Sex-Biased Pharmacotherapeutic Disparities in Hypertension

Abstract

Hypertension manifests with striking sex-based disparities in prevalence, pathophysiology, and therapeutic outcomes, necessitating the reappraisal of current management paradigms. For example, men exhibit higher blood pressure (BP) in early adulthood, while post-menopausal women suffer from accelerated cardiovascular risk owing to estrogen depletion, endothelial dysfunction, and distinct aging trajectories. Moreover, the renin–angiotensin–aldosterone system (RAAS) operates rather divergently: testosterone upregulates vasoconstrictive angiotensin II type 1 receptors in men, whereas estrogen enhances nitric oxide bioavailability and modulates angiotensin II type 2 receptor in premenopausal women. These hormonal influences extend to cardiovascular aging, as women develop greater arterial stiffness post-menopause, predisposing them to heart failure with preserved ejection fraction. Conversely, men demonstrate higher endothelial dysfunction and cardiomyocyte apoptosis. Furthermore, sex-specific pharmacokinetic profiles (e.g., renal clearance, hepatic metabolism) and pharmacodynamic responses to antihypertensives underscore the inadequacy of uniform treatment strategies. This is demonstrated in women by the observed reduced efficacy of angiotensin-converting enzymes inhibitors, but superior blood pressure control using diuretics. Men, however, respond more robustly to beta blockers. Emerging evidence highlights epigenetic modifiers, including X-chromosome-linked microRNAs (miRNAs) and sex-hormone-driven transcriptional regulators, as pivotal mediators of vascular tone and drug metabolism disparities. Despite these insights, clinical guidelines remain relatively inadequately stratified by sex, perpetuating suboptimal outcomes. This review synthesizes molecular, physiologic, and pharmacotherapeutic axes of sexual dimorphism in hypertension. It also advocates for precision medicine approaches that integrate hormonal status, aging-related vascular remodeling, and genetic polymorphisms. Addressing these physiological paradigms promises to bridge the translational gap between bench and bedside, ultimately mitigating the global burden of hypertensive disease, while mitigating shortcomings in sex-based antihypertensive management.

Key Points

Antihypertensive drug efficacy and safety vary by sex, yet current guidelines often overlook these differences.

Women remain underrepresented in hypertension research, limiting evidence on sex-specific treatment responses.

Hormonal and pharmacokinetic/dynamic factors contribute to distinct drug responses between men and women.

Advancing hypertension care requires sex-conscious research standards and evidence-based, individualized treatment approaches.

Introduction

Hypertension remains a major contributor to the global burden of morbidity and mortality, affecting up to 30% of the adult population [1]. While secondary causes account for only 10% of cases, the majority are idiopathic and classified as essential hypertension [2]. Hypertension is known as the “silent killer” owing to its asymptomatic nature, which frequently results in insufficient awareness and delayed management until irreversible symptomatic complications arise [3]. Therefore, hypertension often remains undetected until it progresses to complicated hypertension, marked by its effects on the heart, vasculature, and various end-organs, including the retina and kidneys [4, 5].

Blood pressure (BP) is determined mainly by cardiac output and vascular resistance, underpinned by additional influences from humoral mediators and differential neural stimulation of the vasculature [6]. Hence, the pathophysiological basis of hypertension is multifaceted. Persistent high BP, defined by measurements of ≥ 130/80 mmHg, primarily develops owing to a pathological endogenous autoregulation system, which normally adapts to changes in stroke volume, heart rate, sodium intake, renal function, and sympathetic nervous system activity [7]. This autoregulation is achieved by various mediators, including the components of the renin–angiotensin–aldosterone system (RAAS). This system includes the vasoconstrictors renin, angiotensinogen and angiotensin II (ATII), endothelin, and others such as catecholamines, as well as the vasodilating prostaglandins, kinins, and nitric oxide (NO) [8]. These agents play a role in modulating the phenotype and hence the function of the vascular endothelium. Indeed, extensive remodeling and fibrosis of the vascular wall are key indicators of chronic high blood pressure [9]. A central driver of this remodeling is the phenotypic switch of vascular smooth muscle cells from a contractile to a synthetic, pro-inflammatory and matrix-producing state, which promotes medial thickening and arterial stiffness [10–12]. Sex hormones and RAAS-mediated signaling appear to modulate this transition, offering an additional mechanistic axis for sex-linked differences in vascular aging and hypertensive target-organ damage.

There is growing interest in understanding how different pathophysiological factors contribute to hypertension across different demographic groups. The phenomenon of hypertension has disparate rates across different populations: for instance, men are more likely to have higher BP readings compared with age-matched women [13]. However, in the age bracket of average post-menopausal women, BP readings swing in the other direction, such that 78% of these women have hypertension [13]. Even though both men and women may develop hypertension, distinguishing factors exist regarding the incidence and severity between the two groups; the Heart Disease and Stroke Statistics report indicated that, from 2015 to 2018, the prevalence of hypertension in individuals over 20 years of age in the USA was 42.8% in females and 51.7% in males [14]. Moreover, other contributing factors include levels of education and socioeconomic status, all of which influence global awareness of hypertension, chiefly among females [15]. This review aims to investigate the biological underpinnings of sex-based differences in hypertension, examine the disparities in hypertension rates, and the respectively distinct pathophysiological mechanisms driving these differences, while exploring variations in pharmacological drug responses between the sexes.

Observed Sex-Based Differences

Overview

Population-based sample studies indicate that hypertension is more common in males compared with females; however, primary care data suggest that diagnoses of hypertension are more frequently made in women than in men [16]. The discordance in reporting these diagnostic rates might be explained by differential health-seeking behaviors between the two groups; women are more likely to seek healthcare services, and thus more likely to be diagnosed with distinct diseases, including hypertension [16]. Regardless of the true prevalence of hypertension in each respective group, hypertension is ultimately enforced among men to a greater extent given their disproportionate predisposition to cardiovascular diseases, which typically prompts aggressive anti-hypertension management regimens in healthcare settings [16]. Nevertheless, observed sex-based differences in cardiovascular disease outcomes are thought to stem, at least in part, from the absence of evidence-based, sex-specific guidelines for blood pressure control and therapeutic management [17]. Thus, delineating the biological and pharmacotherapeutic distinctions between sexes remains critical for achieving more precise and equitable approaches to hypertension management.

Aging

Aging is accompanied by a plethora of biological changes, both in men and women; this is especially pertinent when comparing BP diversion trends between the two sexes, namely when compared at various life cycle stages [18]. For instance, systolic and diastolic blood pressure indices are on average higher in young men compared with young women; these metrics are highlighted by specific age ranges, particularly between 12 and 17 years, whereby sex-based differences originate in that interval [18]. This age-based cleft between male and female blood pressure measurements is also echoed across different races, thus layering an additional layer of complexity; for instance, young, white adult men have higher BP readings compared with both white and Black women [18]. However, independent of race, BP indices in women elevate significantly after the fifth decade of life, primarily due to hormonal changes induced by menopause [18]. Interestingly, a population cohort study found that, in early as the 3rd decade, women exhibited faster rates of progressive BP elevation with aging, compared with men, eventually overtaking the average BP reading as women enter their 60s [19]. This is significant as sex-based differences in BP begins relatively early in life, which sets the stage for differences in eventual outcomes.

Moreover, aging affects different components of the human body in a sex-dependent manner; for instance, women remain less sensitive to sympathetic-nervous-system-driven vasoconstriction until menopause, owing to the complex interplay between age, hormones, and sex-specific physiological factors in BP regulation [20]. Also, at all ages, men have higher absolute values of left ventricular mass than women [21]. However, cardiac aging has been shown to affect women to a greater effect than men, with a more pronounced increase in left ventricular wall thickness and concentric remodeling in women, particularly in the presence of risk factors [21]. The higher rates of age-dependent concentric remodeling observed in women contribute to greater rates of diastolic dysfunction, which predisposes them to a greater risk of developing heart failure with preserved ejection fraction (HFpEF), with women outnumbering men by around 2 to 1 in incidence [22]. Although, men are generally considered to bear a higher overall burden of cardiovascular disease than women [21, 23]. Men are also at a higher risk of developing heart failure with reduced ejection fraction (HFrEF), largely owing to their greater susceptibility to macrovascular coronary artery disease and acute myocardial infarction, factors themselves recognized as leading contributors to HFrEF [22]. In contrast, HFpEF has been associated with coronary microvascular dysfunction, a mechanism linked to aging and female sex, a phenomenon which aligns with the “common soil” hypothesis, which suggests that shared risk factors such as hypertension, obesity, and systemic inflammation contribute to both microvascular dysfunction and HFpEF [24].

Furthermore, vascular aging is also a pivotal determinant of BP across the two sex groups [21, 23]. Vascular aging differs between men and women: men exhibit greater endothelial dysfunction compared with women [21]. Arterial stiffness is also significantly more pronounced in men compared with women but the rates of arterial stiffness in women rises sharply with age, particularly following the decline in endogenous estrogen production associated with menopause [21, 23]. This effect is likewise seen in rates of coronary artery disease [21]. Therefore, properly defining sex- and age-specific blood pressure dynamics is essential to address the disproportionate burden of endothelial and microvascular dysfunction-related coronary disease in women and to guide more tailored preventive and therapeutic strategies across populations.

Psychosocial Dimension of Hypertension

There also exists a plethora of non-medical contributors that are very pertinent to the phenomenon of hypertension. This includes socioeconomic status (SES), which is a historically pivotal determinant of psychosocial wellness in society [25]. Accompanying psychosocial factors, such as discrimination, social positioning, and occupational and goal-striving stress, further contribute to poor outcomes [26]. Socioeconomic disparities, such as lower wages in certain racial groups significantly impact healthcare access and decision-making [26]. Also, early low SES is known to predispose individuals to long-term health ailments such as hypertension. Notably, across the socio-economic spectrum, differences are observed in the context of blood pressure control indices, potentially mediated by discordant types and dosages of antihypertensive medication prescribed to men and women [27]. In a cross-sectional analysis of 56,000 individuals stratified by neighborhood socioeconomic position, measured using the Area Deprivation Index, hypertension rates were higher in neighborhoods with greater deprivation [28]. Moreover, while men consistently showed a higher prevalence of hypertension than women across racial groups and deprivation quintiles, the association between socioeconomic deprivation and hypertension risk was more pronounced in women [28]. These concerning findings underscore the need to delineate the differences in the exact pathophysiological mechanisms of hypertension development and drug responses across the male and female sex groups.

Sex-Based Physiological Differences

RAAS Overview

The core physiological mechanisms of the RAAS are key to elucidating the system’s role in sex-specific BP regulation. The RAAS modulates several physiological processes that dictate blood volume and BP control [29] (Fig. 1). The system involves various molecular mediators including renin, angiotensinogen, angiotensin-converting enzyme (ACE), ATII, and aldosterone. The levels of these mediators are well controlled through an autoregulatory feedback loop that involves different organs including the liver, lungs, adrenal glands, brain, and kidneys [30]. The physiological regulation of these mediators begins at the level of the kidneys, where juxtaglomerular (JG) cells, which reside in the walls of afferent renal arterioles, detect blood volume status [31]. JG cells can be activated by neural, physical, and chemical sensory stimuli [31]. JG cells also contain prorenin, a precursor of renin, which when released during activation, gets cleaved into renin that subsequently circulates in the blood [32]. Renin converts angiotensinogen, present in the liver, to angiotensin I, which subsequently is converted to ATII in the lung vasculature by ACE [33]. ATII exerts its effects at the level of the kidneys, vascular system, and adrenal cortex [34]. Furthermore, ATII molecules act on ATII type 1 and type 2 receptors, with the former inducing vasoconstriction, while the latter functions as a protective receptor against the effects of ATII on type 1 receptors [35]. These tightly regulated mediators thus serve as the basis for enacting alterations in BP levels.

Fig. 1.

The RAAS pathway. Juxtaglomerular cells sense volume and pressure changes. When blood pressure decreases, pro-renin gets cleaved into renin and travels from kidney to liver, where it catalyzes conversion of angiotensinogen to Ang I. Ang I gets converted to Ang II by ACE in the lung vasculature. Ang II exerts its effects by targeting its relevant receptors (ATII-R1/ATII-R2). ACTH adrenocorticotropic hormone, Ang I angiotensin I, Ang II angiotensin II, ACE angiotensin-converting enzyme, ATII-R1 angiotensin II receptor 1, ATII-R2 angiotensin II receptor 2, RAAS renin–angiotensin–aldosterone system. Created in BioRender. Yaacoub, S. (2024) https://BioRender.com/r57o861

Hormones

The RAAS components are heavily regulated by sex-specific hormones; this is pertinent given that the hormonal profile of females fluctuates throughout the menstrual cycle, with mediators such as estradiol influencing the levels of RAAS components, including plasma renin [36]. For instance, the effects of angiotensin (Ang I–VII), a protective mediator against ATII, are dictated by the hormonal effects of alternating female hormones such as estradiol [37, 38]. In addition, Ang I–VII is present in greater concentrations in premenopausal women compared with men in healthy volunteers, likely due to sex hormones [38]. Importantly, premenopausal females have higher angiotensinogen levels than both males and post-menopausal females [39–41]. Angiotensinogen contains an estrogen response element in its gene promoter, reinforcing the hypothesis that estrogen increases angiotensinogen production while decreasing plasma renin concentration [42]. Nonetheless, emerging evidence suggests that estrogen is not uniformly vasoprotective; under specific vascular, renal, and neurohormonal conditions, it may also exert pro‑hypertensive actions [43]. In this context‑dependent framework, the net effect of estrogen on blood pressure likely reflects the balance between its favorable impact on endothelial function and RAAS modulation and its capacity, in certain milieus, to augment sympathetic drive, sodium handling, or vascular reactivity.

Moreover, in the central nervous system, both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) are expressed within key nuclei, including the paraventricular nucleus (PVN), rostro ventrolateral medulla (RVLM), and the nucleus tractus solitarius (NTS), which play critical roles in regulating cardiovascular functions such as heart rate and blood pressure [44]. These established hormone-induced alterations of RAAS activity in the female system support the working theory regarding the effect of sex on disease outcomes in hypertensive individuals. Also, these physiological relationships support the working theory of menopause contributing to the pathogenesis of hypertension in women owing to differential estrogen deficits. Importantly, the decline in progesterone levels following menopause has been implicated in the development of salt sensitivity and increased blood pressure among women, particularly in the presence of obesity or type 2 diabetes [45]. Progesterone functions as a natural anti-mineralocorticoid, competing with aldosterone for binding at the mineralocorticoid receptor and inhibiting aldosterone synthase activity, thereby promoting natriuresis and attenuating sodium retention [46]. Loss of this antagonistic effect after menopause results in unopposed mineralocorticoid receptor activation, leading to enhanced renal sodium reabsorption, increased extracellular volume, and heightened salt-sensitive hypertension [47]. This mechanism may also influence therapeutic response to novel nonsteroidal mineralocorticoid receptor antagonists, such as finerenone and esaxerenone, which have demonstrated efficacy in attenuating aldosterone-mediated cardiovascular and renal injury, but whose sex-specific pharmacodynamics remain underexplored [48, 49].

RAAS is thought to be particularly activated to a higher degree in males; this was demonstrated in ATII-exposed rat models fed with high salt diets [50]. Male rats displayed a salt sensitive increase in BP compared with female rats along with higher gene expression of angiotensinogen in the kidney cortex [50]. When an angiotensin receptor blocker was added, BP and urinary angiotensinogen were decreased to a similar degree between sexes, but females exhibited a greater decrease in proteinuria and an increased protective effect in the kidneys [50]. Moreover, in a model using mice fed with high-fat diets, the RAAS system was regulated differently between males and females [51]. Males exhibited reduced ACE2 activity with increased angiotensin I–VII levels, in contrast to females, who had higher levels in both, with estrogen increasing ACE2 mRNA levels [51]. These findings contributed to differences in treatment response to losartan in these mice [51]. To examine the effect of estrogen on BP control in the CNS, female mice were either ovariectomized or knocked out for ERα and exposed to ATII with their BP measured and compared with wild-type female mice [52]. While having similar BP at baseline, ATII induced a greater increase in BP in both the knockout and ovariectomized mice. This effect was counteracted upon infusion of 17β-estradiol centrally [52]. This suggests central expression of ERα plays a crucial role in mediating estrogen’s protective effects against the development of ATII-induced hypertension in female mice [52]. This effect was also observed in male mice, where the central actions of 17β-estradiol contributed to protection against ATII-induced hypertension. The modulation of ATII-induced effects by estrogen appears to involve interactions with reactive oxygen species production [53]. A similar model additionally knocked out ERβ to investigate the regional specificity of different estrogen receptor subtypes in mediating estrogen’s protective effects in a female rat model of aldosterone-induced hypertension. This study found that ERβ in the PVN and RVLM protects against aldosterone-induced hypertension by reducing oxidative stress and sympathetic activity. siRNA knockdown of ERβ, but not ERα, in these regions, augmented hypertension, emphasizing ERβ's key role in the central regulation of blood pressure in response to aldosterone [54]. It is notable that the first study did not investigate the effect of ERβ and used a nonselective ER antagonist which could explain the discrepancies. There remains a critical need to explore sex-based differences in BP regulation, with advances in genomic profiling helping to address this gap in both animal and human models.

Renal Salt Handling

Renal sodium handling is a central determinant of blood pressure regulation, with the nephron orchestrating precise reabsorption of filtered sodium through segment-specific transport mechanisms [55]. Approximately 25 moles of sodium are filtered daily, with over 99% reabsorbed across the nephron [55]. The proximal tubule reclaims 60–65% via the sodium–hydrogen exchanger NHE3, which is regulated by dopamine and PDZ-domain proteins [56]. The thick ascending limb of Henle’s loop reabsorbs approximately 20–30% through the Na–K–Cl cotransporter (NKCC), dependent on potassium recycling via ROMK channels [57]. In the distal convoluted tubule, sodium reabsorption (~ 7 to 10%) occurs via the thiazide-sensitive Na–Cl cotransporter (NCCT) [58]. Fine-tuning occurs in the collecting duct, where epithelial sodium channels (ENaCs), which are regulated by aldosterone, mediate electrogenic sodium uptake [59]; this final step is regulated by potassium secretion and is the target of potassium-sparing diuretics [60]. Across all segments, sodium reabsorption is driven by the basolateral Na⁺/K⁺-ATPase, underscoring the kidney’s pivotal role in maintaining sodium balance and systemic blood pressure [61].

Sex-specific differences in renal sodium handling have been observed in relation to RAAS activity [62]. Androgens in males enhance proximal sodium reabsorption and increase intraglomerular pressure, while females exhibit greater distal sodium transport capacity; additionally, ACE inhibition leads to more pronounced natriuresis and diuresis in men compared with women [62]. Sexual dimorphism also exists in ENaCs, as seen in male rats which exhibit a stronger natriuretic response to ENaC inhibition than females [63]. This is notable because female rodents generally express higher levels of the ENaC α- and γ-subunits compared with males [64]. Despite this elevated ENaC expression, females tend to excrete more sodium during high salt intake, likely due to impaired pressure natriuresis [63]. NCCT activity additionally exhibits sexual dimorphism, with female rats showing increased expression and phosphorylation of NCCT, which was shown to be driven by both estrogen and progesterone [65]. This increased expression led to higher fractional reabsorption of sodium along distal segments [65]. In addition, sex chromosome complement was shown to influence sexual dimorphism in salt handling with SCC, independently influencing the abundance of key renal sodium transporters, including NHE3, NCCT, and ENaC β/γ, highlighting a chromosomal contribution to sexual dimorphism beyond gonadal hormones [66]. Unfortunately, it is difficult to formulate defining conclusions on the basis of rodent models as discrepancies exist between both mice and rat models in the number of different renal transporters [67].

We will briefly acknowledge sex differences in salt sensitivity, as emerging evidence suggests that female sex hormones and chromosomes contribute to heightened salt-sensitive blood pressure responses, an area that intersects with renal sodium handling [68]. While salt-resistant hypertension is more common in men, women show a higher prevalence of salt-sensitive blood pressure responses, with some studies reporting rates up to 30% greater than those seen in men [69]. The variability in blood pressure responses to dietary salt intake reflects a complex interplay between renal sodium reabsorption, extrarenal sodium storage, neurohormonal regulation, and vascular adaptation [70, 71]. While high salt intake is broadly associated with elevated blood pressure, a significant subset of individuals remains normotensive despite consuming large amounts of sodium, indicating a subset of individuals are more sensitive to salt than others [70]. This heterogeneity is driven by differences in renal sodium excretory capacity, tissue sodium buffering—particularly in the skin and interstitium—and the responsiveness of hormonal systems such as the renin–angiotensin–aldosterone axis [70]. Salt-sensitive hypertension involves multiple physiological disruptions, including impairments in the RAAS, natriuretic and kallikrein systems, sympathetic activation, and altered endothelial and ion channel function; emerging evidence also highlights the role of female sex hormones and chromosomes in modulating these pathways and contributing to salt sensitivity [62]. Nevertheless, deeper exploration of salt sensitivity and its sex-specific mechanisms are beyond the scope of the review.

Endothelial Physiology

Endothelial dysfunction is a major driver of hypertension, with sex-based differences influencing hypertension rates and treatment responses [72]. The vascular endothelium is composed of endothelial cells (ECs) that line blood vessels, including arteries, veins, and capillaries [73]. ECs function as a barrier between blood vessels and tissues [73]. They direct immune cells to foreign materials and to areas in need of repair [72]. In relation to vascular health, a proper balance between vasodilatory and vasoconstrictive factors maintains proper function in healthy endothelium [73]. Specifically, vascular tone is regulated by nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS), prostaglandins, and endothelin, along with their subsequent downstream effects [73]. Downstream of these mediators, RhoA/Rho kinase signaling in vascular smooth muscle cells modulates calcium sensitization and vasoconstriction, thereby sustaining peripheral resistance and contributing to hypertension [74, 75]. Moreover, endothelial dysfunction is involved in the pathogenesis of various thrombotic, atherogenic, autoimmune, and infectious processes [73]. The deficiency in vasodilatory factors such as NO, along with an increase in production of proinflammatory cytokines and reactive oxidative species, are thought to play a key role in hypertension [76–78].

Prominent sex differences in EC physiology contribute to disparities in hypertension outcomes. For example, in females, estrogen receptors (ERs) stimulate the release of NO by activating eNOS, whereas activation of the androgen receptor (AR) might lead to reduced nitric oxide release in response to agonists [77, 79]. Differences in NO availability have notably been observed between male and female rats and may contribute to sex-based disparities in hypertension [80, 81]. This finding was also observed in human subjects, with males and menopausal females having lower NO availability; in addition, hormonal replacement therapy was found to restore levels to those seen in pre-menopause [80]. In a study investigating the influence of sex on two vasodilatory agents, intra-brachial acetylcholine and sodium nitroprusside, females exhibited a more modest decrease in vasodilation compared with males until the age of 49 years [82]. Conversely, post-menopausal females displayed a greater decline in vasodilation compared with males [82]. In addition, mRNA and protein levels of eNOS were higher in females, but males had a greater hemodynamic response to eNOS inhibition [83]. This was further validated upon investigating both eNOS gene and protein expression in endothelial cells extracted from umbilical veins ex vivo and grown in vitro. To minimize variability from the maternal environment, endothelial cells were extracted from twins from the same umbilical cord, whereby investigators noted differences in eNOS function as well as the inhibition of eNOS, thusly affecting the migration and sprouting of endothelial cells in females only [84]. Conversely, capillary outgrowth was unaffected by eNOS inhibition in male endothelial cells [84]. These findings highlight the extremely pertinent role of endothelial pathology in informing hypertensive outcomes in various subjects

Immunological Discrepancies

While immune differences between sexes have been well established and extensively studied, their impact on hypertension and responses to antihypertensive treatments remains underexplored [85]. Females account for 80% of cases of autoimmune diseases, and hypertension is a common complication of autoimmune diseases [86]. The immune system, along with the autonomic nervous system, plays a crucial role in the pathophysiology of hypertension (Fig. 2). Innate and adaptive immune cells, along with their proinflammatory cytokines, are key contributors to the pathogenesis of hypertension. The innate immune system includes physical barriers such as epithelial cells, neutrophils, and macrophages; bioactive small defensive molecules; and cytokines and chemokines produced by these cells. Conversely, the adaptive immune system is composed mainly of B and T lymphocytes [87].

Fig. 2.

Physiologic differences pertaining to endothelial physiology and the immune system. (A) Endothelial injury promotes macrophage recruitment and aggregation which is inhibited partly by estrogens. In the endothelium, eNOS produces nitric oxide (NO), with the levels of NO different in females owing to both increased bioavailability and estrogen’s effect on eNOS. NO leads to reduced hypertension, while ROS and proinflammatory cytokines promote a hypertensive state. (B) In the renal system, differences in the production of cytokines and responses to immune cells lead to sex-based differences in hypertension. (C) The NLRP3 inflammasome complex, under the control of both androgens and estrogens, produces proinflammatory cytokines that lead to hypertension. eNOS endothelial nitric oxide synthase, IL interleukin, NO nitric oxide, NLRP3 NOD-like receptor protein 3, ROS reactive oxygen species. Created in BioRender. Bardawil, C. (2024) https://BioRender.com/ d90p914

Innate Immunity and Hypertension

Antigen-presenting cells have been implicated in the pathogenesis of hypertension. Macrophages and dendritic cells present antigens to T lymphocytes, which can produce pro-inflammatory cytokines and lead to further downstream effects [87]. Notably, macrophages can also differentiate into dendritic cells [88]. Macrophage-deficient mice models were found to be resistant to BP increase upon a stimulus; however, the addition of primed dendritic cells from hypertensive mice into naïve normotensive mice, caused a rise in BP [88]. Macrophages are also thought to be mediators involved in the hypertensive effect of angiotensin [88]; in a study involving spontaneously hypertensive rats, angiotensin was observed to potentiate BP increase more rapidly in male rats compared with female rats [88]. While both male and female rats exhibited an increase in macrophage count, males showed a higher count than females [88]. Moreover, carotid injury was found to result in a twelvefold increase in macrophage count in ovariectomized, estrogen-deficient rat models [89]. These findings highlight the potential role of estrogen in macrophage recruitment and sex-based differences in the involvement of the innate immune system in the pathophysiology of hypertension.

Interleukin 1 beta (IL-1β) production and inflammasome signaling have also been found to be key players in the pathogenesis of hypertension. Various factors activate nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) which produces IL-1β and interleukin 18 [88] (Fig. 2). Increased inflammasome gene expression and higher levels of circulating IL-1β in individuals aged 60 years and above are significantly linked to heightened susceptibility to hypertension, vascular dysfunction, and increased risk of mortality from all causes. Moreover, androgens increase inflammasome expression while estrogen suppresses it. Estrogen begins to fall off during menopause, potentially causing higher NLRP3 expression [90]. These insights highlight the extent of the burden of pro-inflammatory mediators within the innate immune system onto hypertensive outcomes, and their intertwined nature with sex-specific hormonal balances.

Adaptive Immunity and Hypertension

Lymphocytes are also thought to play a major role in hypertension development and progression (Fig. 2). T cells have been found in the kidneys of hypertensive rats [91]. Moreover, T cells derived from humans treated with immunosuppressants were found to lower BP in experimental rodent models [91]. In addition, rodent models deficient in T cells, due to a recombination-activating gene 1 (RAG1) mutation or severe combined immunodeficiency, exhibited a blunted prohypertensive response [91–93]. When male T cells were adoptively transferred into T-cell deficient models, ATII significantly increased systolic BP in males to a greater extent than in females, and also enhanced renal lymphocyte infiltration [94]. Male adoptive transfer had a higher BP increase compared with female transfer, with increased proinflammatory cytokine concentrations and a decreased IL-10 concentration [95]. Thus, female mice have sex-specific protective mechanisms against ATII-dependent pro-hypertensive responses, which could be due to the location of T-cell phenotype, activity, and immune infiltration [96].

Notably, the female-sex-based protective effect is hypothesized to diminish upon approaching menopause. Compared with pre-menopausal mice, post-menopausal mice were found to have increased levels of T-cell phosphorylation of MP2K2, an upstream regulator of ERK, which enhances upregulated phosphorylation at ERK sites [97]. Furthermore, post-menopausal mice had decreased T-cell phosphorylation of TLN1, a key regulator of IL‐2Rα and FOXP3 expression [97]. These findings delineate how certain T-cell pathways mediate inflammation during post-menopausal hypertension.

Observed Discrepancies in BP Pharmacological Response

Over the past several decades, pharmacologic management of hypertension has centered on first-line agents such as thiazide diuretics, angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs), with second-line options including beta- and alpha-adrenergic blockers, aldosterone antagonists, renin inhibitors, and vasodilators [98]. While these classes of drugs are widely prescribed across sexes, emerging evidence underscores clinically relevant sex-based differences in both drug utilization and therapeutic response. Women are more frequently prescribed thiazide diuretics—and less often—ACE inhibitors or ARBs, reflecting both a higher incidence of ACEi-induced cough and angioedema and the teratogenic risks associated with renin–angiotensin system blockade in women of childbearing potential [99]. Despite achieving comparable reductions in blood pressure, women exhibit distinct hemodynamic responses, including greater decreases in cardiac output with thiazide use, and may experience enhanced survival benefits with ARBs compared with ACE inhibitors in the context of cardiovascular disease [100, 101]. Although current hypertension guidelines do not explicitly differentiate therapeutic approaches by sex, emerging evidence suggests that sex-specific physiology and pharmacologic response should inform more individualized and equitable treatment strategies for optimal blood pressure control [99, 100].

Importantly, the management of hypertension heavily depends on patient-specific comorbidities and demographic factors that modify both baseline risk and treatment response. [102]. Lifestyle factors such as smoking, weight, alcohol consumption, and physical activity remain key modulators of blood pressure control [103]. In the PRECIOUS trial, while women showed numerically greater reductions in office blood pressure than men during combination therapy, these differences were not statistically significant, and arterial stiffness responses were comparable between groups [105]. Moreover, large cohort analyses have established that pulse wave velocity (PWV) increases with age in both sexes but remains higher in men, whereas augmentation pressure and augmentation index are consistently higher in women, reflecting differences in vascular compliance [105]. Moreover, a 2024 study investigating the differential effects of blood pressure treatment across males and females revealed that diuretic therapy achieved better results in women compared with men with regard to desired BP control, despite only marginal differences [106]. This study also revealed greater reductions of cardiac output and LV mass in women compared with men [106]. In contrast, a prospective cohort study using participants from the Atherosclerosis Risk in Communities study, found that women 61 years and older were more likely to have uncontrolled HTN compared with men, despite similar medication adherence and intensity [107]. Contrasting data from a meta-analysis using the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) dataset, conducted around the same time as the PRECIOUS trial, had revealed consistent antihypertensive responses across sexes, such that comparable reductions in cardiovascular event risk were achieved, as was the case in the reduction of systolic blood pressure (on average) between sexes when both sex groups were subjected to a spectrum of antihypertensive drugs, including calcium channel blockers, ACE inhibitors, beta blockers, angiotensin receptor blockers, and thiazide diuretics [108]. These contrasting findings reveal a great need for investigating blood pressure responses in a population-specific, pharmacologically driven context. In this next section, we aim to discuss further discrepancies in responses across antihypertensive drug classes.

Diuretics

The kidney is prominently involved in regulating BP through body fluid regulation [109]. Elevated BP sensed by the kidney can stimulate the excretion of water and salt beyond intake levels. Conversely, reduced BP triggers water and salt retention. Diuretics, specifically thiazide diuretics, reduce the reabsorption of sodium in renal tubules, consequently diminishing the osmotic gradient between the tubular lumen and cells. This process blocks water reabsorption, leading to increased urine production [110].

Sex hormones can alter the homeostatic set point of the kidney-fluid system in females rather than induce a state of fluid gain or loss; this is achieved through lowering the osmotic threshold for desmopressin and thirst stimulation, which could be replicated through the addition of oral contraceptive pills [79]. Thiazide receptor density is also controlled by sex hormones, with female rats having a higher density compared with their male counterparts [111]. This effect was abolished post-ovariectomy in females or reproduced in males post-orchiectomy [111]. Torasemide, a loop diuretic, was found to be eliminated at a significantly reduced rate in females, which was associated with the SLCO1B1 c.521T>C polymorphism [112].

Calcium Channel Blockers

Calcium channel blockers (CCBs) impart their antihypertensive effect by inhibiting L-type calcium (Ca²⁺) channels, which reduces inward calcium flux [113, 114]. This results in vascular smooth muscle relaxation and consequently decreases BP [113, 114]. In addition, CCBs bind to cardiac tissue and impart a negative inotropic effect [114]. CCBs are metabolized in the liver into lesser active metabolites by cytochrome P-450 CYP3A [114]. Sex differences in Ca²⁺ channels have been observed, with males having increased Ca²⁺ influx along with greater Ca²⁺ intracellular concentration [114]. In addition, estrogen-deficient mice were found to have increased L-type Ca²⁺ channel density and greater Ca²⁺ influx [114]. In addition, 17β-estradiol causes rapid relaxation in vascular smooth muscle tone in rabbits, possibly through an effect on Ca²⁺ channels [115]. Females had a greater BP response to amlodipine compared with males, but were just as likely to receive CCBs [116].

While CCBs are preferentially prescribed to Black patients, owing to their superior blood pressure response compared with ACE inhibitors or ARBs, comparable evidence establishing differential responses based on sex remains limited [117]. Most trials showed no variations in sex-based CCB response, except for the Amlodipine Cardiovascular Community Trail trial, which showed a more significant reduction in BP in women compared with men taking amlodipine [118]. However, edema was more often observed in women. Nevertheless, most randomized controlled trials do not represent their results, such as adverse drug reactions, in a sex-disaggregated manner, making the discernment of discrepancies hard to track.

ACEi/ARBs

The physiological differences in pivotal regulatory systems in the body, such as the RAAS, have differential functionalities between the two sex groups. Despite the absence of pharmacokinetic sex differences in a bioequivalence study involving enalapril, pharmacodynamic differences were noted between the groups [119]. These differences included sex-specific, dose-dependent regulation of ACE levels when concentrations of the ACE inhibitor’s active metabolite, enalaprilat, fell below or exceeded 5 ng/mL [119]. Moreover, in the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) I, Survival and Ventricular Enlargement (SAVE) trial, and Studies of Left Ventricular Dysfunction (SOLVD) trials, women experienced lower mortality risk reduction from ACEi therapy compared with men [120]. The nature of cardiovascular disease suggests that men and women may respond differently to heart failure medications [120, 121].

Moreover, ARBs such as losartan, valsartan, candesartan, and telmisartan were found to reach higher maximum concentrations in women compared with men [122]. However, this difference disappeared after adjusting for body weight. Telmisartan did, however, exhibit higher maximum concentrations without significant BP changes compared with men [122]. Moreover, there were no major differences in heart failure treatment endpoints and safety profiles between the two sexes [123]. More in-depth studies are needed to examine the varying rates of adverse drug effects of antihypertensives when used for blood pressure management, as well as for the treatment of other conditions such as heart failure between the two sexes.

Beta-Blockers

The latest guidelines have relegated beta-blockers as a second-line treatment modality for hypertension. Nevertheless, they remain important pillars of cardiovascular disease treatment [124], especially in patients with co-morbid cardiac conditions: beta-blockers are useful in patients with heart failure, whereby preventing cardiac over-exhaustion and oxygen consumption is preferred [125]. Beta-blockers also exhibit varying patient-specific pharmacological responses: studies have suggested significant pharmacokinetic differences with metoprolol, showing lower oral clearance in women and greater persistence in the body after weight-matching with men [126]. These findings suggest that women may require lower doses compared with men [126]. In addition, propranolol was found to have greater bioavailability levels in women compared with men [127]. These results may be attributed to differences in CYP450 enzyme system activity, with certain drugs categorized as CYP2D6-dependent or independent on the basis of how they are processed and metabolized [99]. CYP2D6-dependent drugs have been shown to cause more adverse drug reactions in women compared with men, unlike CYP2D6-independent drugs [99].

Overall, these drug-specific sex-divergent discrepancies in antihypertensive responses underscore a dire need for personalized BP-modifying regimens.

Observed Discrepancies in BP Pharmacological Adverse Events

Various observational studies have identified female sex as an unmodifiable risk factor for hospitalization due to adverse drug events (ADE): in the UK, it was determined that 59% of women were hospitalized owing to ADE compared with 41% of men, with approximately 10% being attributed to cardiovascular drugs [128, 129]. There are likely multifactorial underpinnings to these phenomena, some of which will be explored in the following sections.

Diuretics

Diuretics have been linked with increased ADE in females, particularly hyponatremia [130]. In a cross-sectional analysis from the Swedish Prescribed Drug Register, females were more likely to report ADEs for thiazides (odds ratio [OR] = 1.78) and diuretics and potassium-sparing agents (OR = 1.62) than males [131]. A case–control study found women using diuretics have a 2–3-fold higher risk of hospitalization because of hyponatremia [130]. In addition, hypokalemia was more common in elderly females with chronic kidney disease compared with males [132].

Calcium Channel Blockers

The main ADE reported by CCBs is leg edema, and is more frequently reported by women [133, 134]. CCB-induced leg edema has the potential to lead to a prescribing cascade, where loop diuretics are used to treat the leg edema, rather than CCB dose-adjustment, which eventually leads to diuretic-induced ADE, as described above [135].

ACEi/ARBs

Data on adverse drug event (ADE) discrepancies between sexes is mixed. An Italian study found no significant sex-based differences in ADEs associated with ACE inhibitors or ARBs, notably no adjustments were made to prescription data in this analysis [136]. In contrast, various studies reported increased ADEs in women, which they attributed primarily to higher reports of dry cough and angioedema [131, 137]. Without sex-specific analyses of ADEs in randomized controlled trials of ACE inhibitors and ARBs, it remains difficult to draw definitive conclusions about sex-based differences.

Beta-Blockers

There is an evident paucity of studies studying differences in ADE rates between sexes taking beta-blockers. An interesting difference in primary outcome rates was shown in the REBOOT trial, which evaluated beta-blocker therapy versus no therapy in patients with acute myocardial infarction and preserved left ventricular function (LVEF > 40%) using a composite outcome of all-cause death, reinfarction, or heart failure hospitalization [138]. Women assigned to the beta-blocker group experienced a higher rate of primary outcome events compared with those in the no-beta-blocker group [138]. Moreover, another observational study appeared to show a similar trend linking worse outcomes in women, but was not statistically significant [139]. Caution should be taken to make concluding statements regarding possible increased harm, as a link has not been found in other studies [131].

Causes of Pharmacological Response Discrepancy

Historically, women have been more likely than men to report bodily distress and symptoms, a trend that was previously used to explain the higher incidence of ADEs in women [140, 141]. However, this represents an oversimplification of the complex pharmacological differences between sexes. The gap in knowledge regarding sex-based differences in drug responses to antihypertensive drugs arises not only from physiological differences between sexes but also from the unequal focus of studies investigating both groups; for instance, the Systolic Blood Pressure Intervention Trial (SPRINT) trial, which impacted BP guidelines, included only 36% women [142]. Moreover, further inspection into the treatment groups of this study portrayed none of the discrepancies in sex-based treatment outcomes [142]. Similarly, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, which included 39.5% women, showed no sex-specific differences in outcomes [143]. Recently trials have begun to include more females into their studies, even those of childbearing age. This paradigm shift in research practices is expected to help explain sex-based differences in hypertension rates. In parallel, the study of the relative effects of pharmacological agents between the two biological sex groups has been on the rise in recent years [144, 145]. Historically, however, women of childbearing age had not been included in pre-clinical and clinical drug trials, limiting our understanding of how treatments may affect this population [146].

Broadly, a plethora of factors determine the extent of response to pharmacological agents across sex groups. For instance, drug concentrations in the bloodstream are affected by their volume of distribution (Vd) and clearance (Cl), which are measures of pharmacodynamics and kinetics [145]. The interplay of these variables impacts drug response. Moreover, comorbid medical conditions, baseline fat percentage discrepancies, standardized baseline weight differences between the sexes, and lack of standardized dosing protocols for many drugs also play a role in sex-based drug response [145]. Moreover, the response to antihypertensive agents is dictated by several factors, including race/ethnicity, geography, body mass index, and biological sex [147]. Hypertension serves as a relatively good disease model to evaluate the phenomenon of heterogeneity of treatment effects (HTE) [148]. HTE refers to the degree of variations in the treatment response of several individuals within the same population when treated with the same agent [148]. The well-established guidelines with rigorous BP measurement cutoffs that delineate a hypertensive state are helpful in evaluating pharmacological drug responses. HTE is therefore posited to be influenced by pharmacogenetics, pharmacodynamics, and pharmacokinetics [149].

Pharmacogenetics

Sex-specific discrepancies in blood pressure alterations have been explored at the genetic level [150]. For example, a large-scale genomics study specifically identified gene loci were found to contribute to constituting a burden of risk, more so in women than men, and at specific age intervals [151]. Specifically, genetic polymorphisms have been shown to contribute to gene-based drug-responses [152]. Genetic polymorphisms refer to the variation of DNA sequences within same gene among different individuals and populations within a species [153]. These polymorphisms impact risk factor indices for a plethora of diseases. Genetic polymorphisms can impact RAAS and consequently cardiovascular health and subsequent treatment [154] (Table 1).

Table 1.

Polymorphisms and mutations associated with the pathophysiology of hypertension

References	Mutation/polymorphism	Gene	Effect on hypertension
[156, 157]	M235T	AGT	Unclear
[157, 158]	T174M	AGT	Unclear
[160]	I/D polymorphism	ACE	Greater response to ACEi → lower BP
[163, 164]	A1166C	AGTR2	Elevated left ventricular dysfunction and aortic stiffness → increased BP
[166]	rs2106809 SNP	ACE 2	Drug response to ACEi
[167, 168]	LSD1 deficiency	LSD1	Increased salt sensitivity → increased BP

ACE angiotensin-converting enzyme, AGT angiotensinogen, AGTR2 ATII type 2 receptor, BP blood pressure, LSD lysine-specific demethylase-1

Several polymorphisms in angiotensinogen, ACE, and the AT1 receptor have been identified [155]. The M235T and T174M polymorphisms have been extensively documented in relation to the angiotensinogen gene [156, 157]. However, the impact of the individual M/T allele combinations on hypertensive risk profiles remains unclear, with multiple study results having conflicting data [158]. The ACE I/D polymorphism is among the most studied and has been linked to cardiovascular, renal, immune, oncological, and neurodegenerative diseases [159]. Patients with the DD variant typically have higher ACE levels, making them more responsive to ACEi [160]. Interestingly, the DD variant was found to predict lower pulse pressure only in males taking antihypertensives, whereas females exhibited higher pulse pressure; this effect was consistent across different ethnic groups and not seen in the AGT-M235T polymorphism [161]. ACE polymorphisms in the female group of a Tibetan population resulted in notable differences in systolic BP, mean arterial BP, and diastolic BP [162]. However, ACE polymorphisms have not yet been definitively linked to consistently higher mortality from cardiovascular causes. Moreover, the polymorphism affecting the ATII type 1 receptor is known as the A1166C mutation [163]. Carriers of the C mutation have a higher conferred risk for left ventricular dysfunction and aortic stiffness; the latter predisposes individuals to higher BP with age [164]. This polymorphism also confers a risk for higher essential hypertension rates in Asian and white populations. Moreover, these carriers also have a better response to ACE inhibitors. Other notable polymorphisms that impact BP and BP-altering drug responses are those pertaining to plasma renin activity (PRA) [165]. Moreover, ACE II, an enzyme that counterbalances traditional ACE, has been newly discovered, along with its important single nucleotide polymorphism (SNP), rs2106809 [166]. It is believed to be a predictive risk factor for ACE inhibitor drug response in Chinese female patients [166]. These relevant genetic polymorphisms across the spectrum therefore heavily contribute to outcomes in hypertension in diverse patient populations.

Furthermore, sex-specific differential expression of certain risk alleles across the human genome have been noted to cause specific physiological phenotypes. For example, specific allele risk variants of the lysine-specific demethylase 1 (LSD1) have been associated with salt-sensitivity of BP, a phenomenon that leads to increased CVD risk, particularly in African American individuals [167]. However, LSD1-risk-allele-induced salt-sensitive BP is different across age, sex, and race. For instance, this phenomenon is prevalent in women with a depleted estrogen state [168]. It has also been suggested that this gene product epigenetically modulates the mineralocorticoid receptor, a known modulator of BP [169]. Aldosterone dysregulation is also evident in individuals with LSD1 risk-allele expression [167]. It therefore remains crucial to bridge the gap between sex-specific pathophysiological states and appropriate drug-appropriate treatments for respective sex and/or race categories.

Genetics have been heavily implicated in controlling drug responses to antihypertensive therapy. Future large-scale genomic studies can guide clinicians on how to communicate disease status and tailor management for both men and women, particularly those with inherited risk, and may also support earlier detection by serving as a screening tool.

Pharmaco-epigenetics

Antihypertensive drug responses can be altered by epigenetic processes [170, 171] (Fig. 3). Epigenetic regulation, defined as heritable yet reversible modifications that alter gene expression without changing the underlying DNA sequence, has emerged as a key determinant of hypertension onset, progression, and therapeutic variability. Among these mechanisms, DNA methylation and its oxidative derivative hydroxy methylation involve the addition or removal of methyl or hydroxymethyl groups to cytosine residues, modulating promoter accessibility and the gene silencing of pathways controlling vascular tone, renal sodium transport, and the renin–angiotensin–aldosterone system [172, 173]. Histone modifications, including acetylation, methylation, and phosphorylation of histone tails, influence chromatin compaction and the transcriptional activity of genes governing endothelial function, vascular remodeling, and arterial stiffness; aberrant activity of histone-modifying enzymes such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) has been linked to inflammation, altered vascular contractility, and salt sensitivity [174]. Noncoding RNAs (ncRNAs), which encompass microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), also play critical regulatory roles in hypertension; while miRNAs are short, approximately 22-nucleotide sequences that post-transcriptionally repress messenger RNA translation, lncRNAs are transcripts longer than 200 nucleotides that serve as molecular scaffolds or recruit chromatin-remodeling complexes to specific genomic loci [172]. These ncRNAs regulate networks underlying oxidative stress, endothelial homeostasis, and renal sodium handling, thereby influencing both hypertension risk and variability in drug response [175, 176]. Limited but emerging evidence also indicates the presence of sex-specific epigenetic signatures, in which sex hormones and X-linked genes modulate the activity of DNA methyltransferases and histone-modifying enzymes; this interaction gives rise to dimorphic vascular and renal phenotypes that may explain the higher prevalence of salt-sensitive hypertension in post-menopausal women and differential therapeutic responses to renin–angiotensin system inhibitors [177, 178].

Fig. 3.

Established epigenetic mechanisms. (A) DNA methylation alters gene expression profiles. (B) Histone modifications are widely established epigenetic processes that encompass (de)methylation and (de)acetylation. (C) Noncoding RNA molecules alter gene expression by targeting mRNA and affecting pre-protein stage expression. Noncoding RNA, such as lncRNA, have also been linked to targeting other ncRNA such as miRNA. ncRNA noncoding RNA, lncRNA long noncoding RNA. Created in BioRender. Yaacoub, S. (2024) https://BioRender.com/m00j218

In relation to hypertension, epigenetic mechanisms involving histones and miRNA have been associated with renal damage, a phenomenon which can impact blood pressure owing to the pivotal role the kidneys play in autoregulatory mechanisms [179, 180]. Epigenetic mechanisms have also been widely linked to several pathological cardiovascular conditions; for example, DNA methylation, hydroxy methylation, histone modifications, and noncoding RNAs have been implicated in the pathogenesis of arterial hypertension [172].

The role of epigenetic mediators, such as histones, has also been increasingly explored in recent years; histone deacetylase inhibitor (HDAC ITF2357) imparted a protective effect in a male murine study with acute kidney injury-induced diastolic dysfunction and hypertension, compared with female mice [181]. This HDAC also had roles in dictating weight changes and muscle mass, but did not prevent renal sequelae such as renal fibrosis [181]. Moreover, miRNAs can serve as biomarkers that could potentially be evaluated to predict drug responses [182]. This was observed in studies involving circulating miRNAs that delineated their potential in predicting rates of thiazide diuretic effectiveness in hypertensive populations [183]. Investigators have thus developed a unique, new genome-wide circulating miRNA profiling panel to detect five miRNA molecules with associations related to antihypertensive drug-response: these included miRNA-423-5p, miRNA-30d, miRNA-142-3p, let-7g, and miRNA 193b-3p [183], all of which also displayed heterogeneity across races (e.g., the African American population).

In addition, a loose association between drug responses to pharmacological agents (e.g., bisoprolol) and DNA methylation patterns in the ACY3 gene has been identified [184]. Other long noncoding RNA such as X-inactive specific transcript (XIST) are also thought to play a role in the sexually dimorphic nature of hypertension emerging from the pulmonary vasculature [185]; women are thus four times more likely to develop pulmonary hypertension compared with men [186]. Importantly, XIST has been studied in the context of X chromosome inactivation, which is prevalent in the genome of women [185]. XIST is an example of a mediator which facilitates differential sex-based prevalence of pulmonary hypertension through epigenetic mechanisms.

These epigenetic modulators serve as the widely described literature-based mediators with regard to shifting vascular predisposition to a hypertensive phenotype, but more insight is required relative to drawing correlative general conclusions. Collectively, these findings suggest that epigenetic mechanisms serve as an integrative bridge between genetic predisposition, environmental exposures, and hormonal influences, shaping both hypertension prevalence and treatment outcomes and highlighting the potential of epigenetic biomarkers and targeted therapies to improve precision and equity in antihypertensive management [187].

Pharmacokinetics

Pharmacokinetics refers to the biological processing that pharmacological agents and other substances undergo in the body [149]. Conventionally, these processes are chronologically: (1) absorption, (2) distribution, (3) metabolism, and (4) elimination [188]. The general variation across these processes between males and females has been studied for several decades (Fig. 4). In fact, it is known that women generally exhibit greater levels of overall drug exposure, a factor predisposing them to a variety of adverse drug reactions across various antihypertensive drug classes [99]. On a physiological level, this is mediated by body composition indices, variations in sex-specific enzymatic activity, and hormonal fluctuations that dictate a plethora of downstream metabolic effects [99]. Nevertheless, pharmacokinetic factors, embodied by all these four processes patently dictate drug effects across both sexes [99].

Fig. 4.

Sex-based differences in pharmacokinetics. The elements of pharmacokinetics include absorption, distribution, metabolism, and excretion. Sex-based differences influence these various factors individually. Distribution, the central element of pharmacokinetics, dictates drug concentration at the site of action. The relevant clinical outcomes are thus dictated by the physiological response to the drug at the molecular level. MOA mechanism of action. Created in BioRender. Yaacoub, S. (2024) https://BioRender.com/u60g783

(1) Absorption

Absorption is primarily determined by the routes of drug intake, namely oral, dermal, rectal, intrathecal, venous, arterial, and peritoneal. Moreover, passages through gastrointestinal (GI), dermal, and respiratory tracts also introduce further variations. Oral administration is the most relevant route for antihypertensives [99]. Firstly, absorption is different among males and females because women possess higher pH environments in the gastric area, in addition to considerably slower gastric emptying with a longer GI transit time [188–190]. This is pertinent with regard to drug intake, including antihypertensives; for example, certain drugs require acidic environments with lower pH indices [191]. Moreover, transporter proteins such as P-glycoprotein (PGP), which facilitate absorption in several organ counterparts, have variant expression profiles in males and females, a factor that may also dictate availability of antihypertensive drugs [188].

(2) Distribution

Drug distribution refers to the spreading of nonmetabolized substances throughout the vasculature and body [120]. Given that men, on average, weigh more than women, and carry a smaller percentage of body fat, lipophilic substances will naturally have a higher Vd in women, compared with hydrophilic substances [188]. Moreover, hormonal factors affect Vd: for instance, estrogen in women reduces plasma albumin (a carrier) via glycosylation in the liver [188]. In addition, the volume of distribution is influenced by systemic metabolic handling: for example, nitrate agents can traverse erythrocyte membranes and be carried within red blood cells, making their bioavailability dependent on the individual’s metabolic profile [188].

(3) Metabolism

The liver is the primary drug metabolism site [192]. Flow of substances into the liver depends on portal circulation and cardiac output, factors that are higher in men than women [120]. The subsequent phase 1 and 2 liver metabolic enzymes also vary by sex, as they are dictated by hormonal status, botanical supplement use, physiologic age, and microbiota, the latter of which has recently been heavily implicated in sex-based differences [120]. Importantly, elements of the microbiome have a role in facilitating the effect of various pharmacological agents owing to considerable exposure in the GI tract [193]. Moreover, the gut microbiome can enhance or inhibit the effect of drugs such as antihypertensives [120]. Dimorphic microbiome populations among males and females affect digestion, absorption, distribution, and elimination.

CYP enzymes are primarily found in the liver: around 77 genes have been identified to have sex-dependent expression in the context of CYP enzyme production [120]. CYP enzymes and transporters post-absorption also have an impact on the bioavailability of drugs [120]. For instance, the differences in the activity of CYP P450 enzymatic system and uridine diphosphate glucuronosyltransferase (UGT) enzymes can lead to pertinent differences in eventual Cl [194]. In relation to drug metabolic processes, some evidence suggests that females have lower activity levels of CYP1A2, CYP2E1, and UGT; higher levels of activity of CYP3A4, CYP2A6, and CYP2B6; and negligible differences in CPY2C9 and CYP2D6 activity compared with males [120]. CYP450 system enzymes such as CYP3A4 and CYP3A5 are known to metabolize a variety of hypertension and cardiovascular disease drugs, such as statins, calcium channel blockers, and beta-blockers.

Moreover, men possess greater levels of drug efflux pump P-glycoprotein (encoded by MDR1) in the ileum (along with the liver and kidney) [195]. Some CCBs, such as verapamil, and other cardiovascular drugs, such as digoxin, have been known to be transported via P-glycoprotein [196, 197]. Portions of antihypertensive drugs are processed and lost in the liver, such as propranolol and spironolactone; the former has its metabolism stimulated by testosterone, as opposed to the case in females where estrogen and other androgens do not modify its metabolism [120]. Moreover, the constitutive androstane receptor AhR and pregnane X receptor, which impact BP, also exhibit sex-biased expression and functionality [120].

Ultimately, integrating diverse enzyme and genomic datasets into artificial intelligence (AI)-guided models, and validating them through inclusive clinical trials, will be essential to close sex- and race-based gaps in antihypertensive pharmacogenomic evidence and optimize individualized therapy.

(4) Elimination

Drugs eliminated by the kidneys must undergo secretion, reabsorption, and filtration, all of which are greater in men compared with women [120]. Weight also independently affects drug elimination [120]. Hence, antihypertensives that are exclusively eliminated via the kidney would subsequently get cleared much slower in women compared with men [120]. Drug transporters in the kidney also have differential sex-based expression; 21 renal drug transporter genes in the human kidney were shown to be expressed in greater numbers in men [198]. Sex hormones modulate the differential dominance of certain renal drug transporter genes by altering the RAAS mediators [120]. Discrepancies across these pharmacokinetic parameters all play a role in yielding various sex-based outcomes in drug elimination.

Despite the stark variations in pharmacokinetic processes across both sexes, the lack of their consideration when incorporating drug management options in clinical trials explains the dearth in quality data in literature when it comes to optimizing sex-specific, drug-specific, personalized treatment options for hypertension.

Pharmacodynamics

Pharmacodynamic discrepancies refer to discordant effects of similar drug concentrations between two different individuals [145] (Fig. 4). These factors are harder to quantify and characterize compared with pharmacokinetics (PK). Moreover, pharmacodynamic discrepancies have been less studied in women owing to smaller amounts of groups included in pre-clinical studies [120]. It has been suggested that women are more pharmacodynamically sensitive compared with men [188]; this may be due to the differential efficacy of signaling pathways and binding affinity with regards to functionally relevant receptors. Several receptors have been implicated in dictating the pharmacodynamic discrepancies between the two sex groups:

Endothelin Receptors

Endothelin 1 (ET-1) is a potent vasoconstrictor in the human body; the endothelin family and its receptors contribute to cardiovascular disease. ET-1 is also involved in natriuresis. Endothelin response and concentration exhibit sex dimorphism. Endothelin levels are greater in males compared with females, whereas post-menopausal females exhibit higher levels than premenopausal females [199, 200]. Estrogen supplementation was found to decrease ET-1 concentration, possibly due to both estrogen-dependent and independent pathways [201–203]. 17-β estradiol supplementation was also found to limit ET-1-induced cardiac fibrosis and remodeling through activated AMP kinase and PKA blocking AngII-inhibition of Rho and activation of Rho kinase [204].

Growing evidence further supports the cardioprotective effect of G protein-coupled estrogen receptors (GPERs) in cardiovascular and renal disease. G1, a GPER agonist, was found to increase sodium excretion in female rats, an effect not observed in male rats; this response was reduced with the inhibition of ET-1. When the rats were ovariectomized, GPER activation decreased BP. This may also explain why endothelin receptor antagonists, used in treating pulmonary hypertension, have a more pronounced effect in females than males, even when baseline characteristics are similar [205]. Consequently, GPERs can serve as potential therapeutic targets in post-menopausal women [206]. Additional studies investigating the endothelin family of molecules and receptors are crucial in the study of the pharmacodynamics of hypertension therapies.

Adrenergic Receptors

Adrenergic receptors are G protein-coupled receptors (GPCRs) that belong to the sympathetic nervous system, which regulates the fight or flight response and are divided into α and β subtypes, consisting of nine subtypes in total: α1A, α1B, α1D, α2A, α2B, α2C, β1, β2, and β3. They interact with their ligands norepinephrine and epinephrine to regulate multiple physiologic processes in the human body, with the cardiovascular system among the most important systems regulated [207, 208]. Adrenergic receptors are the target for multiple antihypertensive drugs such as alpha-adrenergic receptor antagonists and beta-blockers [209]. Stress, which activates the locus coeruleus–norepinephrine system (LC-NE system), is a risk factor for cardiovascular disease. It is also activated during hypovolemia, with increased discharge rates found in rats when hypovolemia was induced using sodium nitroprusside [210].

The LC-NE system exhibits sexual dimorphism attributable to the expression of estrogen receptors and increased neuron density within the LC of females. Estrogen decreases the number of α2 adrenergic receptors in the brain and increases tyrosine hydroxylase (TH) synthesis, which is the rate limiting enzyme for NE synthesis. This contrasts with testosterone decreasing TH synthesis, thereby decreasing NE levels. These findings translate to males having lower levels of NE compared with females, hence a lower risk for cardiovascular disease in response to stress [211]. Interestingly, this correlates with the phenomenon of Takotsubo syndrome, which is triggered by both emotional and physical stress, being more common in females [212]. The exact reasons for this difference have yet to be elucidated and warrant further investigation.

In the heart, β1 activation increases heart rate and contractility. Isoproterenol administration, a β1 and β2 agonist, induced greater contractility, cell shortening, and cAMP production in male myocytes compared with female myocytes in isolated rat heart ventricular myocytes. In addition, there was increased β-receptor density in males. This effect was seen even though female myocytes contained a higher number of calcium channels, suggesting that males have a more prominent response to β receptor stimulation [213]. When examining human subjects, it was observed that women exhibited a heightened vasodilatory response to β2 agonists, presumably attributable to increased β2 receptor density in endothelial vessels in females, a phenomenon subject to variations across the menstrual cycle (Table 2). Heightened sensitivity of β2 receptors could account for the decreased forearm vasoconstriction induced by norepinephrine in women [214]. This difference is age-dependent and is attenuated with increased age specifically post-menopause, highlighting the role of estrogen in β-receptor reactivity [112].

Table 2.

Dimorphic sex-based antihypertensive response elements

Drug class	Pharmacokinetic differences	Pharmacodynamic differences	Observed response differences	Adverse drug events
Thiazide and loop diuretics	Women show slower renal elimination. Torasemide eliminated at reduced rates in women owing to SLCO1B1 c.521T>C polymorphism [112, 216]	Higher thiazide receptor density in females. Estrogen lowers the osmotic threshold for thirst and desmopressin; receptor density changes with gonadectomy [111, 218]	Potentially greater BP reduction in women owing to higher receptor density and hormonal sensitivity [219, 220]	Increased risk of hyponatremia and electrolyte imbalance in women [221, 222]
Calcium channel blockers	Metabolized by CYP3A4, which is more active in women [223]; estrogen influences hepatic enzyme activity. Cleared faster in men compared with women [224]	Males have greater Ca2+ influx along with increased Ca2+ intracellular concentration [225]. Estrogen deficiency increases L-type Ca2+ channel density and increases Ca2+ influx [226]	Women may show greater BP reduction with amlodipine [227]; limited sex-disaggregated data in trials	Higher incidence of peripheral edema in women [133]
ACE inhibitors	No major pharmacokinetic differences for ACEi [99]	Sex-specific ACE regulation at low/high enalaprilat levels; RAAS activity differs by sex [119]; estrogen modulates RAAS components [228]	Lower mortality benefit in women in major trials (CONSENSUS, SAVE, SOLVD) [229]	ACEi-induced cough more frequent in women [230]
ARBs	ARBs reach higher plasma concentrations in women; differences diminish after adjusting for body weight [99]	RAAS activity differs by sex; estrogen modulates RAAS components [231]	Telmisartan shows higher maximum concentration in women without BP endpoint changes [232]	ARBs show similar safety profiles across sexes [233]
Beta-blockers	Lower oral clearance and higher bioavailability in women; CYP2D6 activity varies by sex [229]. Propranolol and metoprolol persist longer in women [127]	Men have higher β1 receptor density → stronger cardiac contractility; women show heightened β2 vasodilatory response [234]	Women may require lower doses compared with men for optimal control [99]	Higher primary outcome events (myocardial infarction, death) in women compared with men [235]

Future Directions: Perspective on Sex-Specific Precision in Hypertension Management

The central implication of this review is that a purely one-size-fits-all approach to hypertension management is increasingly unlikely to be optimal: sex-linked differences in RAAS biology, endothelial and immune pathways, pharmacogenetics, epigenetics, and pharmacokinetic/pharmacodynamic profiles make it unlikely that women and men derive equal benefit or harm from identical drug choices and doses. Future work must therefore move beyond merely documenting sex differences to building an operational precision-medicine framework in which sex, hormonal status, and genetic/epigenetic background are core design variables in research, data infrastructure, and care delivery. This will require prospective enrollment and adequate powering of women and men across the life course including perimenopause, pregnancy, and hormone therapy use with systematic capture of hormonal status, comorbidities, and social determinants, rather than treating these as secondary covariates.

At the research level, multi-omic and systems approaches should be prioritized to link sex-specific genomics, epigenomics, immune profiles, microbiome signatures, and pharmacokinetics/pharmacodynamics to antihypertensive response and toxicity. Large-scale consortia could generate shared, harmonized datasets in which sex, race/ethnicity, age, and reproductive stage are explicitly encoded, enabling robust discovery of sex–treatment interactions and informing trial designs that test class choice, dose, and combinations in a sex-stratified manner.

Artificial intelligence (AI) and machine learning are well positioned to integrate these heterogeneous data streams into actionable tools, provided they are trained and validated on sex-balanced, diverse cohorts. In the near term, AI models could be developed to (i) predict individual blood pressure trajectories and cardiovascular risk under different drug regimens, (ii) estimate sex-specific probability of adverse events for each drug class, and (iii) suggest personalized first- and second-line options that account for sex, hormonal status, pharmacogenomic profile, co-morbid conditions, and concomitant medications [236]. Such models should be prospectively tested against usual care, with clear performance benchmarks and safeguards to detect as well as correct sex and race bias.

Clinically, and at the health-system level, these insights can translate into several tangible changes. Guidelines should move toward sex-informed thresholds and treatment algorithms, with explicit recommendations for when to favor or avoid classes in specific sex–phenotype combinations (e.g., post-menopausal women with salt-sensitive hypertension, women with high risk of diuretic-induced hyponatremia, and men with high β-adrenergic burden). Health systems can monitor performance using sex-disaggregated quality indicators (control rates, hospitalization, adverse drug reactions), while wearables, mobile health tools, and patient education materials are redesigned to reflect sex-specific trajectories of blood pressure and treatment response. Collectively, these steps define a concrete precision-medicine pathway: use sex-conscious research to build predictive tools, deploy AI and pharmacogenomics to personalize therapy, and continuously audit outcomes to ensure that individualized hypertension care closes, rather than widens, existing disparities between women and men.

Conclusions

Hypertension exhibits consistent, clinically meaningful sex differences across epidemiology, vascular and immune biology, RAAS and renal pathways, and pharmacologic response and toxicity. By integrating mechanistic, pharmacokinetic/pharmacodynamic, pharmacogenetic, and pharmaco‑epigenetic data, this review highlights that many apparent inconsistencies in literature become more coherent once sex, hormonal milieu, and life‑course stage are explicitly considered.

These insights reframe sex from a background covariate to a potential key modifier of both disease trajectory and treatment benefit–risk, with direct implications for trial interpretation, guideline development, and everyday prescribing. Rather than assuming therapeutic equivalence between women and men, it will be important for clinicians and investigators to interpret existing evidence through a sex‑conscious lens and recognize where data for women, for specific reproductive phases, or for diverse ancestries remain sparse.

Funding

Open Access funding provided by the Qatar National Library. No external funding was used in the preparation of this manuscript.

Declarations

Conflict of interest

Serge Yaacoub, Charles Bardawil, Ryan Yammine, Ali H. Dakroub, and Ali H. Eid declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

Ethics approval

Not applicable.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated for this manuscript.

Code availability

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Authors contributions

Conceptualization: AHE. Analysis: AHE. Supervision: AHE. Validation: SY and AHD. Visualization: AHD and AHE. Writing—original draft: SY, CB, RY, and AHE. Writing—reviewing and editing: AHD and AHE. Project administration: AHE.