Gender and Blood Pressure

Abstract

The prevalence, impact, and control of hypertension differ between the sexes in the US population. In addition, pregnancy, oral contraceptive use, and menopausal hormone therapy May influence blood pressure regulation in ways that have therapeutic implications for some women. Whether gender should be a significant consideration in the choice of individual antihypertensive drugs continues to be a topic of intense interest and debate. This brief review will discuss recent findings that bear on considerations of gender in the management of hypertension, particularly among older women.

There is a striking age‐dependent sexual dimorphism in the prevalence of hypertension (Figure). Women have lower systolic blood pressure (SBP) levels than men during early adulthood, while the opposite is true after the sixth decade of life. Diastolic blood pressure (DBP) tends to be slightly lower in women than men regardless of age. In early adulthood, hypertension is less common among women than men, but after the fifth decade of life, the incidence of hypertension increases more rapidly in women than men, reaching a prevalence rate that is equal to or greater than in men during the sixth decade. This sexual dimorphism in blood pressure (BP) May, in part, account for the lower incidence of cardiovascular disease and the slower progression of renal disease in young (premenopausal) women, which tend to disappear with menopause.

Figure 1.

Prevalence of high blood pressure in Americans age 20 and older by age and sex. National Health and Nutrition Examination Survey (NHANES): 1999–2002. Reproduced from the 2005 Heart Disease and Stroke Statistical Update, with permission from the American Heart Association.

Mechanisms

The mechanisms responsible for sex differences in BP control and regulation are not fully understood, but appear to involve effects of sex hormones on renal sodium handling and/or vascular resistance. A rightward shift of the pressure‐natriuresis curve with a resultant long‐term increase in BP has been reported in male animal models of hypertension. Castration restores the pressure‐natriuresis relationship, and androgen receptor blockade lowers BP in these models, providing evidence that androgens contribute to the higher BP observed in males. Administration of testosterone to ovariectomized spontaneously hypertensive rats has been shown to elevate BP and blunt the pressure‐natriuresis relationship, suggesting the possibility, as yet untested in clinical studies, that androgens May play a role in the rise in BP that occurs in menopausal women.

Female sex hormones, in contrast, appear to protect against salt‐induced increases in BP, at least in part by increasing sensitivity of the pressure‐natriuresis relationship and augmenting renal excretion of sodium. Studies in animal models have revealed emergence of salt‐sensitive hypertension after ovariectomy. Activation of the sympathetic nervous system, alterations in salt appetite, and modulation of many functions of the renin‐angiotensin‐aldosterone system appear to participate in the pathogenesis of salt‐sensitive hypertension in these models. Additional mechanisms that have been suggested to explain the effects of ovarian hormones on BP include: 1) maintenance of normal endothelial function, with attendant increases in endothelial‐dependent nitric oxide production and vasodilation; 2) reductions in plasma renin activity, angiotensin‐converting enzyme (ACE) activity, vascular AT₁ receptor expression, and superoxide production; and 3) induction of structural and functional alterations in the arterial wall that reduce vascular stiffness and prevent the development of isolated systolic hypertension. While available data concerning the participation of these mechanisms in BP control in women are limited, this is a promising area for future clinical research, particularly in view of the documented major increases in age‐related stiffening of large arteries in women, consistent with changes in hormone status (increases in follicle stimulating hormone) and cardiovascular risk.

Studies carried out in normotensive women during the menstrual cycle, during use of oral contraceptives and after menopause, indicate that the pressure‐natriuresis relationship is steep in young women during all phases of the menstrual cycle and during oral contraceptive use, indicating insensitivity to salt, but is shifted to the right in menopausal women, indicating that BP becomes salt‐sensitive after menopause (Figure). The inability of the kidney of postmenopausal women to handle a salt load is reflected in exaggerated weight gain when going from a low‐ to high‐salt intake. Whether the postmenopausal increase in salt sensitivity is related to aging changes in the kidney and/or to reduced synthesis of estradiol or an imbalance between androgens and female sex hormones is a topic of current study. In any event, the increased salt sensitivity of postmenopausal women supports the use of diuretics in hypertensive women, consistent with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.

Figure 2.

Pressure‐natriuresis relationship in normotensive women during the normal menstrual cycle, during use of oral contraceptives, and after menopause. All women randomly received a diet low in sodium (40 mmol Na/d) and high in sodium (250 mmol Na/d) for 1 week. Blood pressure was measured over 24 hours using ambulatory blood pressure monitoring. Adapted with permission from Pechere‐Bertschlitz A, Burnier M. Am J Hypertens. 2004;17:994–1001.

Awareness, Treatment, and Control

While awareness and treatment rates are higher in hypertensive women than men, control rates are lower. In the National Health and Nutrition Examination Survey (NHANES) 1999–2000, approximately 71% of hypertensive women were aware of their high BP in contrast to just 66% of hypertensive men; 62% of hypertensive women, but only 54% of men, were being treated with antihypertensive medications (Figure). Despite higher treatment rates, only 48% of treated women and 30% of all women had their BP controlled (<140/90 mm Hg), compared with 60% and 33% of treated and all men, respectively.

Figure 3.

Awareness, treatment, and control of blood pressure for men/women in the United States, 1988–2000. Adapted with permission from Hajjar I, Kotchen TA. JAMA. 2003:290:199–206.

The greatest burden of hypertension in the United States in absolute numbers falls on the elderly, in the case of women, on the postmenopausal population. Data from the Women's Health Initiative Observational Study (WHI‐OS) underscore the gravity of the hypertension problem in postmenopausal women. Among the hypertensives enrolled in WHI‐OS, only 36% (12,383) were controlled, while 64% (22,096) were on treatment. Prevalence rates were directly related to age (Figure). Other determinants of hypertension prevalence included alcohol consumption (46% in nondrinkers, 32% in moderate drinkers, and 36% in heavier drinkers), physical activity (45% in those with no moderate or strenuous activity vs. 31% in those with ≥4 sessions/week), and body weight (48% in those with body mass index >27.3 vs. 29% and in those with body mass index <27.3). Concomitant cardiovascular disease and cardiovascular disease risk factors were associated with markedly increased hypertension prevalence.

Figure 4.

Prevalence of hypertension in women and treatment status by age at baseline in the 'Women's Health Initiative Observational Study (WHI‐OS). Adapted with permission from Wassertheil‐Smoller S, Anderson G, Psaty BM, et al. Hypertension and its treatment in postmenopausal women: baseline data from the Women's Health Initiative. Hypertension. 2000;36(5):780–789.

Treatment rates remained stable with age (Figure). Current users of menopausal hormone therapy were more likely than never users to be on antihypertensive drug treatment, supporting the widely held concept that hormone users are generally more health conscious and adherent to medical recommendations than nonusers. BP control rates were inversely related to age, even though treatment rates were comparable in the three decades (Figure). Whether this is related to biological determinants of responsiveness/ resistance to antihypertensive treatment, e.g., increased stiffness and increased pulse‐wave velocity in conduit vessels of older women, or to the possibility that older women May not be treated as aggressively as younger ones, remains to be determined.

The majority of treated hypertensive women in WHI‐OS (57.6%) received a single drug; 31.8% were treated with two drugs from different classes, and only 6.4% were on triple therapy or larger numbers of drugs. Of note, these data were gathered in 1993–1998, long before combination therapy was recommended for stage 2 and uncontrolled hypertensive patients by JNC 7. Control rates were highest with diuretic monotherapy (63%), intermediate with β blockers (57%) or ACE inhibitors (56%), and lowest with calcium channel blockers (CCBs) (50%). Interestingly, adding drugs from different therapeutic classes did not improve control rates. Whether this is related to underdosing of individual drugs, inappropriate choices of combinations, or true resistance to antihypertensive treatment is uncertain. CCBs, the favorite class of antihypertensive agents, were used as monotherapy in 16% and either as monotherapy or in combination in 34% of participants. Diuretics, which were recommended by JNC 7 as first‐line therapy, were used as monotherapy less often (14%). However, consistent with JNC 7 recommendations, diuretics were used more often than any other drug class in combination. The presence of comorbid conditions influenced drug choices: 1) β blockers were used more often in women with a history of myocardial infarction; 2) combination therapy was more common in women with a history of cardiovascular disease; and 3) CCBs were used more frequently in combination with other drugs in diabetics than in nondiabetics. Attention to the results of subsequent outcome trials (reviewed below) and rigorous adherence to recent guidelines for BP management should enhance the intensity of antihypertensive treatment, and therefore BP control rates, in high‐risk older hypertensive women.

Menopause and BP

The effect of menopause on BP is controversial. While longitudinal studies such as Framingham have not documented a rise in BP with menopause, cross‐sectional studies have found significantly higher SBP and DBP in postmenopausal women. NHANES III and the Canadian Heart Health Surveys reported that the rate of rise in SBP tends to steepen in postmenopausal compared with premenopausal women until the sixth decade, when it tends to slow. Even after adjustment for age and body mass index, postmenopausal women have been reported to be more than twice as likely to have hypertension as premenopausal women. An important prospective study of conventional and (the more accurate) ambulatory BP levels in pre‐, peri‐, and postmenopausal women reported that the postmenopausal women had higher SBP (4–5 mm Hg) than the pre‐ and perimenopausal controls. The increase in SBP per decade was 5 mm Hg greater in peri‐ and postmenopausal women than in the premenopausal group. Thus, at least part of the rise in BP (particularly SBP) seen in older women is due to menopause. As discussed previously, the menopause‐related increase in BP has been attributed to a variety of factors, including estrogen withdrawal, overproduction of pituitary hormones, weight gain, or a combination of these and other undefined neurohumoral influences.

Menopausal Hormone Therapy and BP

Results of studies of the effects of menopausal hormone therapy on BP have been inconsistent. The WHI found a 1 mm Hg increase from baseline in SBP among 8506 postmenopausal women randomized to conjugated equine estrogen and medroxyprogesterone acetate compared with a placebo group. In the estrogen‐alone component of WHI, women randomized to conjugated equine estrogen had similar 1.1 mm Hg higher SBP than the placebo group. DBP did not differ between active treatment and placebo in either randomized controlled trial component of WHI. Further, cross‐sectional analysis of almost 100,000 women aged 50–79 years enrolled in WHI‐OS showed that current hormone use was associated with a 25% greater likelihood of having hypertension compared with past use or no prior use. In contrast, smaller observational and interventional studies have found different results. The Baltimore Longitudinal Study on Aging found that normotensive postmenopausal women receiving hormones had a significantly smaller increase in SBP over time than nonusers, while DBP was not affected by hormones. The Postmenopausal Estrogen/Progestin Intervention trial found that hormone therapy had no significant effect on SBP or DBP in normotensive postmenopausal women. Further, several smaller studies that used 24‐hour ambulatory monitoring have suggested that menopausal hormones improve or restore the normal nighttime reduction (“dipping”) in BP that May be diminished in postmenopausal women. Such an effect would tend to reduce total BP load and thereby reduce target organ damage.

Overall, menopausal hormone‐related changes in BP are likely to be modest and should not preclude hormone use in normotensive or hypertensive women. However, menopausal hormones do not reduce BP significantly, and should not be prescribed for that indication. All hypertensive women treated with menopausal hormones should have their BP monitored closely at first and then at 6‐month intervals.

Oral Contraceptives and BP

Many women taking oral contraceptives, even modern preparations that contain only 30 μg estrogen, experience a small, but detectable, increase in BP, and a small percentage experience the onset of frank hypertension, which resolves with withdrawal of oral contraceptive therapy. The Nurses' Health Study found that current users of oral contraceptives had a significantly increased (relative risk=1.8; 95% confidence interval [CI], 1.5–2.3) risk of hypertension compared with never users. Absolute risk was small (41.5 cases of hypertension per 10,000 person‐years of oral contraceptive use) and decreased quickly with cessation of contraceptive treatment. Controlled prospective studies have demonstrated a return of BP to pretreatment levels within 3 months of discontinuing oral contraceptives, indicating that their BP effect is readily reversible.

Susceptibility to oral contraceptive‐induced hypertension is increased by genetic characteristics such as family history of hypertension and by environmental characteristics, including preexisting pregnancy‐induced hypertension, occult renal disease, obesity, middle age (>35 years), and duration of oral contraceptive use. Contraceptive‐induced hypertension appears to be related to the progesterogenic, not the estrogenic, potency of the preparation. The risk of hypertension is greater among users of monophasic combination oral contraceptives than among users of biphasic or triphasic combinations, perhaps because the total dose of progestin is greater with the monophasic preparations.

Oral contraceptive‐induced hypertension is diagnosed by documenting the onset of hypertension de novo during contraceptive therapy and the resolution of the hypertension on drug withdrawal. Regular monitoring of BP throughout contraceptive therapy is recommended. Further, it has been suggested that contraceptive prescriptions be limited to 6 months to ensure at least semiannual reevaluations. Oral contraceptives should generally be withdrawn in cases of contraceptiveinduced hypertension, but May have to be continued in some women (e.g., if other contraceptive methods are not suitable) in combination with antihypertensive therapy.

Outcomes of Antihypertensive Therapy in Women

Antihypertensive treatment is clearly effective in the prevention of cardiovascular disease in women. A subgroup meta‐analysis of individual patient data according to sex based on seven older randomized controlled trials from the Individual Data Analysis of Antihypertensive intervention database showed significant treatment benefits for women. Significant reductions in stroke and major cardiovascular events were seen in women randomized to thiazide diuretic or β‐blocker treatment compared with placebo. Treatment benefits did not differ between the sexes when expressed as relative risk. However, absolute risk reduction for coronary events with treatment was less in women than in men and did not attain statistical significance. This is likely related to the fact that untreated risk for coronary events was substantially lower in women than in men. Similarly, the Systolic Hypertension in Europe (Syst‐Eur) trial, a placebo‐controlled study of CCB treatment, showed treatment benefits for both sexes, although men were at higher risk than women.

Trials that evaluated the newer classes of antihypertensive agents and included larger proportions of older, higher risk women showed even greater treatment benefit in women. For example, ACE inhibitor (ramipril) treatment of the 2480 female participants in the Heart Outcomes Prevention Evaluation study was associated with a 23% reduction in the composite end point of myocardial infarction, stroke, and cardiovascular death, with a number needed to treat to prevent one event of 27. Relative risk reduction for cardiovascular death was 38% in women. Overall, event reductions for women were similar to those for men.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which randomized 9193 high‐risk hypertensive persons with left ventricular hypertrophy by electrocardiographic criteria, 4963 of whom were women, to treatment based on either the angiotensin receptor blocker losartan or the β‐blocker atenolol, showed greater benefit of losartan compared with atenolol treatment in women than in men and in older (>70 years) than in younger participants (Figure).

Figure 5.

Age, gender, and race/ethnicity subgroup analysis from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. Cl=confidence interval. Redrawn with data from Dahlof B, Devereux RB, Kjeldsen SE, et al. Lancet. 2002;359:995–1003.

The Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT) tested the primary hypothesis that the incidence of fatal and nonfatal coronary events is lower in hypertensive persons randomized to a representative of one of the newer classes of antihypertensive agents (the CCB amlodipine, the ACE inhibitor lisinopril, or the α‐blocker doxazosin) than in those randomized to a thiazide‐like diuretic (chlorthalidone) as first‐line therapy. ALLHAT, which included 19,865 women among its 42,448 high‐risk hypertensive participants, showed no difference between treatments in the primary (coronary) end point or in all‐cause mortality, but the diuretic was superior to the CCB in preventing heart failure and to the ACE inhibitor in preventing stroke, heart failure, and the combined cardiovascular disease outcome. Treatment effects were similar in women and men (Figure). These observations, coupled with the additional benefits of thiazide‐type diuretics discussed later in this paper, provide a strong basis for use of these agents in high‐risk older women with hypertension.

Figure 6.

Relative risks and 95% confidence intervals (CIs) for major outcomes comparing amlodipine/chlorthalidone and lisinopril/chlorthalidone in women and men in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). AHT=antihypertensive trial; Ml=myo car dial infarction; CHD=coronary heart disease; CVD=cardiovascular disease. Reproduced with permission from The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high‐risk hypertensive patients randomized to angio‐tensin‐converting enzyme inhibitor or calcium channel blacker vs. diuretic: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–2997.

A recent analysis of data from WHI‐OS attempted to evaluate the effects of treatment with different classes of antihypertensive agents, singly or in combination, on the incidence of coronary heart disease, stroke, and cardiovascular disease mortality in 30,219 women with no history of cardiovascular disease. This observational study related type of antihypertensive medication reported at the baseline visit to cardiovascular disease outcomes over a mean of 5.9 years of follow‐up. The effects of antihypertensive drugs on cardiovascular events in nonrandomized studies May be confounded by indication for prescribing these specific drug classes. In an attempt to minimize this problem, the investigators limited their analysis to women without a history of cardiovascular disease and adjusted their analysis for propensity to be receiving a particular treatment based on risk factor profile and concomitant conditions. However, there were differences between treatment groups that May have influenced outcomes, e.g., a greater proportion of those receiving CCBs or diuretics were black (16.2% and 17.1%, respectively) compared with those receiving ACE inhibitors (7.4%) or β block‐ers (4.9%), and baseline SBP was lowest in the diuretic group (135.5 mm Hg) and highest in the CCB group (139.2 mm Hg). The major findings of the study were that risk of cardiovascular disease death was greater with CCB (either dihydropyridine or nondihydropyridine) monotherapy than diuretic monotherapy and with a diuretic‐CCB combination than with a diuretic‐β blocker combination. None of the other monotherapy or combined‐therapy comparisons was significant. These findings differ from those observed in a large meta‐analysis of randomized controlled trials of antihypertensive treatment, which demonstrated no differences between the effects on cardiovascular mortality of regimens based on CCBs, ACE inhibitors, or diuretics/β blockers. The limitation of WHI‐OS, as of all observational studies, is uncertainty of the ability to control fully for confounding by indication.

Choice of Antihypertensive Therapy for Women

Thresholds for instituting antihypertensive treatment, BP goals, and choices of antihypertensive drugs are generally the same for women as for men (Table I). Current guidelines suggest lifestyle modification and specific drug therapy, including certain drug classes for compelling indications (Table II), for women with hypertension. Lifestyle modification is indicated in all persons with hypertension or with BP in the “prehypertension” range because of its potential for preventing cardiovascular disease outcomes and the progression to higher BPs and for increasing the efficacy of pharmacologic treatment. All women should be encouraged to lower their BP to optimal levels of <120/<80 mm Hg via lifestyle approaches. Aerobic exercise and weight loss are the most efficacious nonpharmacologic approaches to reducing BP and related cardiovascular disease risk factors, such as dyslipidemia.

Table I.

Classification and Management of Blood Pressure for Adults Aged 18 Years or Older

BP Classification	Systolic BP (mm Hg*)		Diastolic BP (mm Hg*)	Lifestyle Modification	Initial Drug Therapy Without Compelling Indications	Initial Drug Therapy With Compelling Indications**
Normal	<120	and	<80	Encourage
Prehypertension	120–139	or	80–89	Yes	No antihypertensive drug indicated	Drugs for the compelling indications†
Stage 1 hypertension	140–159	or	90–99	Yes	Thiazide‐type diuretics for most; May consider ACE inhibitor, ARB, β blocker, CCB, or combination	Drug(s) for the compelling indications; other antihypertensive drugs (diuretic, ACE inhibitor, ARB, β blocker, CCB) as needed
Stage 2 hypertension	≥160	or	≥100	Yes	Two‐drug combination for most (usually thiazidetype diuretic and ACE inhibitor, or ARB or β blocker or CCB)††	Drug(s) for the compelling indications; other antihypertensive drugs (diuretic, ACE inhibitor, ARB, β blocker, CCB) as needed
BP=blood pressure; ACE=angiotensin‐converting enzyme; ARB=angiotensin receptor blocker; CCB=calcium channel blocker; *treatment determined by highest BP category; **heart failure: diuretic, β blocker, ACE inhibitor, ARB, aldosterone antagonist; postmyocardial infarction: β blocker, ACE inhibitor, aldosterone antagonist; high coronary disease risk: diuretic, β blocker, ACE inhibitor, CCB; diabetes: diuretic, β blocker, ACE inhibitor, ARB, CCB; chronic kidney disease: ACE inhibitor, ARB; recurrent stroke prevention: diuretic, ACE inhibitor; †treat patients with chronic kidney disease or diabetes to BP goal of less than 130/80 mm Hg; ††initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. Reproduced with permission from Chobanian AV, Bakris GL, Black HR, et al., and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252.

Table II.

Compelling Indications for Specific Antihypertensive Drug Classes From the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

	Diuretic	β Blocker	Angiotensinconverting Enzyme Inhibitor	Angiotensin Receptor Blocker	Calcium Channel Blocker	Aldosterone Antagonist
Heart failure	✓	✓	✓	✓		✓
Postmyocardial infarction		✓	✓			✓
Coronary artery disease risk	✓	✓	✓		✓
Diabetes mellitus	✓	✓	✓	✓	✓
Renal disease			✓	✓
Recurrent stroke prevention	✓		✓
Adapted with permission from Chobanian AV, Bakris GL, Black HR, et al., and the National High Blood Pressure Education Program Coordinating Committee; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Coordinating Committee. JAMA. 2003;289:2560–C2572.

Persons with multiple cardiovascular risk factors or target organ damage (e.g., renal insufficiency, proteinuria, or heart failure) should be treated to a lower BP goal and often require combination therapy, usually with a thiazide diuretic included in the combination. With the exception that older persons are generally at higher risk and merit particularly aggressive treatment, there are no age‐ or gender‐specific recommendations for BP management. The BP lowering effect of antihypertensive drugs and the outcomes of antihypertensive treatment are generally similar in both sexes, but some special issues May dictate treatment choices for women. ACE inhibitors and angiotensin receptor blockers are contraindicated for women who are, or intend to become, pregnant because of the risk of fetal developmental abnormalities. β blockers tend to be less effective in women than men, while diuretics have added value in older women because of their association with decreased bone loss and reduced risk of hip fracture, and because post‐menopausal women appear to be highly salt sensitive. In addition, some antihypertensive drugs have gender‐specific adverse effect profiles, and women tend to report more adverse effects than men. For example, the Treatment of Mild Hypertension Study, in which 902 women and men received lifestyle modification alone or lifestyle modification plus treatment with a drug chosen at random from each class of antihypertensive agent then available, found that women reported twice as many side effects as men with all treatments, including lifestyle modification only.

Biochemical responses to drugs May also be gender dependent. While men are more likely to develop gout, women are more likely to develop hyponatremia and hypokalemia associated with diuretic therapy. Women develop cough related to ACE inhibitor therapy three times more often than men. Minoxidil‐induced hirsutism and lower extremity edema induced by CCBs are much more common in women than in men. Further, sexual dysfunction related to antihypertensive therapy May be a problem in women as well as in men, and is most often associated with centrally acting agents, β blockers, and thiazide diuretics, while angiotensin receptor blocker therapy May improve these symptoms.

SUMMARY

Hypertension is the most common modifiable risk factor for cardiovascular disease in women. Evidence‐based guidelines recommend lifestyle interventions for all women with “prehypertension” or with clinical disease and pharmacotherapy for those with BP >140/>90 mm Hg. The treatment threshold is even lower for those with target‐organ damage or diabetes. Thiazide‐type diuretics should be first‐line agents, but multi‐drug therapy is usually required to obtain BP control, and additional agents should be aggressively employed.