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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 63  |  Issue : 6  |  Page : 256-262

Effects of female sex hormones on the development of atherosclerosis


1 Department of Physiology, School of Medicine; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
2 Department of Physiology, School of Medicine; Graduate Institute of Medical Sciences, College of Medicine; Cancer Research Center, Taipei Medical University Hospital; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Date of Submission31-Aug-2020
Date of Decision12-Oct-2020
Date of Acceptance23-Oct-2020
Date of Web Publication07-Dec-2020

Correspondence Address:
Prof. Wen-Sen Lee
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_69_20

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  Abstract 


Atherosclerosis and associated pathologies, such as coronary artery disease, peripheral vascular disease, and stroke, are still the leading cause of death in Western society. The impact of female sex hormones on cardiovascular diseases has been studied intensively with conflicting findings. The controversy is mainly due to the differences in groups sampling, animal models used, hormonal treatment regimens, and the data analyzed. In the present article, the results of in vitro and in vivo studies and clinical trials are under review.

Keywords: Atherosclerosis, estradiol, estrogen, progesterone, progestogen


How to cite this article:
Hsu SP, Lee WS. Effects of female sex hormones on the development of atherosclerosis. Chin J Physiol 2020;63:256-62

How to cite this URL:
Hsu SP, Lee WS. Effects of female sex hormones on the development of atherosclerosis. Chin J Physiol [serial online] 2020 [cited 2021 Jan 16];63:256-62. Available from: https://www.cjphysiology.org/text.asp?2020/63/6/256/302576




  Introduction Top


Atherosclerosis, a disorder characterized by yellowish plaques containing cells, connective tissue elements, cellular debris, and excessive lipid in the inner layers of the artery walls,[1] is a term describing any stiffening of arteries associated with the formation of plaques which hamper the blood flow. Atherosclerosis appears to be caused by a combination of factors, including genetic susceptibility and certain lifestyle issues such as diet, smoking, and lack of physical exercise. Epidemiological studies have suggested that the prevalence rate of atherosclerosis is increasing worldwide concurrent with expanding adaptation of Western lifestyle and behaviors.[2],[3] It is anticipated that cardiovascular diseases will become the principal cause of death globally extending to developing countries and into Eastern Europe along with the increasing incidence of diabetes and obesity.[4]


  Underlying Causes of Atherosclerosis Top


The process of atheroma development is called atherogenesis and the overall result of the disease process is called atherosclerosis. Atherosclerotic lesions, asymmetric intimal thickenings of the artery, are preceded by a fatty streak, which is an accumulation of various cells (such as foam cells, T cells, aggregated platelets, and vascular smooth muscle cells) located in the intima. The atheromata are made up of cells (mostly blood-borne inflammatory and immune cells), connective tissue, lipids, and debris.[1] The center of an atherosclerotic lesion is infiltrated by macrophages and T cells. Many of the immune cells can produce inflammatory cytokines.[5],[6],[7]

It has been suggested that the three main personal risk factors of atherosclerosis are the plasma levels of low-density lipoprotein (LDL), elevated blood pressure, and smoking cigarette. The one essential underlying cause of serious atherosclerosis seems to be a high plasma LDL cholesterol (LDL-C) concentration. Cholesterol, a lipophilic molecule, does not dissolve well in the blood and has to be transported within the plasma by binding to lipoproteins. When excessive LDL-C circulates in the bloodstream, it can form the plaque, subsequently developing atherosclerosis, which can narrow the arteries, hence hampering blood flow. On the other hand, high-density lipoprotein (HDL) carries cholesterol away from the arteries and removes excess cholesterol from the arterial plaques. The causal relation between plasma levels of LDL-C and coronary heart disease (CHD) is well established. Patients, who have heterozygous familial hypercholesterolemia with mutations in the LDL receptor, show chronic persistent high LDL-C levels and increases of the risk of early heart attack.[8] The deposition of LDL in the intima induces the infiltration of macrophages, T cells, and mast cells in the artery wall. Many of these infiltrated immune cells produce inflammatory cytokines.[6],[7],[9] The interaction between immune mechanisms and metabolic risk factors initiates, propagates, and activates lesions in the arteries. Although the pathophysiologic mechanisms responsible for atherosclerosis is not fully elucidated, one theory holds that atherosclerosis is a chronic inflammatory disease.[10],[11],[12],[13],[14],[15],[16],[17] In response to injury and to various stimuli, the activated vascular endothelial cells produce cytokines, such as interleukin-10 and transformed growth factor-β, and growth factors, such as vascular endothelial growth factor and platelet-derived growth factor subunit B (PDGF-B), to promote proliferation and migration of vascular smooth muscle cells. Normally, vascular smooth muscle cells are located in the media layer of arteries, and have a very low proliferation rate. However, proliferation and migration of vascular smooth muscle cells (two major events in the formation of atherosclerotic lesions in humans) are increased in the forming neointima in the development of atherosclerosis.[18]


  Anti-Atherosclerotic Effect of Female Sex Hormones Top


Epidemiological studies suggested that cardiovascular diseases continue to be the major cause of death among postmenopausal women in Western society. However, the overall morbidity and mortality from almost all forms of vascular disease in premenopausal women, but not postmenopausal women, are much lower than in men,[19],[20] suggesting that endogenous female sex hormones might protect against cardiovascular diseases during premenopausal years.[21] This hypothesis was supported by the evidence that estrogen replacement in postmenopausal women causes a reduction of cardiovascular disease incidence.[22] Moreover, estrogen treatment reduces the development of experimentally induced atherosclerosis.[23],[24],[25],[26],[27] Rhee et al. showed that estrogen reduced the surgery-induced vascular hyperplasia in rabbit aorta.[28] Estradiol administration suppresses the balloon injury-induced myointimal thickening.[24] Estrogen also exerts a protection effect against the development of atherosclerosis induced by diet in rats[29] and rabbits.[30] Studies in macaques showed that premenopausal macaques have higher levels of HDL than do male macaques, and fewer atherosclerotic lesions of the coronary arteries were developed in such female macaques.[23] On the other hand, ovariectomy (OVX)-induced menopause treated with a moderately atherogenic diet produced progressive atherosclerosis. Moreover, a prominent anti-atherosclerotic effect in OVX monkeys was observed when estrogen replacement therapy (ERT) was initiated at the time of ovariectomy, but not when the estrogen treatment was delayed.[31],[32] A human study showed that the incidence of cardiovascular diseases among postmenopausal women is significantly higher as compared to premenopausal women of the same age, and women who experienced an early menopause showed an increased risk of cardiovascular diseases.[33] Although the cardiovascular protective role of estrogens may be controversial, its beneficial effects indeed were suggested by a certain of influential interventional studies, showing that the cardiovascular diseases and estrogen administration were inversely correlated among postmenopausal women. The Estrogen in the Prevention of Atherosclerosis Trial (ClinicalTrials.gov identifier: NCT00115024) showed that healthy postmenopausal women, who took unopposed ERT with micronized 17 β-estradiol (1 mg/day), rendered a decrease in the increased changes of carotid intima-media thickness (CIMT) compared to placebo recipients, suggesting unopposed ERT imparting a negative effect on the progression of subclinical atherosclerosis.[34] The Early versus Late Intervention Trial with Estradiol (ELITE; ClinicalTrials.gov Identifier: NCT00114517) revealed that healthy women, who received oral 17 β-estradiol (1 mg/day) within 6 years of postmenopause (early intervention group), presented a lower mean CIMT, whereas unopposed ERT of recipients, who were 10 or more years after menopause (late intervention group), did not have significant effect on CIMT.[35] Moreover, the posttrial analysis of ELITE showed that a significantly positive correlation between increased plasma levels of estradiol after ERT and reduced subclinical atherosclerosis progression appeared only in the early intervention group, which further supported “the timing hypothesis of hormone therapy (HT).”[36] By the data analyses of concurrent cohort Multi-Ethnic Study of Atherosclerosis (ClinicalTrials.gov Identifier: NCT00005487), the results showed that the estradiol level was negatively associated with the risk of atherosclerotic cardiovascular diseases (the CHD and heart failure with reduction of ejection fraction) among postmenopausal women.[37] In addition to estrogen, the administration of natural progesterone, but not the synthetic medroxyprogesterone acetate (MPA), enhances the estradiol-mediated benefits in postmenopausal women with cardiovascular diseases, such as coronary artery disease and previous myocardial infarction (MI), during HT.[38] Estradiol given alone for 4 weeks (for 18 days 1 mg/day dosage followed by 2 mg/day for 10 days) significantly delayed the onset of ST segment depression of an electrocardiogram during the treadmill exercise stress test. The administration of transvaginal progesterone gel (90 mg every two days), but not oral MPA (10 mg/day), in estradiol-treated patients further improved this effect, suggesting a role of progesterone ameliorating cardiovascular diseases. Since the detrimental changes of lipid profile is a key factor leading to the progression of atherosclerosis,[39] the beneficial roles of progesterone in oral estrogen-induced effects on the increases of triglycerides and HDL cholesterol (HDL-C) and the decreases of LDL-C were investigated. In the Postmenopausal Estrogen/Progestin Interventions (ClinicalTrials.gov Identifier: NCT00000466), participants who orally took unopposed estrogen (0.625 mg/day) plus cyclic micronized progesterone (MP) (200 mg/day) showed significant increases of HDL-C level superior to that in the recipients who took unopposed estrogen plus MPA. The treatment of unopposed estrogen plus cyclic MP induces increases in triglyceride levels and decreases in LDL-C levels in comparison to the matched placebo group.[40] The Multi-center Clinical Trial on Hormone Replacement Treatment in China (ClinicalTrials.gov Identifier: NCT01698164) indicated that the dosage regimen of unopposed estrogen plus half-dose cyclic MP could significantly elevate the HDL-C levels and decrease the LDL-C levels.[41] The levels of plasma triglyceride were elevated in this dosage regimen, although it did not reach statistical significance. On the other hand, a number of divergent and/or opposed outcomes of interventional studies were also shown. In the Heart and Estrogen-Progestin Replacement Study (HERS; ClinicalTrials.gov Identifier: NCT00319566), the results of a single group assignment of intervention model suggested that the regimen of unopposed estrogen 0.625 mg/day plus MPA 2.5 mg/day did not reduce the occurrence of nonfatal MI and death caused by CHDs as well as the secondary outcomes such as stroke and resuscitated cardiac arrest in postmenopausal women with CHD.[42] In line with HERS, the Estrogen Replacement and Atherosclerosis Trial (ClinicalTrials.gov Identifier: NCT03097120) demonstrated that treatment of postmenopausal women with epicardial coronary stenosis with the same regimen or estrogen alone did not reduce the coronary atherosclerosis development, although significant increases of HDL-C levels and decreases of LDL-C levels appeared.[43] The Kronos Early Estrogen Prevention Study (KEEPS; ClinicalTrials.gov Identifier: NCT00154180) showed that both the regimen of unopposed estrogen 0.45 mg/day and transdermal 17 β-estradiol 50 μg/day (concomitant progesterone 200 mg/day was given at the beginning 12 days of each month) had no significant effects on the CIMT reduction. However, the findings form KEEPS results suggested that recent-initiated health postmenopausal women who received ERT did not show unfavorable consequences.[44] Until now, preclinical studies and clinical trial projects of ERT against cardiovascular diseases are still ongoing for pursuing adjustable regimens to fight the multiple variables in atherosclerosis development.


  Molecular Mechanisms Underlying Female Sex Hormones-Induced Anti-Atherosclerosis Top


Estrogen treatment is regarded as beneficial against the development of atherosclerosis. The beneficial effects include changes of (1) the levels of risk factors in circulating blood, (2) the intima-media of the arterial wall, and (3) the physiology of the endothelial cells. Estrogen has been shown to exert a direct effect to increase the secretion of nitric oxide and the nitric oxide synthase activity,[45],[46],[47] to cause vasodilation,[48],[49] to suppress arterial collagen secretion and extracellular matrix deposition,[50] to act as calcium antagonist properties,[51],[52] to diminish calcification,[53] and to decrease the secretion of inflammatory cytokines, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and fibroblast growth factor.[54],[55] Estrogen also exerts an indirect effect to inhibit LDL oxidation in plasma, to reduce coronary and aortic LDL accumulation, and to increase plasma HDL levels.[56] Intriguingly, some preclinical and clinical studies have shown that a number of microRNA (miR) therapies, such as miR-126 and miR-33, improve the detrimental changes of lipid profile during atherosclerosis development.[57],[58] Since miRs expression can be directly regulated by estrogen,[59] the interplay among estrogen-dependent miRs expression, miRs-modulated lipid profile, and atherosclerosis development might be a key for estrogen to oppose atherogenic dyslipidemia. It has been shown that 17 β-estradiol significantly reduces the plaque size in the aorta sinus, which was remarkably antagonized by antagomir-126-3p administration, in OVX apolipoprotein E−/− (ApoE−/−) mice.[60] Besides, introduction of miR-126-3p mimics to OVX ApoE−/− mice reduced the size of aorta sinus plaque. These foregoing findings imply that the modulation of atherogenic lipid profile by 17 β-estradiol might be through an upregulated miRs fashion. However, this inference deserves more detailed investigations.

Although a large body of literature has pointed to a cardiovascular protective effect of estrogen, there has been little information on the effects of progesterone, the other important female sex hormone, on cardiovascular health and disease. It has been suggested that coadministration with progesterone and estrogen is necessary to prevent endometrial hyperplasia and cancer in the postmenopausal women.[61] However, the effect of progesterone on cardiovascular diseases is still subjected to debate. An epidemiological study showed that the relative risk of major CHD among postmenopausal women who took both estrogen with progesterone together was significantly lower as compared with the risk of those who took estrogen alone.[62] Moreover, OVX baboons receiving estradiol and progesterone together has fewer vascular lesions than those receiving estradiol alone.[31] Taken together, these data suggest that progesterone might also contribute to the cardiovascular protective action. However, there is little evidence of an independent effect of progesterone either in animal studies or in cell culture.


  Molecular Mechanism Underlying Antiproliferation and Antimigration of Female Sex Hormones in Vascular Smooth Muscle Cells Top


Proliferation and migration of vascular smooth muscle cells play a key role in the genesis of the atherosclerotic plaque. In the process of atherogenesis, proliferation and migration of vascular smooth muscle cell are enhanced in the forming neointima. The presence of estrogen receptor (ER) and progesterone receptor (PR) in the medial layer of aorta implies a direct effect of estrogen and progesterone on the proliferation and/or migration of the vascular smooth muscle cells.[63],[64]

Lee et al. showed that progesterone, but not estrogen, reduces the growth of cultured rat aortic smooth muscle cells (RASMCs). Progesterone directly inhibits RASMCs proliferation by activating the cSrc/Kras/Raf-1/AKT/ERK1/2/p38/IκBα signaling pathway, subsequently causing NFκB (p65) nuclear translocation, which in turn results in a p53-dependent increase of the protein levels of p21 and p27, hence inhibiting the cyclin-dependent kinase 2 activity, and eventually causes the cell cycle arrest at the G0/G1 phase.[64],[65] However, Morey et al. showed that both estrogen and progesterone reduce the proliferation of cultured vascular smooth muscle cells.[66] The possible explanations for the difference between these two groups regarding the estrogen effect on the proliferation of vascular smooth muscle cells are (1) the difference of vascular smooth muscle cells used (human umbilical vein smooth muscle cells versus RASMCs) and (2) different serum concentrations used to challenge the cells after starvation (10% vs. 3% of FBS). In fact, it has been indicated that the effect of estrogen on vascular smooth muscle cell proliferation is dependent on cellular phenotype.[67] Takahashi et al. also demonstrated that estrogen inhibits the PDGF-induced increase of cell proliferation in human aortic smooth muscle cells, but not in RASMCs.[68] Geraldes et al. demonstrated that estrogen at a concentration of 10 − 8 mol/L inhibits the PDGF-induced proliferation and migration in porcine smooth muscle cells.[69] Similar findings have been found in cultured human female aortic smooth muscle cells.[70] Interestingly, Barchiesi et al. demonstrated that estradiol reduced the vascular injury-induced formation of vascular lesions in knockout mice that lack either ER-α, or ER-β and claimed that estradiol metabolism instead of estradiol may be an important determinant of cardiovascular protective effects.[71] Moreover, 17 β-estradiol administration of young and aged OVX C-reactive protein (CRP) transgenic mice present a significant decrease and the increased tendency of neointimal hyperplasia, respectively.[72] In parallel, 17 β-estradiol significantly reduces the CRP-increased expression of inflammatory mediators in vascular smooth muscle cells of carotid arteries isolated from young, but not aged mice. As we know, the changes of estrogen levels in blood occur in different ages. Evidently, treatment of vascular smooth muscle cells with low or high concentrations of estrogen that match the different ages showed either increased or decreased cell proliferation, respectively.[73],[74] These results imply that an age-dependent regimen of estrogen might deserve further exploration.

Regarding the effect of female sex hormones on the migration of vascular smooth muscle cells, it has been previously demonstrated that estradiol (0.5–10 ng/mL) concentration dependently inhibits migration of cultured human smooth muscle cells,[70] RASMCs,[75] and porcine smooth muscle cells[69] through an estrogen-dependent pathway. The AKT and ERK1/2 signaling pathways might be critical in estrogen-modulated migration inhibition in vascular smooth muscle cells.[76] The physiologic concentration range of plasma progesterone (5–500 nM) also concentration-dependently inhibited vascular smooth muscle cell migration through the PR-mediated cSrc activation, subsequently suppressing the RhoA activation, and eventually caused migration inhibition.[77] The nongenomic PR/cSrc/AKT/ERK2/p38/p65 signaling pathway upregulates p27 protein expression,[78] which led to p27-dependent RhoA degradation,[79] and thereby inhibits vascular smooth muscle cell migration.


  Conclusions Top


Although the results from clinical trials regarding the impact of female sex hormones on the development of atherosclerosis are still controversial, there is considerable evidence from in vitro and in vivo studies to support the beneficial, protective effects of female sex hormones in the early stages of atherogenesis. Current limitations of HT practices might be the insufficient data of long-term risk evaluation of chronic diseases and the restrict population sizes of examined pre- and post-menopausal women as well as the narrow generalizability of outcomes and the low transferability of updated HT information. However, the findings from previous studies might be also enlightening the selective regimens of HT in treating atherosclerosis in menopausal women, considering the dependencies of timing, age, and dosage as well as the physical status when postmenopausal women take HT. The trend of personalized medicine is in favor of a better developed and optimized multifactorial remedy to treat atherosclerosis.

It seems that estrogen exerts a direct effect on vascular walls to increase nitric oxide synthase activity and the secretion of nitric oxide, to cause vasodilation, to suppress collagen secretion and extracellular matrix deposition, to act as calcium antagonist properties, to diminish calcification, to decrease the secretion of a number of inflammatory cytokines, and to inhibit smooth muscle cell migration, and an indirect effect to inhibit LDL oxidation, to reduce the accumulation of coronary and aortic LDL, and to increase plasma levels of HDL. On the other hand, the progesterone effect on the estrogen-mediated cardiovascular protective effect is still controversial mainly due to the differences in groups sampling, animal models used, hormonal treatment regimens, and the data analyzed. However, it is clear that progesterone alone exerts an anti-atherosclerotic action through a direct inhibition on proliferation and migration of vascular smooth muscle cells. Medical treatment by hypolipidemic agents and individual lifestyle rectification are standard practices for preventing the development of atherosclerosis by reducing atherosclerosis risk factors. On the other hand, HT can not only reduce the risk of atherosclerosis but also inhibit the progression of atherosclerosis by reducing the vascular smooth muscle cell proliferation and migration (two key events in the formation of atherosclerotic lesion). Introduction of female sex hormone treatments combined with standard atherosclerosis therapy might have better benefits for treating atherosclerosis in postmenopausal women. The main idea of this article is illustrated in [Figure 1].
Figure 1: The effects of female sex hormone on atherosclerosis. Preclinical and clinical studies imply that a selective regimen of female sex steroid hormones formulated by multiple time-dependent and age-dependent factors as depicted may be better for anti-atherosclerotic therapy. In spite of controversial or divergent findings, the favorable effects of sex steroid hormones on atherosclerosis development are also evident. We identified the progesterone-activated cSrc/AKT/ERK/p38/NFκB signaling pathway involved in the proliferation and migration inhibition of vascular smooth muscle cells. Estrogen-activated MAPK/ERK and AKT signaling pathways may also be critical for the event. However, the effects of bi-mold cell signaling on differential phenotypic vascular smooth muscle cells induced by estrogen deserve further investigation.

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Financial support and sponsorship

This study was supported by the National Science Council grant NSC 96-2320-B-038-023 and NSC 97-2320-B-038-033-MY3 to Dr. Lee.

Conflicts of interest

There are no conflicts of interest.



 
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