Introduction

Gender differences in blood pressure control that change with age are present in both normotensive and hypertensive individuals. Ambulatory blood pressure monitoring studies showed that blood pressure increases with age in normotensive men and women and that men have higher blood pressures than women until old age when the blood pressures become similar [1]. With regard to hypertension, according to the Centers for Disease Control (CDC) for the United States (US), the prevalence of hypertension is different for men and women for all age groups and ethnicities [2]. For example, the US data from 2015 to 2018 for all individuals over 20 years of age, 50.7% of men and 40.4% of women were hypertensive, defined as blood pressure ≥140/90 mm Hg [2]. For White, Hispanic and Asian individuals, men also had higher prevalence of hypertension than did women, but for Black individuals, the prevalence of hypertension was similar between men and women (males: 58.4%; women: 56.3%) [2]. Also, according to the CDC data from 2015 to 2018, there are gender differences in hypertension prevalence based on age; 34.5% of men, aged 20–44 years, were hypertensive compared to only 17.6% of women, and this trend is consistent until older ages when women had a higher prevalence of hypertension (ages 65–74 years: males, 66.7%, females, 74.3%; ages >75 years: males, 81.5%; females, 86%) [2]. These data do not reflect the new definition of hypertension as outlined in the AHA/ACC Guidelines in 2018, based on the SPRINT Trials in which blood pressure ≥120/80 (≥130/80 for diabetics) was defined as hypertension [3], and as such, it is likely the numbers of hypertensive individuals in the US are even higher. Although the mechanisms responsible for the gender differences in hypertension are not completely clear, the guidelines for standard of care and therapeutic options recommended for hypertension are not different for men and women [3].

As defined by the Institutes of Medicine in 2001 [4], “sex differences” are defined as those that could be mediated either by sex steroids or sex chromosomes. “Gender” is the way an individual describes himself/herself [4]. “Gender” also takes into account societal perception of the individual, based mainly on the individual’s portrayal of their own sex [4]. In contrast, animals, as far as we are aware, do not perceive themselves to have a sex, thus they are defined by their chromosomal milieu of XX or XY and the sex steroids that are prevalent, estrogens or androgens [4]. Thus animal studies provide insight into “sex differences”, but not “gender differences”. For human studies, unless the investigator determines that the differences between men and women are strictly due to sex steroids or sex chromosomes, all studies are considered “gender differences”. For the purposes of this review, animal studies (sex differences) and human studies (gender differences) will both be discussed. In addition to sex steroids, the discussion will focus on areas known to play key roles in blood pressure regulation, such as obesity, the sympathetic nervous system, sodium reabsorption, and the renin-angiotensin system.

Mechanisms responsible for sex and gender differences in hypertension

Androgens and estrogens

The roles that sex steroids play in mediating hypertension in humans is not entirely clear. Sex steroid hormones have been shown to upregulate or downregulate many of the systems that play major roles in blood pressure regulation, such as the renin-angiotensin system. As noted above, men typically have higher blood pressures than women [1, 2], and blood pressure increases in women after menopause and loss of estrogen [1, 2], both suggesting the contribution of sex steroids to blood pressure regulation. However, how sex steroids control blood pressure in men and women is complicated since animal studies show that androgens in females may have different effects on the mechanisms controlling blood pressure than they do in males. For example, androgen increases in young women, as seen in polycystic ovary syndrome (PCOS) and female animal models of PCOS, cause increases in body weight, insulin resistance, hyperlipidemia and elevated blood pressure [5, 6]. In contrast, low levels of androgens in men or male animals are associated with similar changes in body composition, metabolic dysfunction, and elevated blood pressure [6]. Androgens also increase in postmenopausal women without the benefit of estrogens to offset these effects [7], which also likely contributes to the elevated blood pressure in aging women.

Preclinical studies in intact female or ovariectomized Dahl salt sensitive (DS) rats maintained on a low salt diet showed that blood pressure was higher with ovariectomy than in intact females, and estradiol replacement lowered blood pressure to similar or lower levels than in intact females [8]. Blood pressure in male DS rats on low or high salt diet was also higher than in females [8]. Interestingly, with aging, the blood pressure increased in both female and estradiol-supplemented ovariectomized DS rats to the levels found in untreated ovariectomized DS [8], suggesting a waning of the estradiol effects with aging, although the mechanisms are not clear. One could speculate that age-related changes in hormone receptors could play a role in mediating the loss of estrogen protection in the DS females.

In male and female SHR, adult males have higher blood pressure than females [9]. Gonadectomy reduces blood pressure in male SHR, but has no effect on females [9]. In contrast, androgen supplements in ovariectomized female SHR cause an increase in blood pressure to levels similar to males [9], although the exact mechanisms have not been determined but may be due to effects on the renin-angiotensin system as described below [10]. With aging, blood pressure increases in females to similar or higher levels than in male SHR.

Transgender individuals and blood pressure

The role that gender affirming hormone therapy (GAHT) may play in affecting blood pressure over the life span is not clear as yet due to the lack of studies addressing this question and inconsistencies in the data among the few studies that are available. Androgen therapy in female to male transgender individuals has been shown to cause hypertension, whereas estradiol therapy in male to female transgender is associated with an increased risk of myocardial infarction and ischemic stroke [11,12,13]. In other studies, estrogen therapy plus an antiandrogen in female transgender was associated with a decrease in blood pressure [11,12,13].

Another issue is the paucity of information regarding administration of GAHT to interfere with the physiological decline in sex steroids that occurs with normal aging and the consequences on cardiovascular disease and hypertension. Sex steroids, especially androgens, are known to be decreased in individuals who have chronic diseases, such as cancer, chronic obstructive pulmonary disease and chronic kidney disease. The level of sex steroids that transgender individuals receive must be maintained in order for the phenotypes to be consistent. If indeed estrogens plus antiandrogens reduce blood pressure in female transgender individuals [13], this might have a long-term protective effect on the cardiovascular system, but the question remains whether maintaining that same level of sex steroids over the life span would remain beneficial with aging. In male transgender individuals, the fact that androgens may increase blood pressure even in young adult individuals [13] suggests that aging may exacerbate the GAHT-mediated increase in blood pressure, thus promoting cardiovascular disease with aging. Future studies will be necessary to determine the longterm hypertensive and cardiovascular consequences of GAHT, and the mechanisms that may be responsible for any adverse effects in order to determine the best therapeutic options for these individuals.

Obesity

Obesity, defined as body mass index ≥30, is at epidemic proportions in many countries, including the US. Obesity increases the risk for cardiovascular disease, especially since it increases the risk of hypertension [14,15,16]. CDC data from 2015 to 2018 show that there are gender and age-related differences in obesity rates [17]. For ages 20–54 years, the percentages of men and women with BMI ≥ 30 were similar (37.2–42.9% for men and 35.6–43.1% for women) [17]. At older ages, the prevalence of obesity was increased in women. For example, for ages 55–64 years, 43.9% of men and 46.2% of women were obese. By 65–74 years of age, the percentage of men who were obese was 41.9% and for women was 45.9%. Over age 75 years, 36.1% of women and 31.8% of men had BMI ≥ 30 [17]. Notice that these numbers are significantly lower than the percentages of individuals who are hypertensive at the respective age groups [2], suggesting that obesity is only one mechanism responsible for hypertension, although decreasing body weight is commonly recommended for hypertensive individuals [14].

Obesity and sympathetic activation

Animal studies shed light on how obesity may contribute to elevated blood pressure. Obesity is associated with increased sympathetic nerve activity, and sympathetic activation is a major mechanism responsible for hypertension [18]. One likely mechanism by which the sympathetic nervous system is activated with obesity at least in part is via melanocortin-4 receptor (MC4R) activation [19]. As shown in Fig. 1, leptin is released from fat depots in the body which leads to increases in α-melanocortin (α-MSH) that activates MC4Rs in pro-opiomelanocortin (POMC) neurons causing sympathetic activation [19]. In many animal models in which sympathetic activation mediates the hypertension, blockade of the MC4R reduces blood pressure. For example, the MC4R antagonist, SHU-9119, given intracerebroventricularly (ICV), reduces blood pressure in both adult (14 weeks old) and aging (16–18 months old) male SHR [20, 21]. However, the drug fails to reduce the blood pressure in either adult or aging female SHR [21]. Perhaps the sex differences in response to MC4R antagonism in the SHR have to do with the lack of obesity in the SHR females. In contrast, obesity and hypertension exist in a model of polycystic ovary syndrome, the hyperandrogenemic female (HAF) rat [22]. The hypertension in this model is mediated in part by sympathetic activation and SHU-9119 decreases the blood pressure [23]. The brain MC4R protein expression was also increased in HAF rats [23]. One could speculate then that it may be androgens that increase/activate MC4R expression in male SHR, but not females, since the hypertension in males is also mediated by androgens just as in the HAF rat model [9, 10, 23]. Future studies are necessary to determine the full contribution of MC4R to obesity and hypertension and to gender differences, perhaps involving the MC4R polymorphisms [24].

Fig. 1: Obesity and sympathetic activation.
figure 1

Leptin is released from fat depots in the body that increases alpha-melanocortin (α-MSH) in the proopiomelanocortin (POMC) neurons in the brain [18, 19]. α-MSH activates the melanocortin 4 receptor (MC4R) that then increases sympathetic nervous system activity. MC4R activity can be blocked by the antagonist SHU-9119 [20,21,22]. The central sympathetic nervous system can also activate the renal sympathetic nerves that cause renal vasoconstriction, sodium reabsorption, and hypertension.

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Obesity and sodium reabsorption

Since obesity is associated with elevated blood pressure, it is likely that obesity plays a role in mediating sodium handling that may contribute to the sex differences in blood pressure control. Soliman and colleagues reported that both male and female Sprague Dawley rats developed elevated blood pressure in response to 8 weeks of high fat diet, with males developing a higher blood pressure than females [25]. Interestingly, unlike in obese males, there was no difference in the ability to excrete an acute salt load in obese females compared to lean controls [25]. Blood pressure in obese males became salt sensitive with high salt diet (4%), but blood pressure in obese females was not salt sensitive [25]. The obese male rats also exhibited reduced excretion of endothelin (ET-1), with lower ET-1 and ETB receptor mRNA expression in the cortex and outer medulla of the kidney than control males [25]. Obese females did not exhibit differences in ET-1 excretion or mRNA levels compared to controls [25]. These data strongly support sex differences in sodium handling in obesity and the potential role that ET-1 may play.

Sex steroids also play a role in mediating salt sensitivity of blood pressure as seen in postmenopausal women who have low levels of estrogens and become more salt sensitive [26, 27]. It is also likely that salt sensitivity of blood pressure will be further exacerbated by obesity after menopause [28].

Renal sympathetic activation and hypertension

Renal sympathetic activation is also important in mediating hypertension. However, renal denervation as a method to reduce blood pressure in human hypertension is controversial. Some studies show that denervation reduces blood pressure, but other studies do not [29]. There are studies that show that blood pressure may be more responsive to renal denervation in women than in men [29, 30]. In contrast, studies in SHR show that renal denervation reduces blood pressure by similar percentages in both sexes [31]. In any case, future studies will be necessary to determine definitively whether women could benefit more from renal denervation than men.

Renin angiotensin system (RAS)

Both human and animal studies strongly support the concept that sex differences in the RAS affect blood pressure [28]. As shown in Fig. 2, angiotensinogen, mainly released from the liver, is hydrolyzed by intrarenal renin to angiotensin I (Ang I) which is converted to angiotensin II (Ang II) by Ang I converting enzyme (ACE) [32]. Ang II binds and activates the Ang II type I receptor (AT1R) to cause vasoconstriction and sodium reabsorption in the proximal tubule of the kidney [32]. Ang II can also bind to the Ang II type 2 receptor (AT2R) or be hydrolyzed by ACE2 to produce Ang(1–7) that binds and activates the MAS receptor to cause vasodilation [32]. Androgens upregulate angiotensinogen [33] and also increase sodium reabsorption in the proximal tubule via the AT1R [33, 34], thus increasing blood pressure. Estradiol upregulates ACE2 to produce Ang(1–7) to promote vasodilation thus reducing blood pressure [32]. In young adult male and female SHR, ACE inhibition reduces blood pressure to similar levels [10], suggesting that in young adult SHR, the major factor in controlling blood pressure in both sexes is the RAS. Interestingly, in the presence of ACE inhibition, androgens were unable to increase the blood pressure in ovariectomized female SHR [10], suggesting that the androgen-mediated increase in blood pressure in ovariectomized females was mediated by upregulation of the RAS. The AT2R has also been implicated in the sex differences in pressure natriuresis in preclinical rat studies, since females excrete higher levels of sodium than males at higher renal perfusion pressures and this response is attenuated in females treated with AT2R antagonists [35]. Female mice also have an attenuated response to slow pressor Ang II, compared to males [36], but female AT2R knockout mice have similar pressor response to Ang II as males [35], suggesting AT2R protects females from Ang II hypertension.

Fig. 2: Angiotensin mechanisms.
figure 2

Angiotensinogen released by the liver is converted to angiotensin I (Ang I) by renin which is the rate limiting step in the production of angiotensin II (Ang II) [32]. Ang I is converted to Ang II via Ang I converted enzyme (ACE). Ang II activates the Ang 1 receptor (AT1R) that causes renal vasoconstriction, sodium reabsorption, sympathetic activation, all leading to elevated blood pressure [32]. Ang II can also activate AT2R that causes renal vasodilation and reduces blood pressure [32]. Ang II via ACE2 increases Ang(1–7) peptide that activates the MAS receptor leading to vasodilation and lowering of blood pressure. Androgens can upregulate angiotensinogen [33], eventually contributing to increases in Ang II. Estrogens upregulate ACE2 that increase expression of Ang(1–7) [32], leading to vasodilation.

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With aging, blood pressure is similar or higher in female SHR than age-matched males [37]. AT1R antagonism significantly reduces blood pressure in male SHR, but only has a modest effect to reduce blood pressure in post-estrous cycling female SHR (16 months of age) [37]. These data suggest that the mechanisms responsible for hypertension are different in aging male and female SHR. The data suggest that the RAS mechanisms responsible for blood pressure control may also be different in men (favoring vasoconstriction) and women (favoring vasodilation) and may change with aging in both groups (loss of vasodilation in women, attenuation of vasoconstriction in men). There are also racial differences in response to RAS inhibitors. Clemmer et al. showed that hypertension in middle-aged black males is less likely to be controlled when given RAS inhibitors than in whites or black women [38]. Addition of hydrochlorothiazide with the RAS inhibitors was successful in reducing blood pressure in black men [38].

Finally the RAS has been implicated in activation of the sympathetic nervous system [39], and there are likely sex differences in the pressor responses and the mechanisms responsible. Sex differences have been identified in preclinical studies in the workings of the sympathetic nervous system [23, 31], but how Ang II impacts those sex differences is not clear and requires further study. Huang et al. reported that Chinese men who were hypertensive had higher sympathetic activity than did hypertensive women, and that sympathetic nervous system activity was independently associated with blood pressure in men but not women [40].

As noted in the review by Briant et al., one problem in studying sympathetic nervous system and hypertension is that there is significant variability in sympathetic nerve activity among individuals [41]. In men, the variability in sympathetic activity is balanced by cardiac output and vascular adrenergic responses such that blood pressure remains stable and normotensive across various levels of sympathetic nerve activity [41]. In women, there is similar variability in resting sympathetic nerve activity as in men, but women have greater β-adrenergic vasodilation than men and that minimizes the pressor effects of the sympathetic activity. Whether the vasodilator effects of Ang(1–7) contribute to these differences are not clear, but need to be evaluated. With aging, of course, the vasodilatory responses are attenuated in women as they lack estradiol.

Finally, Belin de Chatemele et al. propose that leptin works differently in obese males and females and this is independent of sympathetic activation in females [42]. They propose that while leptin may activate the sympathetic nervous system via MC4R activation in obese males, as we showed above, in obese females leptin from adipose tissue causes increases in aldosterone excretion from the adrenal glands and increased mineralocorticoid receptor (MR) expression in endothelial cells [42]. They further show that progesterone and progesterone receptor are the mechanisms by which the MR is increased in endothelial cells in females [43]. Whether these mechanisms are in place in aging males and females needs further study.

Other mechanisms responsible for sex and gender differences in hypertension

There are many other mechanisms that have been shown in animal studies to play a role in the sex differences in blood pressure control. These include sex or gender differences in nitric oxide since estrogens upregulate the endothelial nitric oxide synthase [44], or differences in oxidative stress because animal studies have shown that blood pressure in females does not respond to antioxidants unless the hypertension is mediated by immune system mechanisms [45]. With that in mind, differences in inflammatory mechanisms may contribute to sex and gender differences in blood pressure regulation since lower blood pressure in females is associated with higher levels of regulatory T cell levels in kidneys of hypertensive female rats compared to males [46, 47], suggesting an inverse relationship between regulatory T cells and hypertension. Other studies have shown there are sex differences in intrarenal 20-HETE that can be either pro-hypertensive or anti-hypertensive depending on the intrarenal localization, whether microvascular (pro-hypertensive) or tubular (anti-hypertensive) [48, 49]. A new area of research in this field is the sex and gender differences in the microRNAs that regulate important hypertension systems, such as the RAS and sympathetic nervous system [50]. Preclinical studies have identified developmental programming as a mechanism for sex differences in blood pressure control that may also provide new insights into the gender differences in blood pressure regulation in humans [51]. Finally, sex differences in the role that the microbiome plays in mediating hypertension, especially via its effects on the sympathetic nervous system [52], is likely to be important in blood pressure control in the future.

Limitations in the field

While there are numerous studies on how sex steroids affect the different mechanisms responsible for blood pressure control, there are no studies to our knowledge on the role of sex steroids themselves on blood pressure control in normotensive populations. As noted above, ambulatory blood pressure monitoring in a normotensive cohort who were not overweight or obese and had no other obvious cardiovascular diseases showed that men have higher blood pressure than women until later ages (>70 years) when the blood pressures are similar [1]. Burl et al., made similar observations with office blood pressures measured in the NHANES III cohort [53]. In addition, it is well known that individuals who are receiving estradiol GAHT (male to female transgender) have reductions in blood pressure, but these individuals also receive an antiandrogen such as spironolactone that is also anti-hypertensive [12]. In contrast, trans males have an increase in blood pressure [12]. As in most GAHT studies, the cohorts are made of individuals under the age of 30 years who have been receiving the therapy for only 5 years or so [12]. Taken together one could infer that normotensive men have higher blood pressure due to androgens, and normotensive women have lower blood pressure due to estrogens. However, whether sex steroids alone affect blood pressure in normotensive human populations who are not transgender has not been studied to our knowledge and would be difficult since long term removal of the sex steroids to test the hypothesis would be unethical.

Summary

As shown in Fig. 3, there are many mechanisms responsible for control of blood pressure and many of these are mediated by sex steroids or exhibit sex differences. Furthermore, sex steroids have been shown to have different physiological effects depending on whether the subject is male or female. Mechanisms of sex and gender differences in blood pressure control are receiving greater attention since the NIH and other granting agencies around the world have made new requirements that both sexes or genders must be included in their funded research [54]. New mechanisms that are identified, along with what is already known, will provide better tools for treatment of hypertension in men and women of all ethnicities thus decreasing the risk of cardiovascular disease in the future.

Fig. 3: Potential mechanisms responsible for sex and gender differences in blood pressure control.
figure 3

Adiposity leads to activation of the sympathetic nervous system (SNS) via the leptin-melanocortin pathway [19]. Activation of the SNS leads to renal nerve activation, renal vasoconstriction and/or sodium reabsorption. In addition, Angiotensin II (Ang II) upregulation can also cause renal vasoconstriction and/or sodium reabsorption [32]. SNS can activate Ang II, and Ang II can activate the SNS [39, 41]. Together they will cause a shift to the right (higher blood pressure) in the pressure-natriuresis relationship leading to hypertension. Sex steroids can impact all of these mechanisms and not necessarily in the same way depending on whether the individual is male or female. For example, in females estrogens protect from adiposity but in males estrogens cause increased adiposity. In males androgens protect against adiposity favoring increases in lean mass, but in females androgens cause increases in food intake and increases in adiposity [22, 23]. All of the major mechanisms responsible for increases in blood pressure can be affected by sex steroids, either to cause stimulation or inhibition. However, in some cases it is not clear whether or how the sex steroid impacts the mechanism, mainly due to lack of studies. For example, androgens likely increase SNS activation via the melanocortin pathway [9, 10, 23]. Whether estrogen affects SNS activation is not clear. Androgens have been shown to increase renal sodium reabsorption via the RAS [34], but whether estrogens affect sodium reabsorption directly is not clear. However, estrogens upregulate expression of the endothelial nitric oxide synthase [42], thus leading to vasodilation that would reduce sodium reabsorption indirectly. Finally, other systems that control blood pressure may also be affected by sex steroids, and these include oxidative stress [45], components of the immune system [46, 47], 20-HETE [48, 49], microRNAs that may upregulate the RAS or SNS [50], or developmental programming that upregulate one or other of the major blood pressure controlling pathways [51].

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