2021 WHO Guideline

Sex-related aspects and recommendations of previous WHO and joint WHO/ISH guidelines are presented in the Data Supplement [12,13,14,15,16,17,18]. In 2021, the WHO released a guideline paper for the pharmacological treatment of hypertension in adults [9].

Sex and gender aspects

Overall, it is recommended that pharmacological treatment of hypertension, including treatment initiation and targets for BP control, should not be different between men and women.

Pregnancy-related aspects

However, it was underlined that different drug treatment algorithms, including renin–angiotensin system blockers, are contraindicated during pregnancy and also in women who could become pregnant. Hypertension in pregnancy is generally diagnosed when BP is ≥140 mmHg and/or ≥90 mmHg on at least two occasions, at least six hours apart. Chronic hypertension is defined as a diagnosis of hypertension before 20 weeks of gestation, while gestational hypertension is defined as hypertension at 20 weeks or later. Preeclampsia and eclampsia are pregnancy-specific medical conditions requiring immediate and specific medical management. It was acknowledged that while BP treatment thresholds for hypertension in pregnancy continue to change, it is generally recommended for both chronic and gestational hypertension that pharmacologic treatment be initiated when the systolic BP is ≥160 mmHg and/or the diastolic BP is ≥105 mmHg. In women diagnosed with hypertension before pregnancy, the antihypertensive treatment may be continued unaltered. However, some medications may have to be changed to preferred medications, while medications contraindicated in pregnancy must be discontinued. The guideline report acknowledged that recommended on-treatment BP target in pregnancy also has been subject to debate and is changing. For instance, achieving lower BP target (diastolic BP of 85 mmHg vs. 100 mmHg) has decreased severe hypertension rates while not increasing maternal or fetal risk [35]. In the case of women with hypertension-mediated target organ damage, the initiation of antihypertensive treatment at a diastolic BP of ≥90 mmHg should be considered. Preferred medications are: methyldopa, beta blockers (particularly labetalol, but not atenolol), calcium channel blockers (particularly nifedipine and, as an alternative, verapamil), and direct-acting vasodilators (particularly hydralazine). There is evidence to suggest that among these agents, beta blockers and calcium channel blockers appear more effective than methyldopa in decreasing the development of severe hypertension later in pregnancy. Thiazide diuretics have been debated, particularly if the individual is already on a thiazide before pregnancy. In this situation, the thiazide diuretic may be continued.

2020 ISH GuidelineSex and gender aspects

In 2020 the ISH issued a guideline report for the global management of hypertension [10]. According to this guideline, hypertensive men 55 or older and women 65 years or older are at higher risk of cardiovascular disease. Moreover, in a simplified classification algorithm of the overall cardiovascular risk, it is stated that risk categories will vary according to age and sex. Regarding alcohol consumption, recommended daily consumption of alcohol is limited to 20 g and 15 g of alcohol for men and women, respectively. Beta blockers should be used in younger women with or planning pregnancy. Fibromuscular dysplasia should always be suspected in women with onset of hypertension below 30 years.

Pregnancy-related aspects

Regarding the management of hypertension during pregnancy [10], identifiable hypertension-related conditions are pre-existing hypertension, gestational hypertension, pre-existing hypertension with superimposed gestational hypertension, preeclampsia, eclampsia, and HELLP (i.e., hemolysis, elevated liver enzymes, and low platelets) syndrome. 2020 ISH guidelines [10] endorsed the traditional definition of preeclampsia (i.e., hypertension and proteinuria). Optimally, ambulatory BP monitoring should be used to evaluate white coat hypertension, diabetes mellitus, and chronic kidney disease during pregnancy. Women at high risk of preeclampsia should be identified and treated with 75–162 mg daily aspirin. Drug treatment initiation is reserved for persistent BP of more than 150/95 mmHg for all pregnant women; however, a threshold of 140/90 mmHg may be used in women with hypertension-mediated organ damage. Methyldopa, slow-release nifedipine, nicardipine, and labetalol are preferred to treat mild hypertension. However, methyldopa should be avoided during puerperium, due to the risk of inducing postpartum depression. Hypertensive disorders in pregnancy are associated with an increased risk of hypertension and cardiovascular disease in later life.

2018 ESC/ESH Guideline

Sex-related aspects of previous ESC/ESH guidelines before 2018 are reported in Data Supplement [26,27,28]. The 2018 ESC/ESH guideline provides an extensive argumentation on sex-related or sex-specific issues for the management of hypertension [2].

Sex and gender aspects

The global age-standardized prevalence of hypertension is 24% and 20% in men and women, respectively. Male sex is associated with greater cardiovascular risk, which is incorporated into the Systematic Coronary Risk Evaluation (SCORE) system to estimate the 10-year fatal cardiovascular risk. However, the risk of total cardiovascular events compared to fatal events alone is approximately three times higher than the rate of fatal cardiovascular events in men and four times higher in women. The guideline further mentions different cut-off points for the diagnosis of left ventricular hypertrophy for men and women regarding electrocardiography (Cornell voltage) and echocardiography [2]. Sexual dysfunction may be triggered or aggravated by treatment with a thiazide or thiazide-like diuretic, conventional beta blockers, or centrally acting agents (e.g., clonidine).

In contrast, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, or vasodilating beta blockers may have neutral or even beneficial effects. Moreover, very limited evidence suggests that antihypertensive medications are not associated with sexual dysfunction in middle-aged or older women. Spironolactone may not be well tolerated in men due to antiandrogenic side effects. However, it can also be associated with menstrual irregularities in women.

Hypertensive women are more likely to receive oral anticoagulation treatment, according to the CHA2DS2-VASc (Cardiac failure, Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age 65–74 and Sex category [Female]) algorithm. Alcohol consumption should be limited to 14 units per week in men and 8 units in women. Waist circumference should be <94 cm in men and <80 cm in women to prevent hypertension or reduce BP.

This guideline [2] also addressed the issue that combined estrogen–progesterone oral contraceptive pills can be associated with a small but significant increase in BP and the development of hypertension in about 5% of users. BP usually decreases promptly following cessation of these pills; consequently, BP should be monitored before and during oral contraceptive treatment. The 2018 ESC/ESH guideline [2] also acknowledges that older studies have demonstrated a relationship between oral contraceptive pills and venous thrombosis or thromboembolism and, to a lesser extent, myocardial infarction (especially with concomitant smoking history) and stroke. More recent studies with newer-generation oral contraceptive pills reported conflicting results. Thus, physicians prescribing oral contraceptives should consider the individual patient’s risks and benefits. Finally, hormone-replacement therapy and selective estrogen receptor modulators should not be used for primary or secondary prevention of cardiovascular disease, while there is no convincing evidence for a significant BP rise in menopausal women due to hormone replacement therapy.

Pregnancy-related aspects

A more expanded definition of different hypertensive disorders in pregnancy was attempted [2] compared to previous ESC/ESH guidelines [26,27,28], including (i) pre-existing hypertension, (ii) gestational hypertension, (iii) pre-existing hypertension plus superimposed gestational hypertension with proteinuria, (iv) preeclampsia, and (v) antenatally unclassifiable hypertension. Guidance on BP measurement in pregnancy at the office or at home with automated devices was reported, as well as the role of ambulatory blood pressure monitoring in pregnant women. To prevent preeclampsia, women at high or moderate risk of hypertensive disorders in pregnancy should receive 100–150 mg of oral aspirin daily from week 12 to week 36 of pregnancy. The 2018 ESC/ESH guidelines have recommended, despite paucity of evidence, initiating of drug treatment in all women with persistent elevation of BP ≥ 150/95 mmHg. Furthermore, pharmacological treatment is recommended in women with gestational hypertension, pre-existing hypertension (with the superimposition of gestational hypertension), or hypertension with subclinical hypertension-mediated target organ damage, when BP is >140/90 mmHg. A BP target of <140/90 was empirically suggested for pregnant women receiving antihypertensive therapy. In mild hypertension in pregnancy (140–159/90–109 mmHg), methyldopa, labetalol, and calcium channel blockers are drugs of choice; however, beta blockers may induce fetal bradycardia, and consequently, their type and dose should be carefully selected, with atenolol best avoided. Women with pre-existing hypertension may continue their current antihypertensive medication, while angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and direct renin inhibitors are, contraindicated due to adverse fetal and neonatal outcomes. Although BP-lowering is mandatory, the agents to use should be individualized for treating severe hypertension (≥160/110 mmHg). All antihypertensive drugs taken are excreted into breast milk. Most drugs are present at very low concentrations except for propranolol and nifedipine, with concentrations similar to those in maternal plasma. Finally, women who develop gestational hypertension or preeclampsia are at increased risk of hypertension, stroke, and ischemic heart disease in later life.

2017 ACC/AHA guideline

Sex-related aspects of previous JNC guidelines in the USA are reported in Data Supplement [19,20,21,22,23,24,25, 36, 37]. The 2017 ACC/AHA guidelines [3] also provided different sex-related aspects and recommendations.

Sex and gender aspects

Male sex was reported among cardiovascular risk factors in patients with hypertension. A gradient of progressively higher cardiovascular risk from normal BP to elevated BP and stage 1 or 2 hypertension is consistent across subgroups defined by sex. The estimated prevalence of hypertension is not different between the sexes by using the threshold of ≥140/90 mmHg (31% vs. 32%), while prevalence in men is somewhat higher compared to women (48% vs. 43%) when the threshold of ≥130/80 mmHg is applied, i.e. the cut-off levels for the definition of hypertension in the 2017 ACC/AHA guideline [3]. Prevalence of hypertension is lower in women than in men until about the fifth decade but is higher later in life. Another sex-related issue is that white-coat hypertension is higher in women than men. A higher incidence of angiotensin converting enzyme inhibitor-induced cough and edema with calcium channel blockers were observed in women. Diuretic use in women is more frequently associated with electrolytic disturbances, whereas gout is less frequent than in men. The prevalence estimates in men and women of hypertension awareness and treatment are higher in women. In contrast, hypertension control rates in those treated were not different between the sexes. Premature birth is associated with a 4-mmHg higher systolic BP and a 3-mmHg higher diastolic BP in adulthood, with somewhat larger effects in women [36]. Early-onset hypertension due to fibromuscular hyperplasia is more common in women. Limiting alcohol to ≤1 drink daily for women and ≤2 drinks for men was recommended. For women receiving oral contraceptives, the following recommendations were made: (1) use of low-dose (e.g., 20–30 mcg ethinyl estradiol) agents or a progestin-only form, or use of alternative forms of birth control where appropriate, and (2) use in women with uncontrolled hypertension should be avoided.

Pregnancy-related aspects

Focusing on special requirements for women in pregnancy, the 2017 ACC/AHA report [3] provided the following statements: (1) BP usually declines during the first trimester of pregnancy and then slowly rises, (2) the classification of hypertensive disorders in pregnancy included, (i) the newly pregnant mother with existing hypertension; (ii) incident hypertension; (iii) preeclampsia; and (iv) severe hypertension, (3) hypertension during pregnancy and preeclampsia are recognized as risk factors for future hypertension and cardiovascular disease, (4) the goal of antihypertensive treatment during pregnancy includes prevention of severe hypertension and prolonging gestation to allow the fetus more time to mature, (5) treatment of mild-to-moderate hypertension during pregnancy reduces the risk of developing severe hypertension, but has not be shown to prevent adverse pregnancy outcome including preeclampsia, (6) beta blockers (mainly labetalol) and calcium channel blockers (mainly nifedipine) appear superior to methyldopa in preventing preeclampsia, (7) it is recommended to screen all pregnant women for preeclampsia by measuring BP at every prenatal visit, (8) women with hypertension who become pregnant, or are planning to become pregnant, should be transitioned to methyldopa, nifedipine, and/or labetalol, (9) women with hypertension who become pregnant should not be treated with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, or direct renin inhibitors, (10) aspirin and magnesium should be used according to the American College of Obstetricians and Gynecologists task force report [38], while reference is made to another report detailing treatment of hypertensive emergencies during pregnancy and postpartum [39].

2017 Latin American Society of Hypertension GuidelineSex and gender aspects

The 2017 report of the Latin American Society of Hypertension [11] states that the prevalence of metabolic syndrome in Latin America is higher in women than men (25.3% vs. 23.2%). Also, to define abdominal obesity, the cutoff values of waist circumference are 94 cm for men and 88 cm for women. In cases of renal artery stenosis in young individuals, fibromuscular dysplasia is more frequent in women.

Pregnancy-related aspects

Preferred drugs to treat mild hypertension in pregnancy are methyldopa, labetalol, nifedipine, or amlodipine. Drugs interfering with the renin-angiotensin system are forbidden and should not be prescribed to pregnant women or woman who are planning to get pregnant. Hypertension during pregnancy is defined as BP values higher than 140/90 mmHg when measured twice (same arm, interval of 15 min). Severe hypertension during pregnancy is defined as BP values higher than 160/110 mmHg. When systolic BP is at least 160 mmHg and/or diastolic BP at least 110 mmHg, BP reduction is mandatory. The Latin American guideline [11] recommends that the unique preeclampsia treatment is delivery. However, magnesium sulfate can be considered to prevent maternal convulsive events before and after delivery. Aspirin may be recommended in women at high risk of eclampsia before the onset or before the sixth week of pregnancy until delivery.

Selected recent National Guidelines

Details of selected national guidelines including the 2019 NICE guideline (https://www.nice.org.uk/guidance/ng136, https://www.nice.org.uk/guidance/ng133), the 2016 guideline of the Australian Society of Hypertension [29, 40], the 2018 guideline of the Korean Society of Hypertension [30,31,32], the 2018 guideline of the Chinese Hypertension League [33], and the 2019 guideline of the Japanese Society of Hypertension [34] are presented in Data Supplement.

Summary of findings

Sex-related aspects and recommendations in international and selective national hypertension guidelines are presented in Table 1. Gender issues are not reported in guidelines reports, while sexual dysfunction problems are largely underrepresented. In Table 2, we present aspects related to management of hypertensive disorders in pregnancy. Although there is consensus about the definition of hypertension in pregnancy, several guidelines still recommend not to treat non-severe hypertension. Furthermore, there is a disparity regarding treatment targets when treating severe or non-severe hypertension.

Table 1 Sex-related aspects and recommendations in hypertension guidelines.Table 2 Recommendations related to pregnancy in hypertension guidelines.