COMMENTARY

Hypertension in Men
PHYLLIS AUGUST
Joan and Sanford Weill Medical College of Cornell University, New York, New York 10021
I
n 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 com-
pared 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 cardiovas-
cular and cerebrovascular disease, and the benefits of treat-
ment; thus, much of what we know about hypertension is
about hypertension in men. Then why a review of hyper-
tension 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 hyperten-
sion 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, comparedwith
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 de-
velopment of all the clinical manifestations of atherosclero-
sis. There are striking and unexplained differences in car-
diovascular mortality in hypertensive men compared with
women. In the Framinghamstudy, 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 com-
plications 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 pres-
sure 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 progres-
sively 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 es-
sential 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 andro-
gens in the pathogenesis of hypertension has not been ex-
tensively investigated. It has been reported that castration in
males slows the progression of hypertension (9). Testoster-
one treatment of ovariectomized females is reported to ex-
acerbate hypertension in the spontaneously hypertensive rat
(10). Reckelhoff et al. (10) have demonstrated that testoster-
Received August 9, 1999. Accepted August 11, 1999.
Address correspondence and requests for reprints to: Phyllis August,
M.D., Division of Hypertension, NewYork Presbyterian Hospital, Weill
Medical College of Cornell University, 520 East 70th Street, Room ST-
420, New York, New York.
0021-972X/99/$03.00/0 Vol. 84, No. 10
The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.
Copyright 1999 by The Endocrine Society
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one administration to the spontaneously hypertensive rat
results in a hypertensive shift in the pressure-natriuresis
relationship, possibly by increasing renal sodium reabsorp-
tion or by activating the renin angiotensin system.
There is increasing evidence that elevatedsystolic 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 ac-
celerate 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 hyper-
tensive subjects with conflicting results. Most investigations
have not reported gender differences in candidate gene DNA
polymorphisms. Of interest is a recent study of the angio-
tensin-converting enzyme deletion-insertion polymophism
in a large population-based sample of men and women (13).
Using association analysis, the ACE DD genotype was as-
sociated 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 eval-
uation 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 lipopro-
tein 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 indica-
tion 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, andinpatients 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 sug-
gestive of left ventricular hypertrophy, or there is a history
of valvular heart disease, or a newly diagnosed heart mur-
mur, 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 hyper-
uricemia is an independent risk factor for cardiovascular
disease is currently being investigated. A recent analysis of
the NHANES III data demonstrated that hypertensive pa-
tients 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 inde-
pendent risk factor for hypertension-associated morbidity
and mortality (17). The implications for therapy of hyper-
tensive 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 (ob-
structive 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 sig-
nificant 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 sus-
tained 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 impor-
tant role of sleep disorders in the pathogenesis of hyperten-
sion, many patients remain undiagnosed (25). Given the
higher prevalence of sleep disorders in men and the potential
3452 AUGUST
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for significant improvement of blood pressure with effective
treatment, this is an important consideration in male hyper-
tensive patients, particularly in those resistant to antihyper-
tensive therapy.
Approach to Treatment
Numerous clinical trials have been performed document-
ing 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, demon-
strating 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 indi-
viduals 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 consideredpreferred,
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 cor-
onary disease are in progress.
The decision regarding when to treat a hypertensive in-
dividual and what agents to use has been the subject of may
reviews, articles, and policy statements. Almost all commit-
tees and organizations agree that before instituting pharma-
cological 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 demon-
strated to lower blood pressure and favorably modify ad-
ditional cardiovascular risk factors. The standard lifestyle
modifications recommended for all hypertensives include
smoking cessation; maintenance of ideal body weight; lim-
iting alcohol intake; moderate sodium restriction; adequate
dietary intake of potassium, calcium, and magnesium; re-
duction of intake of saturated fat; and regular aerobic exer-
cise. 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 hyper-
tension 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 withsignificant cardiovascular risk factors, par-
ticularly 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 car-
diovascular 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 cardiovas-
cular end points and mortality, individual patient biochem-
ical 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 treat-
ment of hypertension, and sexual dysfunction attributed to
antihypertensive therapy is a common reason for poor ad-
herence to therapy in men. The Treatment of Mild Hyper-
tension Study was a double-blind, placebo-controlled, ran-
domized trial comparing six treatments for long-termcare 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 hyper-
tension level than to drug treatment.
Conclusions
Hypertension is a major risk factor for stroke and cardio-
vascular 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 sig-
nificantly 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 medica-
tion, when indicated. Although sexual dysfunction is a com-
mon reason for noncompliance with therapy, recent data
HYPERTENSION IN MEN 3453
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suggest that most antihypertensive agents have minimal ef-
fects on erectile function.
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