found that mean diastolic blood pressure was higher in men than in women at all ages, although mean systolic blood pressure was higher only until age 60 for blacks and age 65 for white men (4).
Despite the increased prevalence of hypertension in men, they are less aware and receive less treatment for hypertension compared with women. Data from the NHANES III survey demonstrated that only 65% of black and white men were aware of their hypertension compared with 75% of women. Only 44% of men were being treated, compared with 61% of hypertensive women. Most distressing is the fact that only 19% of men overall had their blood pressure controlled, compared with 28% of women. Thus, increased efforts to diagnose and aggressively treat hypertension in men are clearly warranted.
Hypertension is a well-established risk factor for the development of all the clinical manifestations of atherosclerosis. There are striking and unexplained differences in cardiovascular mortality in hypertensive men compared with women. In the Framingham study, death rates were doubled among hypertensive men compared with women (5). The risk of cardiovascular disease increases incrementally with each increase in blood pressure; thus, given the higher levels of blood pressure in men compared with women, it is not surprising that they are at greater risk for most of the complications of hypertension, including coronary heart disease, stroke, heart failure, and renal disease. Although both men and women suffer from coronary disease later in life, below the age of 65 yr myocardial infarction has a striking male predominance. The association between higher blood pressure and risk of renal disease has been especially well-documented in men in the large prospective study of 332,544 men screened for the Multiple Risk Factor Intervention Trial (7). The incidence of end-stage renal disease rose progressively with successively higher blood pressure compared with men with optimal blood pressure. Black men had a greater risk of developing end-stage renal disease at every level of blood pressure than did white men.
Pathophysiology
To date, there is only preliminary evidence for gender differences in the pathogenic mechanisms involved in essential hypertension. Of possible relevance to the higher blood pressures observed in men and the higher prevalence of hypertension in younger men compared with women is the lack of endogenous estrogen. Current evidence suggests that estrogen may modulate vascular endothelial function, resulting in vasodilation, which in women may, in part, contribute to lower blood pressures (8). The role of androgens in the pathogenesis of hypertension has not been extensively investigated. It has been reported that castration in males slows the progression of hypertension (9). Testosterone treatment of ovariectomized females is reported to exacerbate hypertension in the spontaneously hypertensive rat (10). Reckelhoff et al. (10) have demonstrated that testosterone administration to the spontaneously hypertensive rat results in a hypertensive shift in the pressure-natriuresis relationship, possibly by increasing renal sodium reabsorption or by activating the renin angiotensin system.
There is increasing evidence that elevated systolic pressure is an important risk factor for progressive atherosclerosis, and measurement of pulse pressure provides important prognostic information for patients with hypertension. In this regard, preliminary studies suggest men demonstrate significantly higher systolic and pulse pressures compared with women (11). Moreover, even mildly elevated systolic blood pressure and pulse pressure have been shown to accelerate the process of preclinical atherosclerosis in men (12). These observations have important implications for overall cardiovascular risk, as well as for choice of antihypertensive therapy.
The genetic basis for hypertension is an important area of research in many laboratories. Polymorphisms of several candidate genes, particularly genes that encode proteins in the renin angiotensin system, have been reported in hypertensive subjects with conflicting results. Most investigations have not reported gender differences in candidate gene DNA polymorphisms. Of interest is a recent study of the angiotensin-converting enzyme deletion-insertion polymophism in a large population-based sample of men and women (13). Using association analysis, the ACE DD genotype was associated with increased diastolic blood pressure in men but not in women. Quantitative trait linkage analyses in 1044 pairs of siblings also supported a role of the ACE locus in influencing blood pressure in men but not in women.
Approach to Evaluation and Treatment
The overall goals of initial evaluation are: 1) to estimate the severity of hypertension; 2) to evaluate the presence of other cardiovascular risk factors; and 3) to investigate secondary hypertension. The important aspects of hypertension evaluation and treatment are not altered by gender. There are, however, certain issues that may be more relevant for male hypertensives.
Risk factors
Cardiovascular risk factors are similar in men and women. However, appropriate treatment of the male patient must take into account the fact that coronary artery disease occurs earlier in men, thus aggressive risk factor modification should begin early in life. Moreover, high-density lipoprotein levels are lower in men, thus particular emphasis should be made on lifestyle modifications that have been shown to increase high-density lipoprotein levels, particularly aerobic exercise. Cardiac evaluation should be considered if there is a high likelihood that coronary artery disease is already present because documented coronary disease is an indication for aggressive treatment of cardiovascular risk factors, including hypertension. Stress testing should be considered in individuals with chest pain syndromes, family history of early coronary disease, and in patients who are embarking on exercise regimens (14). Stress testing may demonstrate an exaggerated blood pressure response to exercise, which may be associated with accelerated target organ damage. Stress mycocardial perfusion imaging is appropriate for patients with baseline abnormalities on electrocardiogram and in particularly high-risk individuals (15). Echocardiography should be considered when the electrocardiogram is suggestive of left ventricular hypertrophy, or there is a history of valvular heart disease, or a newly diagnosed heart murmur, or to further investigate unexplained dyspnea.
Men are also more likely to have elevated serum uric acid levels compared with women (16). Whether or not hyperuricemia is an independent risk factor for cardiovascular disease is currently being investigated. A recent analysis of the NHANES III data demonstrated that hypertensive patients with serum urate concentrations between 5.0 and 6.9 mg/dL had a higher relative risk for both heart attack and stroke, suggesting that increased urate might be an independent risk factor for hypertension-associated morbidity and mortality (17). The implications for therapy of hypertensive subjects with higher uric acid levels are not clear, particularly because diuretics are widely used and effective in many patients.
Secondary forms of hypertension in men
The prevalence of most forms of secondary hypertension is similar in men and women. Important causes of secondary hypertension in both genders include renal parenchymal disease, renovascular hypertension, hyperaldosteronism, and pheochromocytoma.
Recent evidence suggests that sleep-related disorders (obstructive sleep apnea and habitual snoring) play a major role the development of hypertension (18). It is now appreciated that obstructive sleep apnea (OSA), which is a disorder in which there is repetitive collapse and partial or complete closing of the pharynx during sleep, may be present in as much as 10% of the population. This disorder is two times more prevalent in men compared with women (19), and recent studies suggest that gender-related differences in the size and mechanical properties of the pharynx, as well as greater upper airway resistance in men, may be contributing factors (20, 21). Essential hypertension is three times more common in patients with OSA, and recent studies [reviewed by Silverberg et al. (18)] suggest that OSA is an independent risk factor for the development of essential hypertension. OSA may be even more common in patients with resistant hypertension, and a prevalence of 56% was reported in a small study of therapy resistant male hypertensives (22). That OSA may actually be causally related to hypertension is suggested by the evidence that treatment of OSA with either surgery or positive airway pressure resulted in significant lowering of blood pressure (18, 23). Further support for a causal relationship between OSA and hypertension comes from experimental models of OSA in dogs, which demonstrate that OSA can lead to the development of sustained hypertension (24). Habitual snoring is also associated with hypertension, and treatment of habitual snorers with positive airway pressure has been shown to reduce blood pressure (18). Despite accumulating evidence for an important role of sleep disorders in the pathogenesis of hypertension, many patients remain undiagnosed (25). Given the higher prevalence of sleep disorders in men and the potential for significant improvement of blood pressure with effective treatment, this is an important consideration in male hypertensive patients, particularly in those resistant to antihypertensive therapy.
Approach to Treatment
Numerous clinical trials have been performed documenting the benefits of lowering blood pressure in individuals with hypertension. Men have been well represented in all of these clinical trials. Whereas the benefits of drug therapy in malignant hypertension were easy to demonstrate, demonstrating benefits in the treatment of less severe degrees of hypertension took considerable time. The first clinical trials demonstrating protective effects of antihypertensive therapy were conducted exclusively in men. The Veterans Affairs Cooperative Study demonstrated that men with stages 2 and 3 hypertension have fewer cardiovascular complications (26, 27) than untreated men. Subsequently, thousands of individuals have been studied, and meta-analysis of randomized controlled clinical trials have reported a reduction of 3540% in stroke incidence and a reduction of 814% in risk for coronary heart disease (28, 29). Most of the large clinical trials performed in the past have used diuretics or beta-blockers as first line therapy; thus, these agents are considered preferred, unless comorbid conditions exist that would favor newer agents. Large clinical trials that compare four major classes of drugs in terms of their effects on fatal and nonfatal coronary disease are in progress.
The decision regarding when to treat a hypertensive individual and what agents to use has been the subject of may reviews, articles, and policy statements. Almost all committees and organizations agree that before instituting pharmacological therapy, multiple readings should be obtained over a time period of at least 4 weeks unless severe hypertension is present (30). There is also little disagreement regarding the need for nondrug therapies as a first line of therapy in mild hypertensives and as adjunctive therapy in individuals with more severe disease. Such interventions have been demonstrated to lower blood pressure and favorably modify additional cardiovascular risk factors. The standard lifestyle modifications recommended for all hypertensives include smoking cessation; maintenance of ideal body weight; limiting alcohol intake; moderate sodium restriction; adequate dietary intake of potassium, calcium, and magnesium; reduction of intake of saturated fat; and regular aerobic exercise. There is little evidence for gender-based differences in the beneficial effects of these strategies. The Joint National Committee for the Detection and Treatment of Hypertension 6th Report recommends that patients with stage 1 hypertension and no other risk factors are candidates for up to a year of a trial of lifestyle changes and close monitoring of blood pressure before instituting pharmacological therapy (31). Patients with significant cardiovascular risk factors, particularly diabetes, should be treated more aggressively, and pharmacological therapy is recommended even for stage 1 hypertension. Other authorities have recommended higher thresholds for beginning therapy (32, 33), although all groups have emphasized the need to consider overall cardiovascular risk when deciding to start therapy.
Decisions regarding which antihypertensive medication should be used to begin treatment may be based on the results of clinical trials documenting reduction in cardiovascular end points and mortality, individual patient biochemical and hormonal profiling, individual patient and disease characteristics (e.g. presence of diabetes, coronary disease, or hyperlipidemia), and cost. When possible, therapy should be once a day, using the least number of agents possible. There is little evidence for gender-based differences in efficacy of antihypertensive agents. However, gender may influence the spectrum and degree of adverse effects of drugs. Problems with sexual function are a significant concern in the treatment of hypertension, and sexual dysfunction attributed to antihypertensive therapy is a common reason for poor adherence to therapy in men. The Treatment of Mild Hypertension Study was a double-blind, placebo-controlled, randomized trial comparing six treatments for long-term care of individuals with stage 1 hypertension (34). Sixty-two percent of the subjects were men, and the average age was 55 yr. This large trial provided very valuable information regarding sexual dysfunction in hypertensive subjects (35). Complaints of sexual dysfunction in women were rare. In men erection problems at baseline, before randomization, were strongly related to age. Erection problems were also significantly higher when systolic blood pressure was greater than 140 mm Hg. The rate of erection problems in men was low, ranging from 617% across different treatment groups. Men taking the diuretic chlorthalidone experienced the highest incidence of problems with erection (15.7%) compared with placebo (4.9%). Doxazocin treatment was associated with a lower rate of problems with erection than placebo (2.8%). The other treatments (acebutolol, amlodipine, and enalapril) had incidence rates only slightly higher than placebo. These data suggest that it may not be reasonable to attribute erection problems to antihypertensive treatment. Sexual dysfunction in hypertensive individuals may be related more to hypertension level than to drug treatment.
Conclusions
Hypertension is a major risk factor for stroke and cardiovascular disease. In all ethnic groups, men have higher mean systolic and diastolic blood pressure compared with women, and through middle age hypertension is more prevalent in men compared with women. Men are less aware and receive less treatment for hypertension compared with women. The NHANES III survey documented that only 19% of men had their blood pressure controlled. Death rates are higher in hypertensive men compared with women, and men are at greater risk for stroke, coronary heart disease, heart failure, and renal failure. Coronary artery disease develops at significantly younger ages in men, thus risk factor modification and treatment should begin early in life. Men are at greater risk for sleep-related disorders that may contribute to the pathogenesis of hypertension. It is important to diagnose such disorders because effective treatment may improve blood pressure control. Treatment of hypertension should include lifestyle modification and antihypertensive medication, when indicated. Although sexual dysfunction is a common reason for noncompliance with therapy, recent data suggest that most antihypertensive agents have minimal effects on erectile function.
Received August 9, 1999.
Accepted August 11, 1999.
References