Estrogen-mediated mechanisms in hypertension and other cardiovascular diseases

Abstract

Cardiovascular disease (CVD) is the leading cause of death globally for men and women. Premenopausal women have a lower incidence of hypertension and other cardiovascular events than men of the same age, but diminished sex differences after menopause implicates 17-beta-estradiol (E2) as a protective agent. The cardioprotective effects of E2 are mediated by nuclear estrogen receptors (ERα and ERβ) and a G protein-coupled estrogen receptor (GPER). This review summarizes both established as well as emerging estrogen-mediated mechanisms that underlie sex differences in the vasculature during hypertension and CVD. In addition, remaining knowledge gaps inherent in the association of sex differences and E2 are identified, which may guide future clinical trials and experimental studies in this field.

1. Introduction

Hypertension poses a major public health concern, both due to the volume of diagnoses and the associated comorbidities. These conditions primarily include other cardiovascular diseases (CVD) such as stroke, coronary artery disease, heart failure, arrhythmias, and peripheral vascular disease. Overall, deaths caused by hypertension or diseases stemming from this condition rose by 65.3% from 2009 to 2019 in the United States¹. The incidence of hypertension increases dramatically during the lifespan in both men and women, with diagnosis in women surpassing men after midlife. Premenopausal women experience less hypertension and cardiovascular incidents than men of the same age¹, but this cardioprotection is lost after menopause. In fact, postmenopausal women have a higher risk for hypertension and CVD than age-matched men, suggesting that 17β-estradiol (E2) is a protective factor.

During the female reproductive years, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels rise during the follicular phase and then decrease as E2 levels rise in the mid-to-late follicular phase². When women reach menopause at the average age of 52 years, endogenous E2 levels rapid decline by more than 60% while FSH/LH levels rise and promote an abundance of androgen^2–4. The oscillations in circulating E2 and androgens during the menopausal transition (usually lasting between 2–7 years) promotes vasomotor symptoms including hot flashes, night sweats, weight gain, and sleep deprivation and may influence the regulation blood pressure (BP)^5,6. Recent data from the Study of Women’s Health Across the Nation (SWAN) shows that a menopause-induced increase in blood pressure occurs only in a subset of women and is associated with age at menopause and levels of follicle-stimulating hormone⁷. Menopausal hormone therapy (MHT) effectively reduces these symptoms of menopause but has been linked to adverse effects such as stroke and coronary heart disease⁸. While these conditions are dangerous, these adverse effects are dramatically reduced when therapy is initiated within 5 years of the menopausal transition⁹.

In contrast to the somewhat conflicting results in clinical studies, animal data strongly support the favorable effect of E2 on cardiovascular health. Female rodents are protected from increased BP, vascular injury, and heart failure compared to males, but this cardioprotection is abolished after ovariectomy (OVX) and rescued by estrogen treatment^10–12. Additionally, women who undergo oophorectomy are more likely to be diagnosed with hypertension, ischemic heart disease, and stroke due to the sudden loss of endogenous estrogen^13–15. These are clear indicators that estrogen plays a significant role in the sex differences in hypertension and CVD. Here, we provide a comprehensive overview of the literature regarding the direct mechanisms of estrogen receptors in the cardiovascular system and their interactions with hypertensive mechanisms (Figure). Furthermore, we identify remaining knowledge gaps, which may guide future clinical trials and experimental studies in this field.

Figure:

The protective cardiovascular actions of estrogen are mediated by nuclear receptors ERα and ERβ as well as the membrane G protein-coupled estrogen receptor (GPER). In addition to the direct actions of these estrogen receptors on vascular tone, estrogen interacts with a plethora of other systems and conditions that promote hypertension including the renin-angiotensin-aldosterone system, sympathetic nervous system, vascular remodeling, obesity, immunity, gut microbiota, salt-sensitivity, and circadian rhythms.

2. Cardiovascular estrogen receptors and direct signaling mechanisms

E2 is a sex hormone associated with female and male reproduction as well as other functions in the vascular, neuroendocrine, and immune systems. Pioneering work by Edward Doisy and Alfred Butenandt led to the discovery of estrone, followed by E2¹⁶. Elwood Jensen discovered a binding site for E2 in female reproductive tissues, later identified as estrogen receptor alpha (ERα)^17,18. The second nuclear estrogen receptor was cloned by Jan-Åke Gustafsson in the mid-1980’s and named estrogen receptor beta (ERβ). Original characterization of E2 signaling revealed binding in the cytosol, receptor dimerization, and nuclear translocation. The ligand-receptor complexes then bind estrogen response elements in the DNA to regulate gene transcription¹⁹. Estrogen receptor complexes also interact with coactivators and corepressors to enhance or impede gene transcription, allowing the clinical development of selective estrogen receptor modulators (SERMs), which activate nuclear estrogenic signaling in a tissue-specific manner²⁰. Estrogen receptors are localized in the cytosol, nucleus, and membrane compartments of many cell types including cardiovascular tissues such as the vasculature and heart^21–23. Studies have also revealed E2 binding and receptor localization in plasma membranes^24–26 and caveola^27,28, suggesting that estrogen receptors also elicit nongenomic signaling.

2.1. Cardiovascular mechanisms of ERα in females

ERα is abundant in the uterus, followed by the kidney, and is similarly expressed in female and male tissues²². Although growth and development are possible in the absence of ERα, reproductive function is heavily compromised²⁹. In the vasculature, ERα is localized in both endothelial and smooth cells, but expression may vary with sex, age, and vascular bed^21,22,30,31. ERα expression varies with circulating estrogen levels throughout the menstrual cycle and is significantly decreased after menopause³². ERα activation plays critical role in cardiovascular protection against hypertension, pulmonary hypertension, arteriosclerosis, heart failure, and ischemia/injury in the myocardium^33,34.

ERα deletion and aging increase the propensity for hypertension³⁵. In rodents, ERα RNA expression is reduced in the aortas of middle-aged female mice compared with young females²¹. OVX in female rats decreases endothelial ERα and disrupts its ability to induce nitric oxide signaling. Moreover, the reintroduction of E2 is unable to rescue endothelial dysfunction four months post-OVX^36,37. The selective ERα agonist Cpd1471 improves endothelial dysfunction after OVX in spontaneously hypertensive rats³⁸. In angiotensin II-induced hypertension, female ERα knockout (αERKO) mice have higher mean arterial pressure (MAP) than wildtype, which is also exacerbated by a loss of ovarian hormones³⁹.

Both membrane and nuclear mechanisms are implicated in the protective effects of ERα on vascular function in females. There are three identified ERα isoforms (ERα66, ERα46, and ERα36)⁴⁰ which induce endothelial nitric oxide signaling to provide protection against hypertension²⁸. ERα also augments the release of other vasodilator agents such as prostacyclin and decreases the production of vasoconstrictors such as angiotensin II (Ang II) and endothelin⁴¹. However, studies in mice lacking the nuclear activating function AF2 indicate that nuclear ERα signaling underlies the ability of estrogen to mitigate Ang II-induced hypertension³⁵. Recently, the H2NESKI mouse line was generated to investigate only non-genomic signaling due to the lack of a nuclear export signal in ERα. The phenotype of H2NESKI mice is very similar to αERKO mice except for enhanced reendothelialization, which interestingly occurs even in the absence of endogenous estrogen⁴². Taken together, these studies indicate a role for ERα in estrogen’s protective effects, especially with regards to endothelial function.

2.2. Cardiovascular mechanisms of ERα in males

Limited or conflicting data is available regarding the cardioprotective properties of E2 in males. The primary source of E2 in men is from aromatization of testosterone. An imbalance in androgen metabolites and low levels of E2 are associated with an increased risk of CVD and mortality among men^43–45. In humans, a single nucleotide polymorphism in ERα contributes to SBP regulation in men but not in women⁴⁶. ERα is also expressed in male smooth muscle and endothelial cells^47,48. E2 inhibits proliferation and migration of smooth muscle cells with similar responses in both males and females⁴⁸. Chronic supplementation of E2 in aged men does not change flow-mediated vasodilation in the brachial artery or impact nitric oxide metabolites in the blood compared with aged-matched women⁴⁹. In contrast, long-term E2 enhances flow-mediated dilation in the brachial artery of age-matched men, male-to-female transexuals, and premenopausal women⁵⁰. Low dose E2 treatment in hypogonadal men (mean age 68 years old) reduces SBP and DBP, mitigates vasoconstriction in response to Ang II and norepinephrine, and enhances nitric oxide release⁵¹. E2 supplementation has beneficial effects on the vasculature and ameliorates cardiac dysfunction in male mice with myocardial infarction⁵², and deletion of membrane ERα induces similar endothelial dysfunction as seen in aged mesenteric arteries⁵³. Although these findings demonstrate potential cardiovascular protection by E2 in males, there is no evidence that estrogen supplementation in older men is associated with a reduced risk of hypertension or CVD.

2.3. Cardiovascular mechanisms of ERβ

The expression of ERβ in peripheral cardiovascular tissues is debatable, with some studies showing no or little expression in the heart, kidney, and aorta^22,23. However, studies from female ERβ knockout mice or administration of an ERβ agonist suggests this receptor provides protection against ischemia/reperfusion injury through upregulation of cardioprotective genes and activation of nitric oxide^54,55. Since ERβ expression is significantly increased in male rats following vascular injury⁵⁶, the receptor may be inducible by disease. ERβ is expressed at higher levels in the brain²², where its signaling in the paraventricular nucleus is important for counteracting Ang II-induced hypertension in perimenopausal mice⁵⁷. In rats, ERβ activation in the brainstem is protective against aldosterone-induced hypertension⁵⁸.

A variant of ERβ is associated with hypertension in women, although men were not included in the study⁵⁹. It remains to be explored whether the single nucleotide polymorphism of ERβ in hypertensive young women interacts with ovarian hormones. Justin and colleagues established a role for the ERβ variant in DBP regulation in men⁴⁶. However, Ogawa et al. showed single nucleotide polymorphism in Erβ is associated with SBP in Japanese women⁶⁰. The ERβ genetic variation is also associated with salt-sensitive hypertension in premenopausal women but not in men or postmenopausal women⁶¹. While the role of ERβ is not as clear as the other nuclear estrogen receptor, its ability to protect in specific tissues and diseases may prove to be beneficial when designing unique therapies to target this pathway.

2.4. Cardiovascular mechanisms of the G protein-coupled estrogen receptor (GPER)

Discovery of the G protein-coupled estrogen receptor (GPER) transformed the classical concept of estrogen receptors signaling via nuclear mechanisms⁶². GPER is localized to the plasma membrane and/or the endoplasmic reticulum and is activated by E2 rapidly to turn on non-genomic signaling^26,62. GPER activates second messengers including cyclic AMP to induce vasorelaxation but also has downstream influences on gene transcription^63,64. Other vascular signaling mechanisms of GPER include intracellular calcium mobilization and phosphorylation of ERK1/2^65,66. GPER is ubiquitously expressed, with highest levels detected in brain²², and is regulated in cardiovascular tissues in a sex- and age-specific manner^21,22.

GPER induces beneficial effects in a variety of cardiometabolic conditions including hypertension^67–69, arterial stiffening^64,70, stroke⁷¹, vascular oxidative stress^64,72, and obesity and diabetes^65,73,74. Our laboratory and others demonstrate that the GPER agonist G-1 induces rapid non-genomic signaling which is particularly desirable in endothelial-mediated vasorelaxation and the regulation of SBP^65,67,75. GPER decreases with aging and is associated with a decline in the vascular response to E2^21,76. A single nucleotide variant of GPER is associated with higher MAP, SBP, and DBP in young women⁷⁷. In OVX rats, GPER plays a cardioprotective role particularly with regards to diastolic function^78,79, presumably through its ability to reduce inflammation and oxidative stress^80–82. They mechanisms may also be involved in GPER-mediated protection against atherosclerosis⁴¹ and kidney damage^83,84.

These explorations of GPER throughout the cardiovascular system identify this receptor as a plausible target for treating female CVD, but the potential in males is less clear^72,85. Acute administration of E2 attenuates vasoconstriction in coronary arteries from women but not men⁸⁶. In contrast, intravenous administration of conjugated E2 enhances male coronary blood flow in response to acetylcholine after 15 minutes of intervation^87–89. These findings indicate discrepancies regarding the nongenomic effect of E2 and the potential actions of GPER in male vascular cells.

3. Interactions of estrogen with other hypertensive mechanisms

In addition to direct actions of E2 on cardiovascular tissues through nuclear and non-nuclear receptors, this predominant female sex hormone has a plethora of interactions with other hormone systems as well as physiological processes known or hypothesized to impact the regulation of blood pressure. E2 alters the expression of hormone receptors and growth factors and protects from injuries or disorders that promote hypertension. Therefore, this section will explore these interactions with other mechanisms that may be related to the development of hypertension and are potential therapeutic targets.

3.1. Renin-angiotensin-aldosterone (RAAS) system

The RAAS and sympathetic nervous system play crucial roles in the regulation of BP, and imbalances in these systems contribute to hypertension. Both contain vasoconstrictor and vasodepressor mechanisms, and the resulting output is related to the relative expression and activity of the components of each arm of the system. In the RAAS, the vasoconstrictor components include the preprohormone angiotensinogen, angiotensin-converting enzyme (ACE), the peptide angiotensin II (Ang II), and the Ang II type 1 receptor (AT1R)⁹⁰. Components of the RAAS which counteract increased BP include angiotensin-converting enzyme 2 (ACE2), the Ang II type 2 receptor (AT2R), and the Ang II metabolite Ang-(1–7) as well as its receptor (MasR). Similarly, the sympathetic nervous system contains both alpha adrenergic receptors (αAR) that promote vasoconstriction and beta-adrenergic receptors (βAR) that promote vasorelaxation. In both systems, females are associated with enhanced vasodepressor mechanisms while males have higher activity of vasoconstrictor components^91,92.

Numerous studies on animal models of RAAS activation suggest that estrogen augments the ACE2-Ang(1–7)-MasR/AT2R pathways to induce cardiovascular protection while testosterone upregulates the ACE-AngII-AT1R axis⁹¹. In the spontaneously hypertensive rat model, Ang II-induced vasoconstriction is enhanced in OVX female arteries and associated with greater AT1R (vasoconstrictor) and lower AT2R (vasodilator) expression⁹³. Moreover, these alterations are reversed by in vivo E2 replacement. In the mRen2.Lewis congenic rat, a model of renin overexpression, OVX increases SBP in female rats to a similar level as observed in males and elevates circulating Ang II and ACE activity while reducing Ang-(1–7)^94,95. Interestingly, these protective effects of estrogen on the RAAS and SBP occur despite the fact that the angiotensinogen gene contains an estrogen response element which upregulates expression of this preprohormone⁹⁶. The ability of estrogen to impact tissue expression of other components of the RAAS is not associated with direct ER binding to its response element and also shows tissue-specificity, with the greater regulation in kidney versus lung or heart^97,98. Clinical studies confirm that estrogen therapy in postmenopausal women increases angiotensinogen but suppresses other vasoconstrictor components such as renin and ACE^99,100. Importantly, differences in RAAS components may lead to varying therapeutic efficacy for antihypertensive medications in men versus women or pre- versus postmenopausal women¹⁰¹. ACE inhibitors, for example, reduce cardiovascular risk to a greater extent in elderly male versus female hypertensive patients, perhaps due to greater activity of this enzyme¹⁰².

3.2. Sympathetic nervous system

Reproductive hormones also modulate sympathetic nervous system activity. In response to a mental stressor, postmenopausal women display enhanced SBP and norepinephrine responses, while E2 administration in perimenopausal women attenuates the vasoconstriction to norepinephrine^103,104. Animal studies show that greater contraction in male versus female arteries in response to αAR stimulation, while the opposite is found for βAR responses^105,106. Some but not all studies correlate these findings with estrogenic regulation of adrenergic receptors, where βAR are enhanced while αAR are downregulated^105,107,108. In fact, hot flashes are a symptom of estrogen loss during perimenopause that are associated with increased αAR activation¹⁰⁹. While men have overall higher levels of muscle sympathetic nerve activity, the role of hormones in this sex difference is made evident by changes across the menstrual cycle^110,111. However, women on oral contraceptives display a paradoxical vasodilation in response to this stressor compared with non-users¹¹². Baroreceptor dysfunction also contributes to hypertension, and an impact of estrogen on this reflex is observed in both animal and human studies¹¹³. In anesthetized rats, baroreflex sensitivity is increased by OVX and restored by E2 treatment. In postmenopausal women, sensitivity and heart rate variability are both higher in women taking menopausal hormone therapy versus controls¹¹⁴. Taken together, these data indicate interactions between E2 and sympathetic function in women that may underlie increases in hypertension.

3.3. Vascular remodeling

In the vasculature, aging is a complex molecular mechanism process, and sex hormones and genetic factors contribute to the vascular aging phenotype. Matrix metalloproteinases (MMPs) play an essential role in vascular remodeling, cell growth, and extracellular matrix (ECM) degradation and are localized to most vascular cell types¹¹⁵. Female sex hormone fluctuations lead to cyclic changes in MMPs that help to regulate tissue remodeling¹¹⁶. Additionally, sex differences noted in many MMPs and other CVD biomarkers find that large differences between men and premenopausal women are minimized after menopause¹¹⁷. In aging rodents, E2 administration decreases vascular wall thickness and distensibility and is associated with increased MMP-2 activity¹¹⁸. The role of nuclear ER in these effects are not clear, as activation of either ERα or ERβ with selective agonists counteract vascular collagen deposition due to aldosterone infusion¹¹⁹. More recent studies suggest that nuclear E2 signaling via ERα may be detrimental to vascular remodeling while activation of GPER is protective¹²⁰.

Another less understood mechanism associated with vascular remodeling is cellular senescence during natural aging. Telomere shortening occurs with each successive division until cells reach replicative senescence. This process occurs earlier in men despite similar length telomeres when age matched and prevents cellular repair, which may account for some sex differences seen in vascular aging although the reason behind this difference is yet to be uncovered¹²¹. Vascular aging is also associated with calcification and stiffening of blood vessel walls. Studies consistently show that aging and menopause both increase arterial stiffness, but the impact of menopausal hormone therapy is mixed^122–124. Therefore, factors such as timing and age may impact the ability of estrogen to reverse vascular remodeling during aging.

Using a rodent model, our group finds lower pulse wave velocity (PWV; a measure of arterial stiffness) in females, but this protection is lost during hypertension and aging^70,125. Moreover, global deletion of GPER increases PWV in young, healthy female mice¹²⁵. Interestingly, others show a detrimental role for ERα in arterial stiffness, as endothelial cell-specific deletion of this receptor is protective in both male and female mice fed a western diet^126,127. The mineralocorticoid system most likely contributes to sex differences, as aging-induced arterial stiffening occurs earlier in male versus female mice but is blunted by deletion of the mineralocorticoid receptor from smooth muscle cells¹²⁸. Moreover, patients with primary aldosteronism have increased carotid intima-media thickness and endothelial dysfunction in comparison with hypertensive patients¹²⁹. Further information is still needed to identify the mechanisms that contribute to arterial stiffening and the impact of hormone therapies.

3.4. Obesity

Obesity is a major risk factor for hypertension and other CVD¹³⁰. Currently, 42% of adults in the United States are obese, with both higher rates and more severe obesity in women than men¹³¹. Even though females are protected from CVD before menopause, obese premenopausal women lose this protection and have a higher risk for CVD than men, suggesting that obesity may dampen or negate the cardioprotection provided by E2 during the reproductive years¹³⁰. Conversely, loss of E2 during the menopausal transition also promotes obesity, through changes in fat distribution, body composition, and food intake contribute to weight gain¹³². Data from animal models support a direct role for estrogen receptors in metabolism, feeding behavior, adiposity, and physical activity^133,134. Women have higher levels of leptin than men even after controlling for body weight, which stimulates aldosterone release from the adrenal gland and promotes endothelial dysfunction^135,136. Data thus far does not support a role for E2 in regulation of circulating levels of leptin^137,138. However, aldosterone levels in response to an Ang II challenge are significantly lower in E2-treated versus OVX rats¹³⁹. Interestingly, obese middle-aged women have higher plasma aldosterone levels than obese men, and aldosterone blockade is more effective for CVD in women. These studies indicate that the aldosterone-mineralocorticoid receptor pathway may impact the negative effect of obesity on CVD risk in females.

3.5. Immunity

While women are protected from CVD due to E2, they have an increased risk of autoimmune diseases¹⁴⁰. Many autoimmune diseases fluctuate in degree of severity during a woman’s lifetime based upon variations in hormone levels¹⁴¹. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), both of which are more common in women, worsen during pregnancy while estrogen levels are high¹⁴². High levels of E2 have an inhibitory effect on the immune system^143,144 which is likely regulated by estrogen receptors expressed at high levels on activated T cells and other immune cells¹⁴⁵. In healthy women, circulating CD4+ T cells produce more of the anti-inflammatory phenotype marker, IFNγ, while in men more IL-17, a pro-inflammatory marker, is produced¹⁴⁶. Interestingly, SLE is characterized by increased Th17 cells¹⁴⁷ and SLE and RA are both associated with increased hypertension risk¹⁴⁸. Therefore, increased expression of inflammatory cytokines most likely play a crucial role in hypertension risk. The protective effect of female sex on hypertension is maintained in premenopausal but not postmenopausal Rag1^−/− mice, which lack T and B cells^149,150. Moreover, the increased hypertension in postmenopausal Rag1^−/− mice is dependent on the presence of CD3⁺ T cells. These data identify an important role for T cells as well as other immune cells in the protective effects of estrogen in hypertension.

3.6. Gut microbiota

Evolving research shows that gut microbiota may play a larger role in CVD than previously understood. Several metabolites produced in the gut are associated with adverse phenotypes, including specific oral and gut bacterial phylotypes such as Chrysemonas which are found in atherosclerotic plaques^151,152. A direct connection between the gut microbiome and hypertension is shown by the development of high SBP, DBP and MAP in mice after fecal transplants from hypertensive human donors¹⁵³. It has yet to be determined if obesity drives gut microbiota dysfunction or vice versa. Some human studies indicate that higher caloric intake is associated with decreased variability of healthy gut bacteria and can be rescued by weight loss^154,155.

E2 and its receptors play a significant role in the gastrointestinal tract¹⁵⁶. A study of 35 postmenopausal women showed that hormone therapy increases duodenal microbial biodiversity, lowers fasting glucose, and decreases bacteria associated with cardiovascular risk¹⁵⁷. Estrogen deficiency also changes the gut microbiota to promote abnormal lipid metabolism and nonalcoholic fatty liver, a disease that is more prevalent in postmenopausal women and associated with clinical CVD^158,159. Thus, it is essential to consider gut microbial composition when considering the impact of E2 on CVD risk.

3.7. Salt-sensitive hypertension

The consumption of high dietary salt in modern society contributes to chronic kidney diseases, hypertension, and CVD. Some individuals experience a greater than 10% increase in BP, while others are resistant to the effects of salt¹⁶⁰. Salt sensitivity is elevated in hypertensive subjects compared with normotensive postmenopausal women¹⁶¹. In salt-sensitive subjects, the kidneys retain most of the salt due to abnormal overactivity of the sympathetic nervous system and failure to adequately suppress the RAAS¹⁶⁰. Sex differences exist in renal function, with females having greater ability to excrete salt due to distinct expressions of sodium transporters in different segments of the kidneys¹⁶². Estrogen loss improves salt sensitivity in female Dahl salt-sensitive rats, indicating that E2 protects against kidney damage and the development of hypertension¹⁶³. E2 mediates pressure natriuresis by regulating the RAAS and the endothelin system in the kidneys¹⁶⁴ and attenuates kidney injury in hypertensive mRen2 rats fed a high salt diet^10,83,84. Of note, salt sensitivity is a complex disease associated with a strong genetic predisposition, which is crucial for the development of hypertension¹⁶⁰. Whether the protection against kidney damage mediated by E2 in high salt conditions is lost after menopause has not been fully understood, and in fact some animal studies show unexpected results in female models of aging and OVX¹⁶⁵. Therefore, further investigation is necessary to address the essential health outcomes of a high salt diet in the renal system and the impact of sex hormones.

3.8. Circadian rhythms

Blood pressure follows a circadian pattern that repeats every 24 hours in healthy individuals, with a BP reduction of 10–20% from day to night. Healthy individuals with this normal decline in nocturnal BP are known as dippers, while those with a blunted fall in nighttime BP (<10%) are considered non-dippers¹⁶⁶. A blunted or absent nocturnal fall in BP increases the risk for vascular complications, kidney damage, cerebrovascular events, and cardiovascular mortality¹⁶⁷. Impaired autonomic dysfunction may promote non-dipping BP in addition to its negative effect on natriuresis^166,168,¹⁶⁹. RAAS components including renin and ACE follow circadian rhythms and may also contribute to disturbances in circadian BP¹⁷⁰. The presence of diseases such as diabetes, metabolic disorders, salt sensitivity, chronic kidney disease, obstructive sleep apnea, and heart failure are all associated with disrupted circadian rhythms and a non-dipping BP phenotype.

Emerging evidence reveals that elevated nighttime BP is a greater predictor of cardiovascular events in middle-aged women versus men^171,172. In a meta-analysis of 9357 patients from 11 population, women have a greater risk for stroke, cardiac, and coronary complications with disturbances in 24-hour and nocturnal SBP in comparison with men¹⁷¹. Furthermore, non-dipping BP is associated with higher left ventricular mass in hypertensive women but not men¹⁷³. These findings provide evidence of sex-specific risk factors in aging women, especially as cardiovascular risk increases after menopause. In a cross-sectional study, postmenopausal hypertensive women have a higher incidence of non-dipping BP¹⁷⁴, and a randomized double-blind study of 12 postmenopausal non-dippers found that transdermal E2 restored the expected nocturnal SBP and DBP pattern^175,176. However, more studies are needed to investigate the impact of estrogen replacement on non-dipping BP in postmenopausal women.

3.9. Estrogen paradox

Despite the large quantity of evidence supporting the benefits of estrogen, it is essential to recognize that not all health conditions are positively affected by this sex hormone. A prime example is pulmonary arterial hypertension (PAH), a disease targeting the pulmonary circulation and right heart function that carries a devastating 3-year survival rate of <60%^177,178. While women are diagnosed at a 4:1 rate compared with men, female sex is linked to greater survival rates and right ventricular (RV) function^178,179. Loss of E2 via OVX in animal models or menopause in women is sometimes shown to exacerbate the disease, contradicting the sexual dimorphism favoring men and called the “estrogen paradox”¹⁸⁰. Data from animal models indicate this protection by E2 may be associated with a reduction in endothelin-1 and enhanced angiogenesis in the lung and heart^181,182. On the other hand, some clinical studies show a higher rates of menopausal hormone user in pulmonary hypertension patients, and estrogen inhibition prevented and improved disease in mice, suggesting that estrogen may not be protective in all cases^183,184. In conclusion, it is mechanistically unclear why prevalence rates are higher in females and why E2 sometimes exerts protective or detrimental effects. More research on these paradoxical finding may reveal new therapeutic targets.

4. Clinical Perspectives

4.1. Sociocultural factors

Biological differences in males and females are not the only causes of the disparity rates of hypertension and CVD among Americans. The social construction of men and women are determinant factors of lifestyle and health outcomes¹⁸⁵. Gender factors such as education, marriage status, low socioeconomic status, social environment, experience of racial discrimination, traumatic stress, exposure to hazardous, inadequate medical care, and cultural factors are strongly associated with hypertension and ischemic heart diseases^186,187. Gender differences exist in hypertension awareness, and women are more prone to visit primary care services and have their blood pressure levels taken than men^187,188. Even though women are more aware of high BP and appear to respond better to anti-hypertensive drugs^189,190, women in developing countries are more often self-medicated because of several tasks and limited time to take care of their health¹⁹¹. There is a continuous association between low education/economic status and hypertension prevalence in both genders living in rural zones and small center urban, thus intensifying the CVD in these areas¹⁹¹. A similar trend was also observed in different cohorts of developing countries^192,193. Despite growing evidence showing the importance of gender disparities in health and illness, the complex interactions of sex and gender are not taken into account in clinical trials and management of hypertension treatment.

4.2. Diversity in clinical trials

The effect of E2 on vascular remodeling and hypertension has been widely studied in male models. Because of hormonal oscillations and pregnancy, women were excluded from most clinical research before 1993^194,195. A male model for diagnosis, guidelines, and regimen treatment were simplified and followed for all patients with heart disease^191,196. Until recently, cohorts with females have been advanced and included in clinical research but are still scarce in many cardiovascular studies.

In addition to sex differences, hypertension in the United States is characterized by significant racial disparities. Blacks are more likely to develop hypertension, coronary artery disease, and chronic kidney disease in comparison with White, non-Hispanic Asian, and Hispanic counterparts¹. Various factors such as body mass index, social/environmental factors, doctor-patient trust and communication, and lack of access to treatment all contribute to CVD management and control¹⁹⁷. In addition, Black and Hispanic women have a higher likelihood of comorbidities such as diabetes, hypertension, or obesity during acute cardiovascular events such as myocardial infarction¹. Cross-sectional and longitudinal studies may be inconclusive with regards to whether menopause is associated with hypertension due to heterogeneity in the studied populations^7,198. Although sex, racial, and ethnic disparities have been documented for many years, prospective and longitudinal studies addressing underlying mechanisms triggering menopause-associated CVD risk in non-white populations are unfortunately limited. Recently, data from the Study of Women’s Health Across the Nation revealed distinct trajectories of BP rise as well as patterns of estradiol decline and FSH rise among different races during the menopausal transition⁷. These results highlight the complexity of menopausal transition among women from different backgrounds. The inclusion of different racial and ethnic groups will provide a novel understanding of health disparities and new therapeutic options to improve the management of CVD risk in all women.

5. Conclusions

Animal studies show a favorable effect of E2 on protection against hypertension, coronary diseases, stroke, and heart failure. However, there are gaps in knowledge about the exact influence of each estrogen receptor in this protection. Indeed, the combination of age, sex hormones, genetic background, and unhealthy lifestyles all contribute to the onset of hypertension and CVD risk in postmenopausal women. Even though premenopausal women are protected, a wide array of evidence suggests that females may be more susceptible to the effects of lifestyle behaviors on changes in BP, particularly during the menopausal transition. Since females are still underrepresented in clinical trials and experimental studies, the mechanisms underlying the increased vulnerability of women to harmful effects remain elusive. Clinical studies should be inclusive and heterogeneous and designed to address outcomes by sex. The future of medicine is highly personalized, and clinicians must consider the various contributors to sex hormones and how they play a role in disease management and therapeutic strategies to preserve cardiovascular health.