Hypertension is a leading cause of cardiovascular morbidity and mortality both nationally and globally.¹ Based on the most recent NHANES survey from 2011-2014, 85.7 million US adults age ≥20 have hypertension, more than half of whom are women.¹ One in three deaths of women in the US are attributed to cardiovascular disease (CVD).¹ Of the major modifiable CV risk factors, the complete elimination or control of hypertension resulted in the largest impact on CV mortality in women (38% and 7.3% reduction, respectively) when assessed by NHANES data modeling.² Despite the magnitude of its societal impact, awareness, treatment and control of hypertension remain suboptimal in women.³ Although the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults is comprehensive, there is limited discussion on sex and gender differences as it relates to hypertension.⁴ Here, we present a focused review of issues related to hypertension in women. Both sex and gender differences will be explored, since distinguishing between the two is important. Sex differences refer to true biological differences whereas gender differences are influenced by culture and environment.

Pathophysiology of Hypertension Unique to Women

Rates of hypertension increase after menopause when estrogen levels fall.⁵ This suggests estrogen may have a vascular protective effect in premenopausal women. Estrogen plays a role in endothelial homeostasis through its action on vascular, cardiomyocyte and brain receptors.^6-7 Estrogen causes endothelial vasodilation via upregulation of the nitric oxide pathway and inhibition or down-regulation of sympathetic and renin-angiotensin system (RAS) activity, as well as endothelin production.^6-8 Estrogen reduces oxidative stress via lower reactive oxygen species generation and increased antioxidant production and also reduces inflammation via inhibition of pro-fibrotic genes and stimulation of neoangiogenesis.6 Therefore, lower estrogen levels after menopause may partially explain lower arterial compliance and increased risk of hypertension in older women.^9-10

Despite estrogen's potential benefit on vascular function, the addition of exogenous estrogen therapy after menopause has neutral effects on blood pressure (BP).^5,11-13 Similarly, there is no impact of exogenous estrogen on CV outcomes.^14,15 In contrast, exogenous estrogen use with an oral contraceptive pill (OCP) in premenopausal women increases blood pressure.^8,11 Although RAS and sympathetic activation may be underlying mechanisms, whether this is due to the effects of estrogen, progesterone or a complex interaction between the two is not well understood. Studies on the effects of progesterone are limited, with short term follow-up and mostly observational design.^16-18 Nevertheless, data to date suggest no increased risk of hypertension or short-term cardiometabolic outcomes with progesterone-only contraceptive pills.^16-18 Pregnancy related vascular complications, such as preeclampsia and gestational hypertension, are also associated with an increased risk of post-partum hypertension and long-term CVD.¹⁹ Younger women with estrogen imbalance and conditions such as premature ovarian insufficiency, polycystic ovarian disorder and infertility may have an increased risk of developing hypertension.²⁰ Therefore, the role of estrogen on vascular function and homeostasis is complex and not entirely understood.

Epidemiological Data on Hypertension in Women

Global estimates suggest an approximate 31% prevalence of hypertension in adults with similar age-standardized rates in men and women.²¹ Hypertension prevalence increases with age in both sexes.⁵ However, hypertension rates tend to be lower in premenopausal women compared to men of similar age.⁵ After menopause, which occurs at an average age of 51, a steeper rise in hypertension rates is seen in women. Menopause is associated with a two-fold increase in risk of hypertension, with a prevalence of 75% in postmenopausal women in the US.¹¹ Hypertension rates are higher in women than men over the age of 65.¹ In fact, NHANES data (2011-2014) indicates that 81.2% of women age ≥75 have hypertension versus 73.4% of comparably aged men.¹ This difference in hypertension prevalence across age and sex may be partially attributed to true biological differences; however, gender-specific differences in access to care may also partially account for this.²²

Sex Differences in Detection, Evaluation and Management of Hypertension

Although women and men with hypertension have a similar prevalence of CVD, their risk factor profile is different.¹² Hypertensive men have more traditional CV risk factors compared to women, primarily due to increased rates of smoking and dyslipidemia.12 In contrast, hypertensive women are older, with more non-traditional risk factors such as abdominal obesity and kidney disease.¹² Despite differences in CV risk factor profiles, there are limited data on sex and gender specific screening strategies for hypertension.

The current guidelines recommend self-monitored BP as an adjunct to in-office monitoring based on modest data that suggests improved BP control.⁴ However, perimenopausal and menopausal women may have more variability in ambulatory BP measurements.^23,24 Moreover, postmenopausal women are more likely to exhibit a non-dipping pattern of BP, which is described as a <10% drop in nocturnal BP.²⁵ There is evidence for poor CV outcomes and target organ damage with this type of BP pattern, especially in older women compared to men.^22,25 This highlights the need for an exploration of sex-specific diagnostic criteria for hypertension, which in turn may help improve detection, management and, ultimately, prognosis of hypertension among women. Results from the Blood Pressure Lowering Treatment Trialists' Collaboration, which included 87,349 women, suggest a greater percentage of stroke among hypertensive women compared to men, whereas a higher percentage of coronary heart disease and heart failure was observed among men compared to women.²⁶ Comparison of NHANES I and NHANES III data suggest improvement in all-cause mortality rates amongst hypertensive men is much greater than that seen amongst hypertensive women.²⁷ This disparity supports the need for sex/gender specific hypertension management strategies.

Treatment targets are not sex-specific either, as a large meta-analysis evaluating antihypertensive agents using similar cut-offs for men and women, including 87,349 women, showed no differences in CV outcomes.²⁸ Current guidelines recommend more intensive treatment of hypertension to a goal SBP ≤130 based on large trials such as SPRINT (Systolic Blood Pressure Intervention Trial).^4,29 SPRINT enrolled 3332 women (~36%) out of 9361 participants. Given the large female subgroup in SPRINT, the benefit of intensive therapy applies to both sexes.²⁹ Therefore, the same blood pressure goals should be applied for men and women based on SPRINT and the meta-analysis data.²⁹ In addition, there is strong evidence to support the treatment of hypertensive older women. The HYVET (Hypertension in the Very Elderly) trial, which enrolled 60% women including 2326 women over the age of 80, showed a significant reduction in fatal and non-fatal stroke, heart failure, CV and all-cause mortality in the hypertensive treatment group compared to placebo.³⁰ No difference in CV outcomes was found when adjusted for variables, including sex.³⁰ Although comparison of differences in both hypertension treatment and outcomes among men versus women may be important, the greater issue is whether the intervention is equally effective in women. Individual (female-specific) risk versus benefit ratio for the treatment under evaluation should be a primary focus of any comprehensive anti-hypertensive program.

Specific Pharmacological Treatment Recommendations for Hypertension

There is currently no substantial evidence for differential effects of antihypertensive therapy based on sex or gender.^5,21,28 However, comorbidities in women may influence the choice of antihypertensive treatment. Diuretic therapy, via reduced urinary calcium excretion, may have a positive effect on the prevention of bone loss and osteoporosis in postmenopausal women.³¹ One meta-analysis suggests that calcium channel blockers may be more beneficial in women than ACE inhibitors for stroke prevention.²⁸ Women may also experience more antihypertensive medication side effects than men that may impact choice of treatment and adherence.^28,32 However, adherence to antihypertensive therapy does not appear to differ by sex according to a recent cohort study examining barriers to antihypertensive medication adherence in adults over the age of 65.³³

Non-Pharmacological Interventions for Hypertension

Salt restriction has theoretical benefits in women given the possible upregulation of RAS after menopause.^5,21 Weight loss strategies may be beneficial in older hypertensive women with obesity and midlife weight gain. Weight loss, in addition to dietary intervention such as the DASH diet, has been studied in women and shows incremental benefits on BP lowering and CV biomarkers.³⁴ Moreover, reducing alcohol consumption may lower BP in a dose-dependent manner above a threshold of two drinks per day.³⁵ A recent systematic review and meta-analysis of 36 trials, including 401 women, suggests a 1.2% decrease in the proportion of women with systolic BP >140 mmHg when alcohol intake is reduced.³⁵ The current guideline recommends no more than one standard alcohol drink per day for women.⁴ The role for CV fitness in improving hemodynamics and long-term CV outcomes has been well established. Combined aerobic and resistance exercises reduce arterial stiffness and BP in postmenopausal women.³⁶

The larger issue of societal gender differences in how women and men approach preventive strategies for hypertension needs to be addressed in this era of personalized medicine. The intersection of sex, gender and culture also warrants further exploration. For example, NCHS data examining hypertension prevalence and control among US adults between 2011-2014 showed higher prevalence but lower control rates amongst non-Hispanic black women compared to non-Hispanic white women.³⁷ Culture-specific barriers to health care access and aggressive therapy may account for this. These areas lack data but may have significant implications for patient care. Social and environmental factors that influence behaviours and impact risk for CVD are different in women.²² Community characteristics, including lack of access to timely and quality health care, low education and income levels and poor social support all impact women's health and have implications for screening and treatment of hypertension.²² Greater understanding of how sex and gender influence the prevalence, diagnosis and management of hypertension is needed given that the health impact and economic burden of hypertension among women is only expected to increase as the population ages.

Table 1: Women and Hypertension Highlights

	Female sex/gender-specific factors
Pathophysiology	Vascular protective effects of estrogen: up-regulation of NO pathway & downregulation of sympathetic pathway, RAS and endothelin production Menopause – change in estrogen levels Pregnancy related vascular risks such as preeclampsia and gestational hypertension States of estrogen imbalance such as polycystic ovarian disorder, premature ovarian insufficiency and infertility Inconclusive data on progesterone
Epidemiology	Lower hypertension rates in premenopausal women Two-fold increase in risk of hypertension with menopause ~80% of women aged ≥75 have hypertension
Screening and Diagnosis	Hypertensive women have more non-traditional CV risk factors More variability in ambulatory BP measurements in perimenopausal and menopausal women Postmenopausal women more likely to exhibit non-dipping pattern of blood pressure
Treatment – Pharmacological	Diuretic therapy may be more beneficial in postmenopausal women with osteoporosis CCB may be more beneficial in women for stroke prevention Women may experience more antihypertensive side effects
Treatment – Non-pharmacological	Salt restriction may benefit women given possible upregulation of RAS after menopause Weight loss after midlife weight gain DASH diet plus weight loss may have incremental benefits on BP lowering No more than one standard alcoholic drink/day Combined aerobic and resistance exercises reduce arterial stiffness and BP in postmenopausal women

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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension, Smoking, Stress

Keywords: Alcohol Drinking, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Biomarkers, Blood Pressure, Calcium Channel Blockers, Cohort Studies, Comorbidity, Contraceptives, Oral, Coronary Disease, Diuretics, Down-Regulation, Dyslipidemias, Endothelins, Estrogens, Follow-Up Studies, Heart Failure, Homeostasis, Hypertension, Pregnancy-Induced, Hypertension, Inflammation, Kidney Diseases, Medication Adherence, Menopause, Menopause, Premature, Nitric Oxide, Myocytes, Cardiac, Nutrition Surveys, Obesity, Obesity, Abdominal, Osteoporosis, Oxidative Stress, Patient Care, Perimenopause, Postmenopause, Pre-Eclampsia, Prevalence, Progesterone, Prognosis, Proliferating Cell Nuclear Antigen, Reactive Oxygen Species, Receptors, Estrogen, Renin-Angiotensin System, Risk Factors, Sex Characteristics, Smoking, Sodium Chloride, Dietary, Stroke, Systole, Treatment Outcome, Up-Regulation, Vascular Stiffness, Vasodilation, Weight Gain, Weight Loss, Primary Prevention, Secondary Prevention

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