Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling

Sarika Chaudhari, Spencer C. Cushen, Oluwatobiloba Osikoya, Paresh A. Jaini, Rachel Posey, Keisa W. Mathis, Styliani Goulopoulou

10.1002/cphy.c180003

Source: Volume 9, Issue 1, January 2019

Published online: December 2018

Full Article on Wiley Online Library



ABSTRACT

Epidemiological studies demonstrate disparities between men and women in cardiovascular disease prevalence, clinical symptoms, treatments, and outcomes. Enrollment of women in clinical trials is lower than men, and experimental studies investigating molecular mechanisms and efficacy of certain therapeutics in cardiovascular disease have been primarily conducted in male animals. These practices bias data interpretation and limit the implication of research findings in female clinical populations. This review will focus on the biological origins of sex differences in cardiovascular physiology, health, and disease, with an emphasis on the sex hormones, estrogen and testosterone. First, we will briefly discuss epidemiological evidence of sex disparities in cardiovascular disease prevalence and clinical manifestation. Second, we will describe studies suggesting sexual dimorphism in normal cardiovascular function from fetal life to older age. Third, we will summarize and critically discuss the current literature regarding the molecular mechanisms underlying the effects of estrogens and androgens on cardiac and vascular physiology and the contribution of these hormones to sex differences in cardiovascular disease. Fourth, we will present cardiovascular disease risk factors that are positively associated with the female sex, and thus, contributing to increased cardiovascular risk in women. We conclude that inclusion of both men and women in the investigation of the role of estrogens and androgens in cardiovascular physiology will advance our understanding of the mechanisms underlying sex differences in cardiovascular disease. In addition, investigating the role of sex‐specific factors in the development of cardiovascular disease will reduce sex and gender disparities in the treatment and diagnosis of cardiovascular disease. © 2019 American Physiological Society. Compr Physiol 9:375‐411, 2019.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Proportion of women that were enrolled in randomized controlled trials (RCT) compared with (A) proportion of women in the general population with a given disease and (B) proportion of women that died from each disease (325). In this study, the authors reviewed all RCTs that used to construct the American Heart Association guidelines for cardiovascular disease in women (270). The proportion of women enrolled in randomized controlled trials is lower compared with their representation in the disease populations being treated. The major diseases presented in this figure include coronary artery disease, heart failure, diabetes, hypercholesteremia, and hypertension. Whiskers represent the upper 95th percentile of the confidence interval for the proportion of women in RCTs. Hypercholesteremia is defined as low‐density lipoprotein cholesterol >130 mg/dL. Reprinted with permission (249).
Figure 2. Figure 2. Longitudinal trajectories of systolic and diastolic blood pressures (BP) from childhood to adulthood by race‐sex groups. Curve parameters that were compared statistically: β0 = the intercept (the level of BP) at age point of 20.1 years; β1 = overall linear slopes (the tangent line) at age point of 20.1 years; β2 = nonlinear slopes in young adulthood during 20 to 35 years; β3 = nonlinear slopes in middle‐aged adulthood during 36 to 51 years. All curve parameters (β0, β1, β2, and β3) were significantly different from 0 (P < 0.001) except β2 = − 0.05 (P = 0.023) and β3 = 0.0001 (P = 0.965) for diastolic BP in black men. Reprinted with permission (353).
Figure 3. Figure 3. Changes in left ventricular parameters with age in healthy males (left) and females (right). A total of 96 subjects were recruited in this study (76 adults aged 21‐81 years and 20 children aged 11‐15 years, all Caucasian). Solid lines represent rational polynomial curve fit and dashed lines the 95% prediction intervals of this fit. LVM = left ventricular mass, BSA = body surface area, EDV = end‐diastolic volume. Reprinted from (52), an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).
Figure 4. Figure 4. Changes in the total (A) and bioavailable (B) estrogen with age in men (solid lines, squares) and women (dashed lines, circles). Subjects were recruited from an age‐stratified random sample of Rochester, MN, using the medical records linkage system of the Rochester Epidemiology Project. Estrogen was measured by RIA in fasting serum samples collected between 0800 and 0900 h. There was a reduction in serum total and bioavailable estrogen concentrations around the time of menopause and an age‐related reduction in bioavailable concentrations of estrogen in men. Reprinted with permission (186).
Figure 5. Figure 5. Nongenomic estrogen receptor signaling in vascular endothelial (A) and smooth muscle cells (B). ERs are localized to caveolae in the cell membrane of endothelial and vascular smooth muscles cells by interacting with caveolin‐1 and scaffold protein striatin. (A) In vascular endothelial cells, binding of estrogen to ERs causes ER‐G protein complex formation with subsequent activation of tyrosine kinase Src, serine/threonine kinase PI3K, Akt, and MAPK. Kinases induce phosphorylation of eNOS (at serine 1177). Activation of eNOS leads to production of NO that contributes to vasodilatation, proliferation, and migration of endothelial cells. (B) In vascular smooth muscle cells, activation of ERs by estrogen induces activation of phosphatases and inhibition of kinases. These events result in cell proliferation and migration. Akt: protein kinase B; eNOS: endothelial nitric oxide synthase; ER: estrogen receptor; MAPK: mitogen‐activated protein kinase; NO: nitric oxide; PI3K: phosphatidylinositol‐3‐OH kinase. Reprinted with permission (250).
Figure 6. Figure 6. Mechanisms of coronary artery relaxation mediated by estrogen via GPR‐30. (A) Endothelium‐independent mechanism: Binding of estrogen to GPR‐30 leads to activation of BK channels, causing potassium efflux, hyperpolarization, and relaxation of the coronary smooth muscle cells. (B) Endothelium‐dependent mechanism: GPR‐30 activation leads to NO synthesis and vascular relaxation. BK: large conductance calcium‐activated potassium channel; GPR‐30: G‐protein‐coupled receptor; NO: nitric oxide. Reprinted with permission (250).
Figure 7. Figure 7. ER β mRNA expression in the hearts of patients with aortic stenosis (AS) in total population (A) and comparisons between men and women (B) in control and patient samples. (A) ER‐β mRNA content was significantly increased in AS patients (P < 0.0001). (B) ER‐β mRNA content was significantly higher in hearts from healthy men compared with healthy women (P < 0.005) and in men and women with AS, as compared to their respective controls (P < 0.05, P < 0.001, respectively). The percent increase in ER‐β mRNA was more pronounced in female than in male patients (P < 0.005, not shown in the figure). Reprinted with permission (277).
Figure 8. Figure 8. Gene ontology (GO) analysis for identification of genes that are different between sexes. GO analysis was performed using Metacore. The gene set identified at predetermined number of false discovery rate was used to probe the cellular localization of genes, the processes in which they are involved, the metabolic networks, and their potential pathways. The P values on the graph (x‐axis) indicate the probability of mapping of an experiment to a process to arise by chance. Reprinted with permission (92).
Figure 9. Figure 9. Estradiol or an estrogen‐dendrimer conjugate (EDC) improves functional recovery and infarct size in ovariectomized mice after ischemia/reperfusion (I/R) injury. (A) I/R protocol in bilaterally ovariectomized C57BL/6 J mice with subcutaneous Alzet mini‐pumps implantation for drug treatments for two weeks. Two‐week treatment with estradiol or EDC improved functional cardiac parameters. (B, E) left ventricular diastolic pressure (LVDP), (C, F) rate pressure product (RPP), (D, G) infarct size. To assess postischemic recovery of parameters LVDP and RPP, values were expressed as percentage of their preischemic values. Infarct size was expressed as percentage of total area of cross‐sectional slices. (n = 6 for each group). Values are mean ± SEM. **P < 0.01. Reprinted with permission (251).
Figure 10. Figure 10. Changes in the diameter of coronary arteries from female (left) and male (right) patients in response to intracoronary infusion of acetylcholine (1.6 μmol/min, open bars; 16 μmol/min, stippled bars) before and after 2.5 μmol intracoronary infusion of 17β‐estradiol. In females, net constriction before estrogen was converted to dilatation after estrogen (* indicates P < 0.01 before vs. after estrogen). The study population included nine postmenopausal women (59 ± 3 years old) and seven men (52 ± 4 years old) with coronary artery disease. Values are mean ± SEM. Reprinted with permission (74).
Figure 11. Figure 11. Changes in the total (A) and bioavailable (B) testosterone with age in men (solid lines, squares) and women (dashed lines, circles). Subjects were recruited from an age‐stratified random sample of Rochester, MN, using the medical records linkage system of the Rochester Epidemiology Project. Testosterone was measured by RIA in fasting serum samples collected between 0800 and 0900 h. There was a decline in serum total and bioavailable testosterone concentrations in both men and women but the drop in bioavailable testosterone was twice that in total testosterone. Bioavailable testosterone was reduced by 64% and 28% in the men and women, respectively. Reprinted with permission (186).
Figure 12. Figure 12. Cumulative concentration‐response curves to (A) progesterone (Prog, 10 nmol/L‐300 μmol/L) and (B) estradiol (E2, 10 nmol/L‐30 μmol/L) in the presence or absence propargylglycine (PAG), an inhibitor of H2S‐synthesizing enzyme cystathionine‐γ lyase (CSE). H2S production was determined in aortic tissues incubated with (C) Prog (100 μmol/L) and (D) E2 (10 μmol/L) for 15 or 30 min and (C and D) testosterone (T, 10 umol/L) for 30 min in presence of L‐cysteine (L‐Cys). ###P < 0.001 versus basal; °°°P < 0.001 versus L‐Cys; n = 6. Values are mean ± SEM. Reprinted with permission (40).
Figure 13. Figure 13. Time from pregnancy to time of onset of cardiovascular disease (comprised ischemic heart disease, stroke, and heart disease) in women who had experienced a hypertensive disorder of pregnancy (HDP) or a normal pregnancy. The cardiovascular disease composite outcome was greater in women with HDP as compared with women who remained normotensive during pregnancy. Reprinted with permission (390).
Figure 14. Figure 14. Circulating concentrations of testosterone (A), estradiol (B), testosterone‐to‐estradiol ratio (C), and placental aromatase and 17[beta]‐HSD3 (17[beta]‐hydroxysteroid dehydrogenase 3) expression (D and E) in women diagnosed with early‐onset preeclampsia (E‐PE) and normotensive pregnant women matched for gestational age (26‐34 weeks). E‐PE patients had higher concentrations of testosterone, lower concentration of estradiol, higher testosterone to estradiol ratio and greater protein expression of placental aromatase and 17[beta]‐HSD3. Values are mean ± SEM (A‐C) or mean ± SD (E). *P < 0.05; **P < 0.01. Reprinted with permission (348).
Figure 15. Figure 15. Dose‐response analysis of parity number. Nine prospective studies were included in this meta‐analysis. The summary risk estimates for per live birth was 1.01 (95% CI, 0.97‐1.05), with significant heterogeneity (I2  =  86.4%; P < 0.001). Nonlinear dose‐response analysis revealed a J‐shaped relationship between parity number and mortality from cardiovascular disease. Reprinted from (222), an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).


Figure 1. Proportion of women that were enrolled in randomized controlled trials (RCT) compared with (A) proportion of women in the general population with a given disease and (B) proportion of women that died from each disease (325). In this study, the authors reviewed all RCTs that used to construct the American Heart Association guidelines for cardiovascular disease in women (270). The proportion of women enrolled in randomized controlled trials is lower compared with their representation in the disease populations being treated. The major diseases presented in this figure include coronary artery disease, heart failure, diabetes, hypercholesteremia, and hypertension. Whiskers represent the upper 95th percentile of the confidence interval for the proportion of women in RCTs. Hypercholesteremia is defined as low‐density lipoprotein cholesterol >130 mg/dL. Reprinted with permission (249).


Figure 2. Longitudinal trajectories of systolic and diastolic blood pressures (BP) from childhood to adulthood by race‐sex groups. Curve parameters that were compared statistically: β0 = the intercept (the level of BP) at age point of 20.1 years; β1 = overall linear slopes (the tangent line) at age point of 20.1 years; β2 = nonlinear slopes in young adulthood during 20 to 35 years; β3 = nonlinear slopes in middle‐aged adulthood during 36 to 51 years. All curve parameters (β0, β1, β2, and β3) were significantly different from 0 (P < 0.001) except β2 = − 0.05 (P = 0.023) and β3 = 0.0001 (P = 0.965) for diastolic BP in black men. Reprinted with permission (353).


Figure 3. Changes in left ventricular parameters with age in healthy males (left) and females (right). A total of 96 subjects were recruited in this study (76 adults aged 21‐81 years and 20 children aged 11‐15 years, all Caucasian). Solid lines represent rational polynomial curve fit and dashed lines the 95% prediction intervals of this fit. LVM = left ventricular mass, BSA = body surface area, EDV = end‐diastolic volume. Reprinted from (52), an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).


Figure 4. Changes in the total (A) and bioavailable (B) estrogen with age in men (solid lines, squares) and women (dashed lines, circles). Subjects were recruited from an age‐stratified random sample of Rochester, MN, using the medical records linkage system of the Rochester Epidemiology Project. Estrogen was measured by RIA in fasting serum samples collected between 0800 and 0900 h. There was a reduction in serum total and bioavailable estrogen concentrations around the time of menopause and an age‐related reduction in bioavailable concentrations of estrogen in men. Reprinted with permission (186).


Figure 5. Nongenomic estrogen receptor signaling in vascular endothelial (A) and smooth muscle cells (B). ERs are localized to caveolae in the cell membrane of endothelial and vascular smooth muscles cells by interacting with caveolin‐1 and scaffold protein striatin. (A) In vascular endothelial cells, binding of estrogen to ERs causes ER‐G protein complex formation with subsequent activation of tyrosine kinase Src, serine/threonine kinase PI3K, Akt, and MAPK. Kinases induce phosphorylation of eNOS (at serine 1177). Activation of eNOS leads to production of NO that contributes to vasodilatation, proliferation, and migration of endothelial cells. (B) In vascular smooth muscle cells, activation of ERs by estrogen induces activation of phosphatases and inhibition of kinases. These events result in cell proliferation and migration. Akt: protein kinase B; eNOS: endothelial nitric oxide synthase; ER: estrogen receptor; MAPK: mitogen‐activated protein kinase; NO: nitric oxide; PI3K: phosphatidylinositol‐3‐OH kinase. Reprinted with permission (250).


Figure 6. Mechanisms of coronary artery relaxation mediated by estrogen via GPR‐30. (A) Endothelium‐independent mechanism: Binding of estrogen to GPR‐30 leads to activation of BK channels, causing potassium efflux, hyperpolarization, and relaxation of the coronary smooth muscle cells. (B) Endothelium‐dependent mechanism: GPR‐30 activation leads to NO synthesis and vascular relaxation. BK: large conductance calcium‐activated potassium channel; GPR‐30: G‐protein‐coupled receptor; NO: nitric oxide. Reprinted with permission (250).


Figure 7. ER β mRNA expression in the hearts of patients with aortic stenosis (AS) in total population (A) and comparisons between men and women (B) in control and patient samples. (A) ER‐β mRNA content was significantly increased in AS patients (P < 0.0001). (B) ER‐β mRNA content was significantly higher in hearts from healthy men compared with healthy women (P < 0.005) and in men and women with AS, as compared to their respective controls (P < 0.05, P < 0.001, respectively). The percent increase in ER‐β mRNA was more pronounced in female than in male patients (P < 0.005, not shown in the figure). Reprinted with permission (277).


Figure 8. Gene ontology (GO) analysis for identification of genes that are different between sexes. GO analysis was performed using Metacore. The gene set identified at predetermined number of false discovery rate was used to probe the cellular localization of genes, the processes in which they are involved, the metabolic networks, and their potential pathways. The P values on the graph (x‐axis) indicate the probability of mapping of an experiment to a process to arise by chance. Reprinted with permission (92).


Figure 9. Estradiol or an estrogen‐dendrimer conjugate (EDC) improves functional recovery and infarct size in ovariectomized mice after ischemia/reperfusion (I/R) injury. (A) I/R protocol in bilaterally ovariectomized C57BL/6 J mice with subcutaneous Alzet mini‐pumps implantation for drug treatments for two weeks. Two‐week treatment with estradiol or EDC improved functional cardiac parameters. (B, E) left ventricular diastolic pressure (LVDP), (C, F) rate pressure product (RPP), (D, G) infarct size. To assess postischemic recovery of parameters LVDP and RPP, values were expressed as percentage of their preischemic values. Infarct size was expressed as percentage of total area of cross‐sectional slices. (n = 6 for each group). Values are mean ± SEM. **P < 0.01. Reprinted with permission (251).


Figure 10. Changes in the diameter of coronary arteries from female (left) and male (right) patients in response to intracoronary infusion of acetylcholine (1.6 μmol/min, open bars; 16 μmol/min, stippled bars) before and after 2.5 μmol intracoronary infusion of 17β‐estradiol. In females, net constriction before estrogen was converted to dilatation after estrogen (* indicates P < 0.01 before vs. after estrogen). The study population included nine postmenopausal women (59 ± 3 years old) and seven men (52 ± 4 years old) with coronary artery disease. Values are mean ± SEM. Reprinted with permission (74).


Figure 11. Changes in the total (A) and bioavailable (B) testosterone with age in men (solid lines, squares) and women (dashed lines, circles). Subjects were recruited from an age‐stratified random sample of Rochester, MN, using the medical records linkage system of the Rochester Epidemiology Project. Testosterone was measured by RIA in fasting serum samples collected between 0800 and 0900 h. There was a decline in serum total and bioavailable testosterone concentrations in both men and women but the drop in bioavailable testosterone was twice that in total testosterone. Bioavailable testosterone was reduced by 64% and 28% in the men and women, respectively. Reprinted with permission (186).


Figure 12. Cumulative concentration‐response curves to (A) progesterone (Prog, 10 nmol/L‐300 μmol/L) and (B) estradiol (E2, 10 nmol/L‐30 μmol/L) in the presence or absence propargylglycine (PAG), an inhibitor of H2S‐synthesizing enzyme cystathionine‐γ lyase (CSE). H2S production was determined in aortic tissues incubated with (C) Prog (100 μmol/L) and (D) E2 (10 μmol/L) for 15 or 30 min and (C and D) testosterone (T, 10 umol/L) for 30 min in presence of L‐cysteine (L‐Cys). ###P < 0.001 versus basal; °°°P < 0.001 versus L‐Cys; n = 6. Values are mean ± SEM. Reprinted with permission (40).


Figure 13. Time from pregnancy to time of onset of cardiovascular disease (comprised ischemic heart disease, stroke, and heart disease) in women who had experienced a hypertensive disorder of pregnancy (HDP) or a normal pregnancy. The cardiovascular disease composite outcome was greater in women with HDP as compared with women who remained normotensive during pregnancy. Reprinted with permission (390).


Figure 14. Circulating concentrations of testosterone (A), estradiol (B), testosterone‐to‐estradiol ratio (C), and placental aromatase and 17[beta]‐HSD3 (17[beta]‐hydroxysteroid dehydrogenase 3) expression (D and E) in women diagnosed with early‐onset preeclampsia (E‐PE) and normotensive pregnant women matched for gestational age (26‐34 weeks). E‐PE patients had higher concentrations of testosterone, lower concentration of estradiol, higher testosterone to estradiol ratio and greater protein expression of placental aromatase and 17[beta]‐HSD3. Values are mean ± SEM (A‐C) or mean ± SD (E). *P < 0.05; **P < 0.01. Reprinted with permission (348).


Figure 15. Dose‐response analysis of parity number. Nine prospective studies were included in this meta‐analysis. The summary risk estimates for per live birth was 1.01 (95% CI, 0.97‐1.05), with significant heterogeneity (I2  =  86.4%; P < 0.001). Nonlinear dose‐response analysis revealed a J‐shaped relationship between parity number and mortality from cardiovascular disease. Reprinted from (222), an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).
References
 1.A BA, Salloum‐Asfar S, Perez‐Sanchez C, Teruel‐Montoya R, Navarro S, Garcia‐Barbera N, Luengo‐Gil G, Roldan V, Hansen JB, Lopez‐Pedrera C, Vicente V, Gonzalez‐Conejero R, Martinez C. Regulation of TFPIalpha expression by miR‐27a/b‐3p in human endothelial cells under normal conditions and in response to androgens. Sci Rep 7: 43500, 2017.
 2.Acromite MT, Mantzoros CS, Leach RE, Hurwitz J, Dorey LG. Androgens in preeclampsia. Am J Obstet Gynecol 180: 60‐63, 1999.
 3.Adams KF, Sueta CA, Gheorghiade M, O'Connor CM, Schwartz TA, Koch GG, Uretsky B, Swedberg K, McKenna W, Soler‐Soler J. Gender differences in survival in advanced heart failure. Circulation 99: 1816‐1821, 1999.
 4.Adams T, Yeh C, Bennett‐Kunzier N, Kinzler WL. Long‐term maternal morbidity and mortality associated with ischemic placental disease. Semin Perinatol 38: 146‐150, 2014.
 5.Ahimastos AA, Formosa M, Dart AM, Kingwell BA. Gender differences in large artery stiffness pre‐ and post puberty. J Clin Endocrinol Metab 88: 5375‐5380, 2003.
 6.Alexander BT, Dasinger JH, Intapad S. Fetal programming and cardiovascular pathology. Compr Physiol 5: 997‐1025, 2015.
 7.Allison MA, Wright CM. Age and gender are the strongest clinical correlates of prevalent coronary calcification (R1). Int J Cardiol 98: 325‐330, 2005.
 8.Alsnes IV, Janszky I, Forman MR, Vatten LJ, Okland I. A population‐based study of associations between preeclampsia and later cardiovascular risk factors. Am J Obstet Gynecol 211: 657.e651‐657, 2014.
 9.Amaral LM, Cornelius DC, Harmon A, Moseley J, Martin JN, Jr., LaMarca B. 17‐hydroxyprogesterone caproate significantly improves clinical characteristics of preeclampsia in the reduced uterine perfusion pressure rat model. Hypertension 65: 225‐231, 2015.
 10.Anderson JL, May HT, Lappé DL, Bair T, Le V, Carlquist JF, Muhlestein JB. Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system. Am J Cardiol 117: 794‐799, 2016.
 11.Andersson IJ, Jiang YY, Davidge ST. Maternal stress and development of atherosclerosis in the adult apolipoprotein E‐deficient mouse offspring. Am J Physiol Regul Integr Comp Physiol 296: R663‐R671, 2009.
 12.Angell PJ, Chester N, Green DJ, Shah R, Somauroo J, Whyte G, George K. Anabolic steroid use and longitudinal, radial, and circumferential cardiac motion. Med Sci Sports Exerc 44: 583‐590, 2012.
 13.Anversa P, Hiler B, Ricci R, Guideri G, Olivetti G. Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J Am Coll Cardiol 8: 1441‐1448, 1986.
 14.Apaijai N, Charoenphandhu N, Ittichaichareon J, Suntornsaratoon P, Krishnamra N, Aeimlapa R, Chattipakorn SC, Chattipakorn N. Estrogen deprivation aggravates cardiac hypertrophy in non‐obese type 2 diabetic Goto‐kakizaki (GK) rats. Biosci Rep 37: pii: BSR20170886, 2017.
 15.Appiah D, Winters SJ, Hornung CA. Bilateral oophorectomy and the risk of incident diabetes in postmenopausal women. Diabetes Care 37: 725‐733, 2014.
 16.Arany Z, Elkayam U. Peripartum cardiomyopathy. Circulation 133: 1397‐1409, 2016.
 17.Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J. Membrane and nuclear estrogen receptor alpha actions: From tissue specificity to medical implications. Physiol Rev 97: 1045‐1087, 2017.
 18.Arnold AP, Cassis LA, Eghbali M, Reue K, Sandberg K. Sex hormones and sex chromosomes cause sex differences in the development of cardiovascular diseases. Arterioscler Thromb Vasc Biol 37: 746‐756, 2017.
 19.Atsma F, Bartelink ML, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: A meta‐analysis. Menopause 13: 265‐279, 2006.
 20.Ayaz O, Howlett SE. Testosterone modulates cardiac contraction and calcium homeostasis: Cellular and molecular mechanisms. Biol Sex Differ 6: 9, 2015.
 21.Basaria S, Nguyen T, Rosenson RS, Dobs AS. Effect of methyl testosterone administration on plasma viscosity in postmenopausal women. Clin Endocrinol (Oxf) 57: 209‐214, 2002.
 22.Beesley RD, Palmer BM, Casson PR, Toth MJ. Effects of testosterone on cardiomyocyte calcium homeostasis and contractile function in female rats. Exp Physiol 98: 161‐171, 2013.
 23.Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre‐eclampsia and risk of cardiovascular disease and cancer in later life: Systematic review and meta‐analysis. Bmj 335: 974, 2007.
 24.Bello N, Rendon ISH, Arany Z. The relationship between pre‐eclampsia and peripartum cardiomyopathy: A systematic review and meta‐analysis. J Am Coll Cardiol 62: 1715‐1723, 2013.
 25.Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P. Heart Disease and Stroke Statistics‐2017 Update: A Report From the American Heart Association. Circulation 135: e146‐e603, 2017.
 26.Berends AL, de Groot CJ, Sijbrands EJ, Sie MP, Benneheij SH, Pal R, Heydanus R, Oostra BA, van Duijn CM, Steegers EA. Shared constitutional risks for maternal vascular‐related pregnancy complications and future cardiovascular disease. Hypertension 51: 1034‐1041, 2008.
 27.Berger JS, Elliott L, Gallup D, Roe M, Granger CB, Armstrong PW, Simes RJ, White HD, Van de Werf F, Topol EJ, Hochman JS, Newby LK, Harrington RA, Califf RM, Becker RC, Douglas PS. Sex differences in mortality following acute coronary syndromes. Jama 302: 874‐882, 2009.
 28.Berkane N, Liere P, Oudinet JP, Hertig A, Lefevre G, Pluchino N, Schumacher M, Chabbert‐Buffet N. From pregnancy to preeclampsia: A key role for estrogens. Endocr Rev 38: 123‐144, 2017.
 29.Bernardes J, Goncalves H, Ayres‐de‐Campos D, Rocha AP. Linear and complex heart rate dynamics vary with sex in relation to fetal behavioural states. Early Hum Dev 84: 433‐439, 2008.
 30.Bernelot Moens SJ, Schnitzler GR, Nickerson M, Guo H, Ueda K, Lu Q, Aronovitz MJ, Nickerson H, Baur WE, Hansen U, Iyer LK, Karas RH. Rapid estrogen receptor signaling is essential for the protective effects of estrogen against vascular injury. Circulation 126: 1993‐2004, 2012.
 31.Berry CL, Looker T, Germain J. Nucleic acid and scleroprotein content of the developing human aorta. J Pathol 108: 265‐274, 1972.
 32.Bhatnagar P, Wickramasinghe K, Wilkins E, Townsend N. Trends in the epidemiology of cardiovascular disease in the UK. Heart 102: 1945‐1952, 2016.
 33.Bjornadal L, Yin L, Granath F, Klareskog L, Ekbom A. Cardiovascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: Results from a Swedish population based study 1964‐95. J Rheumatol 31: 713‐719, 2004.
 34.Blenck CL, Harvey PA, Reckelhoff JF, Leinwand LA. The importance of biological sex and estrogen in rodent models of cardiovascular health and disease. Circ Res 118: 1294‐1312, 2016.
 35.Bloomer LD, Nelson CP, Eales J, Denniff M, Christofidou P, Debiec R, Moore J, Zukowska‐Szczechowska E, Goodall AH, Thompson J, Samani NJ, Charchar FJ, Tomaszewski M. Male‐specific region of the Y chromosome and cardiovascular risk: Phylogenetic analysis and gene expression studies. Arterioscler Thromb Vasc Biol 33: 1722‐1727, 2013.
 36.Boese AC, Kim SC, Yin KJ, Lee JP, Hamblin MH. Sex differences in vascular physiology and pathophysiology: Estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol 313: H524‐h545, 2017.
 37.Bopassa JC, Eghbali M, Toro L, Stefani E. A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia‐reperfusion injury. Am J Physiol Heart Circ Physiol 298: H16‐H23, 2010.
 38.Bordallo J, Cantabrana B, Suárez L, Sánchez M. Testosterone inhibits cAMP‐phosphodiesterases in heart extracts from rats and increases cAMP levels in isolated left atria. Pharmacology 87: 155‐160, 2011.
 39.Bourque SL, Gragasin FS, Quon AL, Mansour Y, Morton JS, Davidge ST. Prenatal hypoxia causes long‐term alterations in vascular endothelin‐1 function in aged male, but not female, offspring. Hypertension 62: 753‐758, 2013.
 40.Brancaleone V, Vellecco V, Matassa DS, d'Emmanuele di Villa Bianca R, Sorrentino R, Ianaro A, Bucci M, Esposito F, Cirino G. Crucial role of androgen receptor in vascular H2S biosynthesis induced by testosterone. Br J Pharmacol 172: 1505‐1515, 2015.
 41.Brinkmann AO. Molecular mechanisms of androgen action–a historical perspective. Methods Mol Biol 776: 3‐24, 2011.
 42.Broughton BR, Miller AA, Sobey CG. Endothelium‐dependent relaxation by G protein‐coupled receptor 30 agonists in rat carotid arteries. Am J Physiol Heart Circ Physiol 298: H1055‐H1061, 2010.
 43.Bucci M, Roviezzo F, Cicala C, Pinto A, Cirino G. 17‐beta‐oestradiol‐induced vasorelaxation in vitro is mediated by eNOS through hsp90 and akt/pkb dependent mechanism. Br J Pharmacol 135: 1695‐1700, 2002.
 44.Bucholz EM, Butala NM, Rathore SS, Dreyer RP, Lansky AJ, Krumholz HM. Sex differences in long‐term mortality after myocardial infarction: A systematic review. Circulation 130: 757‐767, 2014.
 45.Bugiardini R. Normal coronary arteries: Clinical implications and further classification. Herz 30: 3‐7, 2005.
 46.Bunone G, Briand PA, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. Embo j 15: 2174‐2183, 1996.
 47.Burger HG. Androgen production in women. Fertil Steril 77 Suppl 4: S3‐S5, 2002.
 48.Burke AP, Farb A, Malcom G, Virmani R. Effect of menopause on plaque morphologic characteristics in coronary atherosclerosis. Am Heart J 141: S58‐S62, 2001.
 49.Burns KA, Li Y, Arao Y, Petrovich RM, Korach KS. Selective mutations in estrogen receptor alpha D‐domain alters nuclear translocation and non‐estrogen response element gene regulatory mechanisms. J Biol Chem 286: 12640‐12649, 2011.
 50.Buyon JP, Kalunian KC, Skovron ML, Petri M, Lahita R, Merrill J, Sammaritano L, Yung C, Licciardi F, Belmont HM, Hahn BH. Can women with systemic lupus erythematosus safely use exogenous estrogens? J Clin Rheumatol 1: 205‐212, 1995.
 51.Cain MA, Salemi JL, Tanner JP, Kirby RS, Salihu HM, Louis JM. Pregnancy as a window to future health: Maternal placental syndromes and short‐term cardiovascular outcomes. Am J Obstet Gynecol 215: 484.e481‐484.e414, 2016.
 52.Cain PA, Ahl R, Hedstrom E, Ugander M, Allansdotter‐Johnsson A, Friberg P, Arheden H. Age and gender specific normal values of left ventricular mass, volume and function for gradient echo magnetic resonance imaging: A cross sectional study. BMC Med Imaging 9: 2, 2009.
 53.Cano A, Van Baal WM. The mechanisms of thrombotic risk induced by hormone replacement therapy. Maturitas 40: 17‐38, 2001.
 54.Catov JM, Lewis CE, Lee M, Wellons MF, Gunderson EP. Preterm birth and future maternal blood pressure, inflammation, and intimal‐medial thickness: The CARDIA study. Hypertension 61: 641‐646, 2013.
 55.Cavasin MA, Sankey SS, Yu AL, Menon S, Yang XP. Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. Am J Physiol Heart Circ Physiol 284: H1560‐H1569, 2003.
 56.Cavasin MA, Tao Z, Menon S, Yang X‐P. Gender differences in cardiac function during early remodeling after acute myocardial infarction in mice. Life Sci 75: 2181‐2192, 2004.
 57.Cavasin MA, Tao ZY, Yu AL, Yang XP. Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function. Am J Physiol Heart Circ Physiol 290: H2043‐H2050, 2006.
 58.Chapman AB, Abraham WT, Zamudio S, Coffin C, Merouani A, Young D, Johnson A, Osorio F, Goldberg C, Moore LG, Dahms T, Schrier RW. Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Kidney Int 54: 2056‐2063, 1998.
 59.Charlton F, Tooher J, Rye KA, Hennessy A. Cardiovascular risk, lipids and pregnancy: Preeclampsia and the risk of later life cardiovascular disease. Heart Lung Circ 23: 203‐212, 2014.
 60.Cheetham TC, An J, Jacobsen SJ, Niu F, Sidney S, Quesenberry CP, VanDenEeden SK. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern Med 177: 491‐499, 2017.
 61.Chen CW, Jaffe IZ, Karumanchi SA. Pre‐eclampsia and cardiovascular disease. Cardiovasc Res 101: 579‐586, 2014.
 62.Chen JQ, Delannoy M, Cooke C, Yager JD. Mitochondrial localization of ERalpha and ERbeta in human MCF7 cells. Am J Physiol Endocrinol Metab 286: E1011‐E1022, 2004.
 63.Chen Z, Yuhanna IS, Galcheva‐Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 103: 401‐406, 1999.
 64.Cheng S, Fernandes VR, Bluemke DA, McClelland RL, Kronmal RA, Lima JA. Age‐related left ventricular remodeling and associated risk for cardiovascular outcomes: The Multi‐Ethnic Study of Atherosclerosis. Circ Cardiovasc Imaging 2: 191‐198, 2009.
 65.Chignalia AZ, Oliveira MA, Debbas V, Dull RO, Laurindo FR, Touyz RM, Carvalho MH, Fortes ZB, Tostes RC. Testosterone induces leucocyte migration by NADPH oxidase‐driven ROS‐ and COX2‐dependent mechanisms. Clin Sci (Lond) 129: 39‐48, 2015.
 66.Chignalia AZ, Schuldt EZ, Camargo LL, Montezano AC, Callera GE, Laurindo FR, Lopes LR, Avellar MC, Carvalho MH, Fortes ZB, Touyz RM, Tostes RC. Testosterone induces vascular smooth muscle cell migration by NADPH oxidase and c‐Src‐dependent pathways. Hypertension 59: 1263‐1271, 2012.
 67.Chinnathambi V, More AS, Hankins GD, Yallampalli C, Sathishkumar K. Gestational exposure to elevated testosterone levels induces hypertension via heightened vascular angiotensin II type 1 receptor signaling in rats. Biol Reprod 91: 6, 2014.
 68.Chiuve SE, Martin LA, Campos H, Sacks FM. Effect of the combination of methyltestosterone and esterified estrogens compared with esterified estrogens alone on apolipoprotein CIII and other apolipoproteins in very low density, low density, and high density lipoproteins in surgically postmenopausal women. J Clin Endocrinol Metab 89: 2207‐2213, 2004.
 69.Chou AY, Saw J. Basis for sex‐specific expression of Takotsubo cardiomyopathy, cardiac syndrome X, and spontaneous coronary artery dissection. Can J Cardiol 30: 738‐746, 2014.
 70.Chu SH, Sutherland K, Beck J, Kowalski J, Goldspink P, Schwertz D. Sex differences in expression of calcium‐handling proteins and beta‐adrenergic receptors in rat heart ventricle. Life Sci 76: 2735‐2749, 2005.
 71.Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, Mariani R, Gunson K, Jui J. Epidemiology of sudden cardiac death: Clinical and research implications. Prog Cardiovasc Dis 51: 213‐228, 2008.
 72.Chung CC, Hsu RC, Kao YH, Liou JP, Lu YY, Chen YJ. Androgen attenuates cardiac fibroblasts activations through modulations of transforming growth factor‐beta and angiotensin II signaling. Int J Cardiol 176: 386‐393, 2014.
 73.Clur SA, Oude Rengerink K, Mol BW, Ottenkamp J, Bilardo CM. Is fetal cardiac function gender dependent? Prenat Diagn 31: 536‐542, 2011.
 74.Collins P, Rosano GM, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG, Poole‐Wilson PA. 17 beta‐Estradiol attenuates acetylcholine‐induced coronary arterial constriction in women but not men with coronary heart disease. Circulation 92: 24‐30, 1995.
 75.Cravioto MD, Durand‐Carbajal M, Jimenez‐Santana L, Lara‐Reyes P, Seuc AH, Sanchez‐Guerrero J. Efficacy of estrogen plus progestin on menopausal symptoms in women with systemic lupus erythematosus: A randomized, double‐blind, controlled trial. Arthritis Care Res (Hoboken) 63: 1654‐1663, 2011.
 76.Crews JK, Khalil RA. Antagonistic effects of 17β‐estradiol, progesterone, and testosterone on Ca 2+ entry mechanisms of coronary vasoconstriction. Arterioscler Thromb Vasc Biol 19: 1034‐1040, 1999.
 77.Crews JK, Khalil RA. Gender‐specific inhibition of Ca2+ entry mechanisms of arterial vasoconstriction by sex hormones. Clin Exp Pharmacol Physiol 26: 707‐715, 1999.
 78.Crislip GR, Sullivan JC. T‐cell involvement in sex differences in blood pressure control. Clin Sci (Lond) 130: 773‐783, 2016.
 79.Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol Med 19: 197‐209, 2013.
 80.Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, Straub RH. Estrogens and autoimmune diseases. Ann N Y Acad Sci 1089: 538‐547, 2006.
 81.D'Andrea A, Caso P, Salerno G, Scarafile R, De Corato G, Mita C, Di Salvo G, Severino S, Cuomo S, Liccardo B, Esposito N, Calabro R. Left ventricular early myocardial dysfunction after chronic misuse of anabolic androgenic steroids: A Doppler myocardial and strain imaging analysis. Br J Sports Med 41: 149‐155, 2007.
 82.Dai W, Li Y, Zheng H. Estradiol/testosterone imbalance: Impact on coronary heart disease risk factors in postmenopausal women. Cardiology 121: 249‐254, 2012.
 83.Dasinger JH, Alexander BT. Gender differences in developmental programming of cardiovascular diseases. Clin Sci (Lond) 130: 337‐348, 2016.
 84.Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, Farber MA, Ford CE, Levy D, Massie BM, Nawaz S. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid‐lowering treatment to prevent heart attack trial. Circulation 118: 2259‐2267, 2008.
 85.Davis SR, Walker KZ, Strauss BJ. Effects of estradiol with and without testosterone on body composition and relationships with lipids in postmenopausal women. Menopause 7: 395‐401, 2000.
 86.Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: Changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 90: 3847‐3853, 2005.
 87.Death AK, McGrath KC, Sader MA, Nakhla S, Jessup W, Handelsman DJ, Celermajer DS. Dihydrotestosterone promotes vascular cell adhesion molecule‐1 expression in male human endothelial cells via a nuclear factor‐κB‐dependent pathway. Endocrinology 145: 1889‐1897, 2004.
 88.Debortoli AR, Rouver WDN, Delgado NTB, Mengal V, Claudio ERG, Pernomian L, Bendhack LM, Moyses MR, Santos RLD. GPER modulates tone and coronary vascular reactivity in male and female rats. J Mol Endocrinol 59: 171‐180, 2017.
 89.Delbeck M, Golz S, Vonk R, Janssen W, Hucho T, Isensee J, Schafer S, Otto C. Impaired left‐ventricular cardiac function in male GPR30‐deficient mice. Mol Med Rep 4: 37‐40, 2011.
 90.Deschamps AM, Murphy E. Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats. Am J Physiol Heart Circ Physiol 297: H1806‐H1813, 2009.
 91.Deshmukh A, Kumar G, Pant S, Rihal C, Murugiah K, Mehta JL. Prevalence of Takotsubo cardiomyopathy in the United States. Am Heart J 164: 66‐71.e61, 2012.
 92.Devanathan S, Whitehead T, Schweitzer GG, Fettig N, Kovacs A, Korach KS, Finck BN, Shoghi KI. An animal model with a cardiomyocyte‐specific deletion of estrogen receptor alpha: Functional, metabolic, and differential network analysis. PloS one 9: e101900, 2014.
 93.Dior UP, Hochner H, Friedlander Y, Calderon‐Margalit R, Jaffe D, Burger A, Avgil M, Manor O, Elchalal U. Association between number of children and mortality of mothers: Results of a 37‐year follow‐up study. Ann Epidemiol 23: 13‐18, 2013.
 94.Dobs AS, Nguyen T, Pace C, Roberts CP. Differential effects of oral estrogen versus oral estrogen‐androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab 87: 1509‐1516, 2002.
 95.Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin Sci (Lond) 104: 195‐201, 2003.
 96.Donekal S, Venkatesh BA, Liu YC, Liu CY, Yoneyama K, Wu CO, Nacif M, Gomes AS, Hundley WG, Bluemke DA, Lima JA. Interstitial fibrosis, left ventricular remodeling, and myocardial mechanical behavior in a population‐based multiethnic cohort: The Multi‐Ethnic Study of Atherosclerosis (MESA) study. Circ Cardiovasc Imaging 7: 292‐302, 2014.
 97.Dreyer RP, Dharmarajan K, Kennedy KF, Jones PG, Vaccarino V, Murugiah K, Nuti SV, Smolderen KG, Buchanan DM, Spertus JA, Krumholz HM. Sex differences in 1‐year all‐cause rehospitalization in patients after acute myocardial infarction: A prospective observational study. Circulation 135: 521‐531, 2017.
 98.Dubey RK, Imthurn B, Barton M, Jackson EK. Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen. Cardiovasc Res 66: 295‐306, 2005.
 99.Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 14: 591‐602, 2017.
 100.Duran J, Oyarce C, Pavez M, Valladares D, Basualto‐Alarcon C, Lagos D, Barrientos G, Troncoso MF, Ibarra C, Estrada M. GSK‐3beta/NFAT signaling is involved in testosterone‐induced cardiac myocyte hypertrophy. PLoS One 11: e0168255, 2016.
 101.Ekblom‐Kullberg S, Kautiainen H, Alha P, Helve T, Leirisalo‐Repo M, Julkunen H. Reproductive health in women with systemic lupus erythematosus compared to population controls. Scand J Rheumatol 38: 375‐380, 2009.
 102.Elkayam U. Clinical characteristics of peripartum cardiomyopathy in the United States: Diagnosis, prognosis, and management. J Am Coll Cardiol 58: 659‐670, 2011.
 103.Er F, Michels G, Brandt MC, Khan I, Haase H, Eicks M, Lindner M, Hoppe UC. Impact of testosterone on cardiac L‐type calcium channels and Ca2+ sparks: Acute actions antagonize chronic effects. Cell Calcium 41: 467‐477, 2007.
 104.Fairley AS, Mathis KW. Cholinergic agonists reduce blood pressure in a mouse model of systemic lupus erythematosus. Physiol Rep 5, pii: e13213: 2017.
 105.Fairweather D, Frisancho‐Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol 173: 600‐609, 2008.
 106.Faupel‐Badger JM, McElrath TF, Lauria M, Houghton LC, Lim KH, Parry S, Cantonwine D, Lai G, Karumanchi SA, Hoover RN, Troisi R. Maternal circulating angiogenic factors in twin and singleton pregnancies. Am J Obstet Gynecol 212: 636.e631‐638, 2015.
 107.Fernandez‐Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos‐Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM. Clinical review 1: Adverse effects of testosterone therapy in adult men: A systematic review and meta‐analysis. J Clin Endocrinol Metab 95: 2560‐2575, 2010.
 108.Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF, Jr., Hoover RN. Increased risk of non‐fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 9: e85805, 2014.
 109.Fliegner D, Schubert C, Penkalla A, Witt H, Kararigas G, Dworatzek E, Staub E, Martus P, Noppinger PR, Kintscher U. Female sex and estrogen receptor‐β attenuate cardiac remodeling and apoptosis in pressure overload. Am J Physiol Regul Integr Comp Physiol 298: R1597‐R1606, 2010.
 110.Forte P, Kneale BJ, Milne E, Chowienczyk PJ, Johnston A, Benjamin N, Ritter JM. Evidence for a difference in nitric oxide biosynthesis between healthy women and men. Hypertension 32: 730‐734, 1998.
 111.Fowler K, Partridge L. A cost of mating in female fruitflies. Nature 338: 760‐761, 1989.
 112.Fox KA, Longo M, Tamayo E, Gamble P, Makhlouf M, Mateus JF, Saade GR. Sex‐specific effects of nicotine exposure on developmental programming of blood pressure and vascular reactivity in the C57Bl/6J mouse. Am J Obstet Gynecol 207: 208.e201‐209, 2012.
 113.Francisco C, Wright D, Benko Z, Syngelaki A, Nicolaides KH. Competing‐risks model in screening for pre‐eclampsia in twin pregnancy by maternal characteristics and medical history. Ultrasound Obstet Gynecol 50: 501‐506, 2017.
 114.Franco OH, Muka T, Colpani V, Kunutsor S, Chowdhury S, Chowdhury R, Kavousi M. Vasomotor symptoms in women and cardiovascular risk markers: Systematic review and meta‐analysis. Maturitas 81: 353‐361, 2015.
 115.Francomano D, Fattorini G, Gianfrilli D, Paoli D, Sgrò P, Radicioni A, Romanelli F, Di Luigi L, Gandini L, Lenzi A. Acute endothelial response to testosterone gel administration in men with severe hypogonadism and its relationship to androgen receptor polymorphism: A pilot study. J Endocrinol Invest 39: 265‐271, 2016.
 116.Franklin RM, Ploutz‐Snyder L, Kanaley JA. Longitudinal changes in abdominal fat distribution with menopause. Metabolism 58: 311‐315, 2009.
 117.Freeman BM, Univers J, Fisher RK, Kirkpatrick SS, Klein FA, Freeman MB, Mountain DJ, Grandas OH. Testosterone replacement attenuates intimal hyperplasia development in an androgen deficient model of vascular injury. J Surg Res 207: 53‐62, 2017.
 118.Gaborit N, Varro A, Le Bouter S, Szuts V, Escande D, Nattel S, Demolombe S. Gender‐related differences in ion‐channel and transporter subunit expression in non‐diseased human hearts. J Mol Cell Cardiol 49: 639‐646, 2010.
 119.García‐Cruz E, Leibar‐Tamayo A, Romero J, Piqueras M, Luque P, Cardeñosa O, Alcaraz A. Metabolic syndrome in men with low testosterone levels: Relationship with cardiovascular risk factors and comorbidities and with erectile dysfunction. J Sex Med 10: 2529‐2538, 2013.
 120.Gaudet MM, Carter BD, Hildebrand JS, Patel AV, Campbell PT, Wang Y, Gapstur SM. Associations of parity and age at first pregnancy with overall and cause‐specific mortality in the Cancer Prevention Study II. Fertil Steril 107: 179‐188.e176, 2017.
 121.Gebhard C, Stahli BE, Gebhard CE, Tasnady H, Zihler D, Wischnewsky MB, Jenni R, Tanner FC. Age‐ and gender‐dependent left ventricular remodeling. Echocardiography 30: 1143‐1150, 2013.
 122.Georget V, Terouanne B, Nicolas JC, Sultan C. Mechanism of antiandrogen action: key role of hsp90 in conformational change and transcriptional activity of the androgen receptor. Biochemistry 41: 11824‐11831, 2002.
 123.Geraldes P, Gagnon S, Hadjadj S, Merhi Y, Sirois MG, Cloutier I, Tanguay JF. Estradiol blocks the induction of CD40 and CD40L expression on endothelial cells and prevents neutrophil adhesion: an ERalpha‐mediated pathway. Cardiovasc Res 71: 566‐573, 2006.
 124.Gerber Y, Jacobsen SJ, Frye RL, Weston SA, Killian JM, Roger VL. Secular trends in deaths from cardiovascular diseases: A 25‐year community study. Circulation 113: 2285‐2292, 2006.
 125.Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ, Price K, Karumanchi SA, Valdes G. Endothelial dysfunction: A link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension 49: 90‐95, 2007.
 126.Gilbert EL, Ryan MJ. Estrogen in cardiovascular disease during systemic lupus erythematosus. Clin Ther 36: 1901‐1912, 2014.
 127.Giraud GD, Louey S, Jonker S, Schultz J, Thornburg KL. Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus. Endocrinology 147: 3643‐3649, 2006.
 128.Gold EB, Colvin A, Avis N, Bromberger J, Greendale GA, Powell L, Sternfeld B, Matthews K. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women's health across the nation. Am J Public Health 96: 1226‐1235, 2006.
 129.Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 371: 75‐84, 2008.
 130.Gong Y, Xiao H, Li C, Bai J, Cheng X, Jin M, Sun B, Lu Y, Shao Y, Tian H. Elevated t/e2 ratio is associated with an increased risk of cerebrovascular disease in elderly men. PloS one 8: e61598, 2013.
 131.Goodale T, Sadhu A, Petak S, Robbins R. Testosterone and the heart. Methodist Debakey Cardiovasc J 13: 68‐72, 2017.
 132.Gopalakrishnan K, Mishra JS, Chinnathambi V, Vincent KL, Patrikeev I, Motamedi M, Saade GR, Hankins GD, Sathishkumar K. Elevated testosterone reduces uterine blood flow, spiral artery elongation, and placental oxygenation in pregnant rats. Hypertension 67: 630‐639, 2016.
 133.Gorodeski GI. Impact of the menopause on the epidemiology and risk factors of coronary artery heart disease in women. Exp Gerontol 29: 357‐375, 1994.
 134.Goulopoulou S. Maternal vascular physiology in preeclampsia. Hypertension 70: 1066‐1073, 2017.
 135.Green A, Beral V, Moser K. Mortality in women in relation to their childbearing history. Bmj 297: 391‐395, 1988.
 136.Grohe C, Kahlert S, Lobbert K, Stimpel M, Karas RH, Vetter H, Neyses L. Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett 416: 107‐112, 1997.
 137.Lupus Federal Work Group. Action plan for lupus. National Institute of Arthritis and Musculoskeletal and Skin Diseases. 2017.
 138.Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA, Kajstura J, Anversa P. Myocyte death in the failing human heart is gender dependent. Circ Res 85: 856‐866, 1999.
 139.Gustafson CM, Shepherd AJ, Miller VM, Jayachandran M. Age‐ and sex‐specific differences in blood‐borne microvesicles from apparently healthy humans. Biol Sex Differ 6: 10, 2015.
 140.Haas E, Bhattacharya I, Brailoiu E, Damjanovic M, Brailoiu GC, Gao X, Mueller‐Guerre L, Marjon NA, Gut A, Minotti R, Meyer MR, Amann K, Ammann E, Perez‐Dominguez A, Genoni M, Clegg DJ, Dun NJ, Resta TC, Prossnitz ER, Barton M. Regulatory role of G protein‐coupled estrogen receptor for vascular function and obesity. Circ Res 104: 288‐291, 2009.
 141.Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, Roentgen P, Tsikas D, Jordan J, Lichtinghagen R, von Kaisenberg CS, Struman I, Bovy N, Sliwa K, Bauersachs J, Hilfiker‐Kleiner D. Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy. Basic Res Cardiol 108: 366, 2013.
 142.Hahnel ME, Martin JD, Michael CA, Hahnel R. Metabolism of androstenedione by placental microsomes in pregnancy hypertension. Clin Chim Acta 181: 103‐108, 1989.
 143.Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007‐2008 to 2015‐2016. Jama 319: 1723‐1725, 2018.
 144.Hannaford P, Ferry S, Hirsch S. Cardiovascular sequelae of toxaemia of pregnancy. Heart 77: 154‐158, 1997.
 145.Haring R, Volzke H, Steveling A, Krebs A, Felix SB, Schofl C, Dorr M, Nauck M, Wallaschofski H. Low serum testosterone levels are associated with increased risk of mortality in a population‐based cohort of men aged 20‐79. Eur Heart J 31: 1494‐1501, 2010.
 146.Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 86: 724‐731, 2001.
 147.Harper MA, Meyer RE, Berg CJ. Peripartum cardiomyopathy: Population‐based birth prevalence and 7‐year mortality. Obstet Gynecol 120: 1013‐1019, 2012.
 148.Harvey RE, Coffman KE, Miller VM. Women‐specific factors to consider in risk, diagnosis and treatment of cardiovascular disease. Womens Health (Lond) 11: 239‐257, 2015.
 149.Hashimoto M, Akishita M, Eto M, Ishikawa M, Kozaki K, Toba K, Sagara Y, Taketani Y, Orimo H, Ouchi Y. Modulation of endothelium‐dependent flow‐mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation 92: 3431‐3435, 1995.
 150.Haynes MP, Li L, Sinha D, Russell KS, Hisamoto K, Baron R, Collinge M, Sessa WC, Bender JR. Src kinase mediates phosphatidylinositol 3‐kinase/Akt‐dependent rapid endothelial nitric‐oxide synthase activation by estrogen. J Biol Chem 278: 2118‐2123, 2003.
 151.Heinlein CA, Chang C. The roles of androgen receptors and androgen‐binding proteins in nongenomic androgen actions. Mol Endocrinol 16: 2181‐2187, 2002.
 152.Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA. Estrogen receptors: How do they signal and what are their targets. Physiol Rev 87: 905‐931, 2007.
 153.Henderson‐Smart DJ, Hutchinson JL, Donoghue DA, Evans NJ, Simpson JM, Wright I. Prenatal predictors of chronic lung disease in very preterm infants. Arch Dis Child Fetal Neonatal Ed 91: F40‐F45, 2006.
 154.Hertig A, Liere P, Chabbert‐Buffet N, Fort J, Pianos A, Eychenne B, Cambourg A, Schumacher M, Berkane N, Lefevre G, Uzan S, Rondeau E, Rozenberg P, Rafestin‐Oblin ME. Steroid profiling in preeclamptic women: Evidence for aromatase deficiency. Am J Obstet Gynecol 203: 477.e471‐479, 2010.
 155.Hilfiker‐Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K, Forster O, Quint A, Landmesser U, Doerries C, Luchtefeld M, Poli V, Schneider MD, Balligand JL, Desjardins F, Ansari A, Struman I, Nguyen NQ, Zschemisch NH, Klein G, Heusch G, Schulz R, Hilfiker A, Drexler H. A cathepsin D‐cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128: 589‐600, 2007.
 156.Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang‐Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 374: 1221‐1231, 2016.
 157.Hogg ME, Vavra AK, Banerjee MN, Martinez J, Jiang Q, Keefer LK, Chambon P, Kibbe MR. The role of estrogen receptor α and β in regulating vascular smooth muscle cell proliferation is based on sex. J Surg Res 173: e1‐e10, 2012.
 158.Honda S, Asaumi Y, Yamane T, Nagai T, Miyagi T, Noguchi T, Anzai T, Goto Y, Ishihara M, Nishimura K. Trends in the clinical and pathological characteristics of cardiac rupture in patients with acute myocardial infarction over 35 years. J Am Heart Assoc 3: e000984, 2014.
 159.Hougaku H, Fleg JL, Najjar SS, Lakatta EG, Harman SM, Blackman MR, Metter EJ. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab 290: E234‐E242, 2006.
 160.Hsieh TF, Chen CC, Ma WL, Chuang WM, Hung XF, Tsai YR, Lin MH, Zhang Q, Zhang C, Chang C, Shyr CR. Epidermal growth factor enhances androgen receptormediated bladder cancer progression and invasion via potentiation of AR transactivation. Oncol Rep 30: 2917‐2922, 2013.
 161.Hu X, Rui L, Zhu T, Xia H, Yang X, Wang X, Liu H, Lu Z, Jiang H. Low testosterone level in middle‐aged male patients with coronary artery disease. Eur J Intern Med 22: e133‐e136, 2011.
 162.Huang C, Gu H, Wang Y, Wang M. Estrogen‐induced SDF‐1 production is mediated by estrogen receptor‐alpha in female hearts after acute ischemia and reperfusion. Surgery 150: 197‐203, 2011.
 163.Hunter TM, Boytsov NN, Zhang X, Schroeder K, Michaud K, Araujo AB. Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004‐2014. Rheumatol Int 37: 1551‐1557, 2017.
 164.Hutanu C, Cox BE, DeSpain K, Liu XT, Rosenfeld CR. Vascular development in early ovine gestation: carotid smooth muscle function, phenotype, and biochemical markers. Am J Physiol Regul Integr Comp Physiol 293: R323‐R333, 2007.
 165.Iellamo F, Volterrani M, Caminiti G, Karam R, Massaro R, Fini M, Collins P, Rosano GM. Testosterone therapy in women with chronic heart failure: A pilot double‐blind, randomized, placebo‐controlled study. J Am Coll Cardiol 56: 1310‐1316, 2010.
 166.Ikeda Y, Aihara K, Sato T, Akaike M, Yoshizumi M, Suzaki Y, Izawa Y, Fujimura M, Hashizume S, Kato M, Yagi S, Tamaki T, Kawano H, Matsumoto T, Azuma H, Kato S, Matsumoto T. Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II‐induced cardiac fibrosis. J Biol Chem 280: 29661‐29666, 2005.
 167.Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre‐eclampsia: population based cohort study. Bmj 323: 1213‐1217, 2001.
 168.Isensee J, Ruiz Noppinger P. Sexually dimorphic gene expression in mammalian somatic tissue. Gend Med 4(Suppl B): S75‐95, 2007.
 169.Jakacka M, Ito M, Weiss J, Chien PY, Gehm BD, Jameson JL. Estrogen receptor binding to DNA is not required for its activity through the nonclassical AP1 pathway. J Biol Chem 276: 13615‐13621, 2001.
 170.James AH. Pregnancy‐associated thrombosis. Hematology Am Soc Hematol Educ Program 277‐285, 2009.
 171.Jang IH, Heo SC, Kwon YW, Choi EJ, Kim JH. Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis. Adv Biol Regul 57: 162‐172, 2015.
 172.Jeanes HL, Tabor C, Black D, Ederveen A, Gray GA. Oestrogen‐mediated cardioprotection following ischaemia and reperfusion is mimicked by an oestrogen receptor (ER) α agonist and unaffected by an ERβ antagonist. J Endocrinol 197: 493‐501, 2008.
 173.Jin HJ, Kim J, Yu J. Androgen receptor genomic regulation. Transl Androl Urol 2: 157‐177, 2013.
 174.Jirecek S, Joura EA, Tempfer C, Knofler M, Husslein P, Zeisler H. Elevated serum concentrations of androgens in women with pregnancy‐induced hypertension. Wien Klin Wochenschr 115: 162‐166, 2003.
 175.Jobe SO, Tyler CT, Magness RR. Aberrant synthesis, metabolism, and plasma accumulation of circulating estrogens and estrogen metabolites in preeclampsia implications for vascular dysfunction. Hypertension 61: 480‐487, 2013.
 176.Julkunen HA. Oral contraceptives in systemic lupus erythematosus: Side‐effects and influence on the activity of SLE. Scand J Rheumatol 20: 427‐433, 1991.
 177.Kanasaki K, Palmsten K, Sugimoto H, Ahmad S, Hamano Y, Xie L, Parry S, Augustin HG, Gattone VH, Folkman J, Strauss JF, Kalluri R. Deficiency in catechol‐O‐methyltransferase and 2‐methoxyoestradiol is associated with pre‐eclampsia. Nature 453: 1117‐1121, 2008.
 178.Kappert K, Bohm M, Schmieder R, Schumacher H, Teo K, Yusuf S, Sleight P, Unger T. Impact of sex on cardiovascular outcome in patients at high cardiovascular risk: Analysis of the Telmisartan Randomized Assessment Study in ACE‐Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). Circulation 126: 934‐941, 2012.
 179.Kararigas G, Bito V, Tinel H, Becher E, Baczko I, Knosalla C, Albrecht‐Kupper B, Sipido KR, Regitz‐Zagrosek V. Transcriptome characterization of estrogen‐treated human myocardium identifies myosin regulatory light chain interacting protein as a sex‐specific element influencing contractile function. J Am Coll Cardiol 59: 410‐417, 2012.
 180.Kato S. Estrogen receptor‐mediated cross‐talk with growth factor signaling pathways. Breast Cancer 8: 3‐9, 2001.
 181.Kelly DM, Jones TH. Testosterone: A vascular hormone in health and disease. J Endocrinol 217: R47‐R71, 2013.
 182.Kessous R, Shoham‐Vardi I, Pariente G, Sergienko R, Holcberg G, Sheiner E. Recurrent pregnancy loss: A risk factor for long‐term maternal atherosclerotic morbidity? Am J Obstet Gynecol 211: 414.e411‐411, 2014.
 183.Kharazmi E, Dossus L, Rohrmann S, Kaaks R. Pregnancy loss and risk of cardiovascular disease: A prospective population‐based cohort study (EPIC‐Heidelberg). Heart 97: 49‐54, 2011.
 184.Kher A, Wang M, Tsai BM, Pitcher JM, Greenbaum ES, Nagy RD, Patel KM, Wairiuko GM, Markel TA, Meldrum DR. Sex differences in the myocardial inflammatory response to acute injury. Shock 23: 1‐10, 2005.
 185.Khetawat G, Faraday N, Nealen ML, Vijayan KV, Bolton E, Noga SJ, Bray PF. Human megakaryocytes and platelets contain the estrogen receptor β and androgen receptor (AR): Testosterone regulates AR expression. Blood 95: 2289‐2296, 2000.
 186.Khosla S, Melton LJ, 3rd, Atkinson EJ, O'Fallon WM, Klee GG, Riggs BL. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: A key role for bioavailable estrogen. J Clin Endocrinol Metab 83: 2266‐2274, 1998.
 187.Kim JK, Pedram A, Razandi M, Levin ER. Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms. J Biol Chem 281: 6760‐6767, 2006.
 188.Kim KH, Bender JR. Membrane‐initiated actions of estrogen on the endothelium. Mol Cell Endocrinol 308: 3‐8, 2009.
 189.Kim KN, Park YS, Hoh JK. Sex‐related differences in the development of fetal heart rate dynamics. Early Hum Dev 93: 47‐55, 2016.
 190.Kim SC, Boese AC, Moore MH, Cleland RM, Chang L, Delafontaine P, Yin KJ, Lee JP, Hamblin MH. Rapid estrogen receptor alpha signaling mediated by ERK activation regulates vascular tone in male and ovary‐intact female mice. Am J Physiol Heart Circ Physiol 314: H330‐H342, 2017.
 191.Kiprono LV, Wallace K, Moseley J, Martin J, Jr., Lamarca B. Progesterone blunts vascular endothelial cell secretion of endothelin‐1 in response to placental ischemia. Am J Obstet Gynecol 209: 44.e41‐46, 2013.
 192.Kitagawa Y, Gotoh F, Koto A, Okayasu H. Stroke in systemic lupus erythematosus. Stroke 21: 1533‐1539, 1990.
 193.Klingberg S, Brekke HK, Winkvist A, Engstrom G, Hedblad B, Drake I. Parity, weight change, and maternal risk of cardiovascular events. Am J Obstet Gynecol 216: 172.e171‐172.e115, 2017.
 194.Klinge CM, Blankenship KA, Risinger KE, Bhatnagar S, Noisin EL, Sumanasekera WK, Zhao L, Brey DM, Keynton RS. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J Biol Chem 280: 7460‐7468, 2005.
 195.Kneale BJ, Chowienczyk PJ, Brett SE, Coltart DJ, Ritter JM. Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J Am Coll Cardiol 36: 1233‐1238, 2000.
 196.Knopp RH, Paramsothy P, Retzlaff BM, Fish B, Walden C, Dowdy A, Tsunehara C, Aikawa K, Cheung MC. Sex differences in lipoprotein metabolism and dietary response: Basis in hormonal differences and implications for cardiovascular disease. Curr Cardiol Rep 8: 452‐459, 2006.
 197.Knowlton A, Lee A. Estrogen and the cardiovascular system. Pharmacol Ther 135: 54‐70, 2012.
 198.Koenig T, Hilfiker‐Kleiner D, Bauersachs J. Peripartum cardiomyopathy. Herz 43: 431‐437, 2018.
 199.Kolte D, Khera S, Aronow WS, Palaniswamy C, Mujib M, Ahn C, Jain D, Gass A, Ahmed A, Panza JA, Fonarow GC. Temporal trends in incidence and outcomes of peripartum cardiomyopathy in the United States: A nationwide population‐based study. J Am Heart Assoc 3: e001056, 2014.
 200.Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson J‐Ak. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 138: 863‐870, 1997.
 201.Kumar P, Wu Q, Chambliss KL, Yuhanna IS, Mumby SM, Mineo C, Tall GG, Shaul PW. Direct interactions with G alpha i and G betagamma mediate nongenomic signaling by estrogen receptor alpha. Mol Endocrinol 21: 1370‐1380, 2007.
 202.Kyriakides ZS, Petinakis P, Kaklamanis L, Sbarouni E, Karayannakos P, Iliopoulos D, Dontas I, Kremastinos DT. Intramuscular administration of estrogen may promote angiogenesis and perfusion in a rabbit model of chronic limb ischemia. Cardiovasc Res 49: 626‐633, 2001.
 203.Labrie F, Luu‐The V, Lin SX, Labrie C, Simard J, Breton R, Belanger A. The key role of 17 beta‐hydroxysteroid dehydrogenases in sex steroid biology. Steroids 62: 148‐158, 1997.
 204.Lam CS, McEntegart M, Claggett B, Liu J, Skali H, Lewis E, Kober L, Rouleau J, Velazquez E, Califf R, McMurray JJ, Pfeffer M, Solomon S. Sex differences in clinical characteristics and outcomes after myocardial infarction: Insights from the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Eur J Heart Fail 17: 301‐312, 2015.
 205.Lamb MJ. The effects of radiation on the longevity of female Drosophila subobscura. J Ins Physiol 10: 487‐497, 1964.
 206.Langer C, Gansz B, Goepfert C, Engel T, Uehara Y, von Dehn G, Jansen H, Assmann G, von Eckardstein A. Testosterone up‐regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem Biophys Res Commun 296: 1051‐1057, 2002.
 207.Lazdam M, de la Horra A, Diesch J, Francis J, Kenworthy Y, Shore A, Neubauer S, Kharbanda R, Alp N, Redman C, Kelly B, Leeson P. PP032. Unique features of long‐term cardiovascular phenotype in young women with early‐onset pre‐eclampsia. Pregnancy Hypertens 2: 259‐260, 2012.
 208.Leao LM, Duarte MP, Silva DM, Bahia PR, Coeli CM, de Farias ML. Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study. Eur J Endocrinol 154: 131‐139, 2006.
 209.Lejskova M, Pitha J, Adamkova S, Auzky O, Adamek T, Babkova E, Lanska V, Alusik S. Bilateral oophorectomy may have an unfavorable effect on glucose metabolism compared with natural menopause. Physiol Res 63(Suppl 3): S395‐402, 2014.
 210.Levelt E, Mahmod M, Piechnik SK, Ariga R, Francis JM, Rodgers CT, Clarke WT, Sabharwal N, Schneider JE, Karamitsos TD, Clarke K, Rider OJ, Neubauer S. Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes. Diabetes 65: 44‐52, 2016.
 211.Li L, Hisamoto K, Kim KH, Haynes MP, Bauer PM, Sanjay A, Collinge M, Baron R, Sessa WC, Bender JR. Variant estrogen receptor‐c‐Src molecular interdependence and c‐Src structural requirements for endothelial NO synthase activation. Proc Natl Acad Sci U S A 104: 16468‐16473, 2007.
 212.Li WL, Xiang W, Ping Y. Activation of novel estrogen receptor GPER results in inhibition of cardiocyte apoptosis and cardioprotection. Mol Med Rep 12: 2425‐2430, 2015.
 213.Liao CH, Wu YN, Lin FY, Tsai WK, Liu SP, Chiang HS. Testosterone replacement therapy can increase circulating endothelial progenitor cell number in men with late onset hypogonadism. Andrology 1: 563‐569, 2013.
 214.Lieb W, Xanthakis V, Sullivan LM, Aragam J, Pencina MJ, Larson MG, Benjamin EJ, Vasan RS. Longitudinal tracking of left ventricular mass over the adult life course: Clinical correlates of short‐ and long‐term change in the framingham offspring study. Circulation 119: 3085‐3092, 2009.
 215.Liu P, Li X, Song F, Li P, Wei J, Yan Q, Xu X, Yang J, Li C, Fu X. Testosterone promotes tube formation of endothelial cells isolated from veins via activation of Smad1 protein. Mol Cell Endocrinol 446: 21‐31, 2017.
 216.Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev 24: 313‐340, 2003.
 217.Lobo RA, Davis SR, De Villiers TJ, Gompel A, Henderson VW, Hodis HN, Lumsden MA, Mack WJ, Shapiro S, Baber RJ. Prevention of diseases after menopause. Climacteric 17: 540‐556, 2014.
 218.Loeb S, Folkvaljon Y, Damber J‐E, Alukal J, Lambe M, Stattin P. Testosterone replacement therapy and risk of favorable and aggressive prostate cancer. J Clin Oncol 35: 1430‐1436, 2017.
 219.Lopes RA, Neves KB, Pestana CR, Queiroz AL, Zanotto CZ, Chignalia AZ, Valim YM, Silveira LR, Curti C, Tostes RC. Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria‐generated reactive oxygen species involvement. Am J Physiol Heart Circ Physiol 306: H1485‐H1494, 2014.
 220.Loy CJ, Sim KS, Yong EL. Filamin‐A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions. Proc Natl Acad Sci U S A 100: 4562‐4567, 2003.
 221.Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. Proc Natl Acad Sci U S A 101: 17126‐17131, 2004.
 222.Lv H, Wu H, Yin J, Qian J, Ge J. Parity and cardiovascular disease mortality: A dose‐response meta‐analysis of cohort studies. Sci Rep 5: 13411, 2015.
 223.Lykke JA, Langhoff‐Roos J, Lockwood CJ, Triche EW, Paidas MJ. Mortality of mothers from cardiovascular and non‐cardiovascular causes following pregnancy complications in first delivery. Paediatr Perinat Epidemiol 24: 323‐330, 2010.
 224.Lykke JA, Langhoff‐Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 53: 944‐951, 2009.
 225.Ma Q, Wang J, Jin J, Gao M, Liu F, Zhou S, Tian F, Liu J, Liu Y, Chen Y. Clinical characteristics and prognosis of acute coronary syndrome in young women and men: A systematic review and meta‐analysis of prospective studies. Int J Cardiol 228: 837‐843, 2017.
 226.Maas AH, Appelman YE. Gender differences in coronary heart disease. Neth Heart J 18: 598‐602, 2010.
 227.Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P. The hypertensive disorders of pregnancy (29.3). Best Pract Res Clin Obstet Gynaecol 29: 643‐657, 2015.
 228.Magnussen EB, Vatten LJ, Smith GD, Romundstad PR. Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors. Obstet Gynecol 114: 961‐970, 2009.
 229.Makhsida N, Shah JAY, Yan G, Fisch H, Shabsigh R. Hypogonadism and metabolic syndrome: Implications for testosterone therapy. J Urol 174: 827‐834, 2005.
 230.Makieva S, Saunders PT, Norman JE. Androgens in pregnancy: Roles in parturition. Hum Reprod Update 20: 542‐559, 2014.
 231.Maliqueo M, Echiburu B, Crisosto N. Sex steroids modulate uterine‐placental vasculature: Implications for obstetrics and neonatal outcomes. Front Physiol 7: 152, 2016.
 232.Mankad R. Atherosclerotic vascular disease in the autoimmune rheumatologic patient. Curr Atheroscler Rep 17: 497, 2015.
 233.Manson JE. The Kronos Early Estrogen Prevention Study by Charlotte Barker. Womens Health (Lond) 9: 9‐11, 2013.
 234.Maravelias C, Dona A, Stefanidou M, Spiliopoulou C. Adverse effects of anabolic steroids in athletes: A constant threat. Toxicol Lett 158: 167‐175, 2005.
 235.Marcus J, DeWaal L, Götte M, Van der Geest R, Heethaar R, Van Rossum A. MRI‐derived left ventricular function parameters and mass in healthy young adults: relation with gender and body size. Int J Card Imaging 15: 411‐419, 1999.
 236.Marino M, Galluzzo P, Ascenzi P. Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics 7: 497‐508, 2006.
 237.Martin JA, Hamilton BE, Osterman MJK. Births in the United States, 2016. NCHS Data Brief 1‐8, 2017.
 238.Masuda H, Kalka C, Takahashi T, Yoshida M, Wada M, Kobori M, Itoh R, Iwaguro H, Eguchi M, Iwami Y, Tanaka R, Nakagawa Y, Sugimoto A, Ninomiya S, Hayashi S, Kato S, Asahara T. Estrogen‐mediated endothelial progenitor cell biology and kinetics for physiological postnatal vasculogenesis. Circ Res 101: 598‐606, 2007.
 239.Mathis KW, Broome HJ, Ryan MJ. Autoimmunity: An underlying factor in the pathogenesis of hypertension. Curr Hypertens Rep 16: 424, 2014.
 240.Mathis KW, Taylor EB, Ryan MJ. Anti‐CD3 antibody therapy attenuates the progression of hypertension in female mice with systemic lupus erythematosus. Pharmacol Res 120: 252‐257, 2017.
 241.Mathis KW, Venegas‐Pont M, Flynn ER, Williams JM, Maric‐Bilkan C, Dwyer TM, Ryan MJ. Hypertension in an experimental model of systemic lupus erythematosus occurs independently of the renal nerves. Am J Physiol Regul Integr Comp Physiol 305: R711‐R719, 2013.
 242.Mathis KW, Venegas‐Pont M, Masterson CW, Wasson KL, Ryan MJ. Blood pressure in a hypertensive mouse model of SLE is not salt‐sensitive. Am J Physiol Regul Integr Comp Physiol 301: R1281‐R1285, 2011.
 243.Maturana MA, Breda V, Lhullier F, Spritzer PM. Relationship between endogenous testosterone and cardiovascular risk in early postmenopausal women. Metabolism 57: 961‐965, 2008.
 244.McCrohon JA, Death AK, Nakhla S, Jessup W, Handelsman DJ, Stanley KK, Celermajer DS. Androgen receptor expression is greater in macrophages from male than from female donors. Circulation 101: 224‐226, 2000.
 245.McCrohon JA, Jessup W, Handelsman DJ, Celermajer DS. Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule‐1. Circulation 99: 2317‐2322, 1999.
 246.McMurray RW, May W. Sex hormones and systemic lupus erythematosus: Review and meta‐analysis. Arthritis Rheum 48: 2100‐2110, 2003.
 247.McNamara DM, Elkayam U, Alharethi R, Damp J, Hsich E, Ewald G, Modi K, Alexis JD, Ramani GV, Semigran MJ, Haythe J, Markham DW, Marek J, Gorcsan J, 3rd, Wu WC, Lin Y, Halder I, Pisarcik J, Cooper LT, Fett JD. Clinical outcomes for peripartum cardiomyopathy in North America: Results of the IPAC Study (Investigations of Pregnancy‐Associated Cardiomyopathy). J Am Coll Cardiol 66: 905‐914, 2015.
 248.Melaragno MG, Cavet ME, Yan C, Tai LK, Jin ZG, Haendeler J, Berk BC. Gas6 inhibits apoptosis in vascular smooth muscle: Role of Axl kinase and Akt. J Mol Cell Cardiol 37: 881‐887, 2004.
 249.Melloni C, Berger JS, Wang TY, Gunes F, Stebbins A, Pieper KS, Dolor RJ, Douglas PS, Mark DB, Newby LK. Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes 3: 135‐142, 2010.
 250.Menazza S, Murphy E. The expanding complexity of estrogen receptor signaling in the cardiovascular system. Circ Res 118: 994‐1007, 2016.
 251.Menazza S, Sun J, Appachi S, Chambliss KL, Kim SH, Aponte A, Khan S, Katzenellenbogen JA, Katzenellenbogen BS, Shaul PW, Murphy E. Non‐nuclear estrogen receptor alpha activation in endothelium reduces cardiac ischemia‐reperfusion injury in mice. J Mol Cell Cardiol 107: 41‐51, 2017.
 252.Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 308: 1583‐1587, 2005.
 253.Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 340: 1801‐1811, 1999.
 254.Meyer MR, Amann K, Field AS, Hu C, Hathaway HJ, Kanagy NL, Walker MK, Barton M, Prossnitz ER. Deletion of G protein‐coupled estrogen receptor increases endothelial vasoconstriction. Hypertension 59: 507‐512, 2012.
 255.Meyer MR, Baretella O, Prossnitz ER, Barton M. Dilation of epicardial coronary arteries by the G protein‐coupled estrogen receptor agonists G‐1 and ICI 182,780. Pharmacology 86: 58‐64, 2010.
 256.Meyer MR, Fredette NC, Howard TA, Hu C, Ramesh C, Daniel C, Amann K, Arterburn JB, Barton M, Prossnitz ER. G protein‐coupled estrogen receptor protects from atherosclerosis. Sci Rep 4: 7564, 2014.
 257.Mielniczuk LM, Williams K, Davis DR, Tang AS, Lemery R, Green MS, Gollob MH, Haddad H, Birnie DH. Frequency of peripartum cardiomyopathy. Am J Cardiol 97: 1765‐1768, 2006.
 258.Miller VM. Why are sex and gender important to basic physiology and translational and individualized medicine? Am J Physiol Heart Circ Physiol 306: H781‐H788, 2014.
 259.Miller VM, Harman SM. An update on hormone therapy in postmenopausal women: Mini‐review for the basic scientist. Am J Physiol Heart Circ Physiol 313: H1013‐H1021, 2017.
 260.Mirić L, Mirić D, Duplančić D, Kokić S, Ljutić D, Pešutić V, Čulić V, Fabijanić D, Titlić M. Specific and gender differences between hospitalized and out of hospital mortality due to myocardial infarction. Coll Antropol 32: 361‐367, 2008.
 261.Mishra JS, Hankins GD, Kumar S. Testosterone downregulates angiotensin II type‐2 receptor via androgen receptor‐mediated ERK1/2 MAP kinase pathway in rat aorta. J Renin Angiotensin Aldosterone Syst 17, 2016.
 262.Modena MG, Molinari R, Muia N, Jr., Castelli A, Pala F, Rossi R. Double‐blind randomized placebo‐controlled study of transdermal estrogen replacement therapy on hypertensive postmenopausal women. Am J Hypertens 12: 1000‐1008, 1999.
 263.Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 56: 481‐490, 2003.
 264.Mok CC, Lau CS, Ho CT, Lee KW, Mok MY, Wong RW. Safety of hormonal replacement therapy in postmenopausal patients with systemic lupus erythematosus. Scand J Rheumatol 27: 342‐346, 1998.
 265.Morales A. The long and tortuous history of the discovery of testosterone and its clinical application. J Sex Med 10: 1178‐1183, 2013.
 266.Morato T, Hayano M, Dorfman RI, Axelrod LR. The intermediate steps in the biosynthesis of estrogens from androgens. Biochem Biophys Res Commun 6: 334‐338, 1961.
 267.Morris JM, Gopaul NK, Endresen MJ, Knight M, Linton EA, Dhir S, Anggard EE, Redman CW. Circulating markers of oxidative stress are raised in normal pregnancy and pre‐eclampsia. Br J Obstet Gynaecol 105: 1195‐1199, 1998.
 268.Morselli E, Santos RS, Criollo A, Nelson MD, Palmer BF, Clegg DJ. The effects of oestrogens and their receptors on cardiometabolic health. Nature Reviews Endocrinology 13: 352‐364, 2017.
 269.Morton JS, Rueda‐Clausen CF, Davidge ST. Mechanisms of endothelium‐dependent vasodilation in male and female, young and aged offspring born growth restricted. Am J Physiol Regul Integr Comp Physiol 298: R930‐R938, 2010.
 270.Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, Ganiats TG, Gomes AS, Gornik HL, Gracia C, Gulati M, Haan CK, Judelson DR, Keenan N, Kelepouris E, Michos ED, Newby LK, Oparil S, Ouyang P, Oz MC, Petitti D, Pinn VW, Redberg RF, Scott R, Sherif K, Smith SC, Jr., Sopko G, Steinhorn RH, Stone NJ, Taubert KA, Todd BA, Urbina E, Wenger NK. Evidence‐based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 115: 1481‐1501, 2007.
 271.Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd‐Jones DM, Newby LK, Pina IL, Roger VL, Shaw LJ, Zhao D, Beckie TM, Bushnell C, D'Armiento J, Kris‐Etherton PM, Fang J, Ganiats TG, Gomes AS, Gracia CR, Haan CK, Jackson EA, Judelson DR, Kelepouris E, Lavie CJ, Moore A, Nussmeier NA, Ofili E, Oparil S, Ouyang P, Pinn VW, Sherif K, Smith SC, Jr., Sopko G, Chandra‐Strobos N, Urbina EM, Vaccarino V, Wenger NK. Effectiveness‐based guidelines for the prevention of cardiovascular disease in women–2011 update: A guideline from the American Heart Association. J Am Coll Cardiol 57: 1404‐1423, 2011.
 272.Moss KE, Ioannou Y, Sultan SM, Haq I, Isenberg DA. Outcome of a cohort of 300 patients with systemic lupus erythematosus attending a dedicated clinic for over two decades. Ann Rheum Dis 61: 409‐413, 2002.
 273.Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB. Heart Disease and Stroke Statistics‐2016 Update: A report from the American Heart Association. Circulation 133: e38‐e360, 2016.
 274.Murphy G, Isenberg D. Effect of gender on clinical presentation in systemic lupus erythematosus. Rheumatology (Oxford) 52: 2108‐2115, 2013.
 275.Naik JS, Osmond JM, Walker BR, Kanagy NL. Hydrogen sulfide‐induced vasodilation mediated by endothelial TRPV4 channels. Am J Physiol Heart Circ Physiol 311: H1437‐H1444, 2016.
 276.Nathan L, Shi W, Dinh H, Mukherjee TK, Wang X, Lusis AJ, Chaudhuri G. Testosterone inhibits early atherogenesis by conversion to estradiol: Critical role of aromatase. Proc Natl Acad Sci U S A 98: 3589‐3593, 2001.
 277.Nordmeyer J, Eder S, Mahmoodzadeh S, Martus P, Fielitz J, Bass J, Bethke N, Zurbrugg HR, Pregla R, Hetzer R, Regitz‐Zagrosek V. Upregulation of myocardial estrogen receptors in human aortic stenosis. Circulation 110: 3270‐3275, 2004.
 278.Notation AD, Tagatz GE. Unconjugated estriol and 15alpha‐hydroxyestriol in complicated pregnancies. Am J Obstet Gynecol 128: 747‐756, 1977.
 279.Nottin S, Nguyen LD, Terbah M, Obert P. Cardiovascular effects of androgenic anabolic steroids in male bodybuilders determined by tissue Doppler imaging. Am J Cardiol 97: 912‐915, 2006.
 280.Okano H, Jayachandran M, Yoshikawa A, Miller VM. Differential effects of chronic treatment with estrogen receptor ligands on regulation of nitric oxide synthase in porcine aortic endothelial cells. J Cardiovasc Pharmacol 47: 621‐628, 2006.
 281.Olivetti G, Giordano G, Corradi D, Melissari M, Lagrasta C, Gambert SR, Anversa P. Gender differences and aging: Effects on the human heart. J Am Coll Cardiol 26: 1068‐1079, 1995.
 282.Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 68: 1560‐1568, 1991.
 283.Orshal JM, Khalil RA. Gender, sex hormones, and vascular tone. Am J Physiol Regul Integr Comp Physiol 286: R233‐R249, 2004.
 284.Osol G, Moore LG. Maternal uterine vascular remodeling during pregnancy. Microcirculation 21: 38‐47, 2014.
 285.Paauw ND, Joles JA, Spradley FT, Bakrania B, Zsengeller ZK, Franx A, Verhaar MC, Granger JP, Lely AT. Exposure to placental ischemia impairs postpartum maternal renal and cardiac function in rats. Am J Physiol Regul Integr Comp Physiol 312: R664‐R670, 2017.
 286.Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J‐Å, Kushner PJ, Scanlan TS. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277: 1508‐1510, 1997.
 287.Pagan E, Chatenoud L, Rodriguez T, Bosetti C, Levi F, Malvezzi M, La Vecchia C, Negri E, Bertuccio P. Comparison of trends in mortality from coronary heart and cerebrovascular diseases in North and South America: 1980 to 2013. Am J Cardiol 119: 862‐871, 2017.
 288.Palatini P, Giada F, Garavelli G, Sinisi F, Mario L, Michieletto M, Baldo‐Enzi G. Cardiovascular effects of anabolic steroids in weight‐trained subjects. J Clin Pharmacol 36: 1132‐1140, 1996.
 289.Pancholy SB, Shantha GP, Patel T, Cheskin LJ. Sex differences in short‐term and long‐term all‐cause mortality among patients with ST‐segment elevation myocardial infarction treated by primary percutaneous intervention: A meta‐analysis. JAMA Intern Med 174: 1822‐1830, 2014.
 290.Pandey A, Omar W, Ayers C, LaMonte M, Klein L, Allen NB, Kuller LH, Greenland P, Eaton CB, Gottdiener JS, Lloyd‐Jones DM, Berry JD. Sex and race differences in lifetime risk of heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Circulation 137: 1814‐1823, 2018.
 291.Papalia MA, Davis SR. What is the rationale for androgen therapy for women? Treat Endocrinol 2: 77‐84, 2003.
 292.Parikh NI, Cnattingius S, Dickman PW, Mittleman MA, Ludvigsson JF, Ingelsson E. Parity and risk of later‐life maternal cardiovascular disease. Am Heart J 159: 215‐221.e216, 2010.
 293.Park K, Wei J, Minissian M, Bairey Merz CN, Pepine CJ. Adverse pregnancy conditions, infertility, and future cardiovascular risk: Implications for mother and child. Cardiovasc Drugs Ther 29: 391‐401, 2015.
 294.Parker DR, Lu B, Sands‐Lincoln M, Kroenke CH, Lee CC, O'Sullivan M, Park HL, Parikh N, Schenken RS, Eaton CB. Risk of cardiovascular disease among postmenopausal women with prior pregnancy loss: The women's health initiative. Ann Fam Med 12: 302‐309, 2014.
 295.Parks RJ, Bogachev O, Mackasey M, Ray G, Rose RA, Howlett SE. The impact of ovariectomy on cardiac excitation‐contraction coupling is mediated through cAMP/PKA‐dependent mechanisms. J Mol Cell Cardiol 111: 51‐60, 2017.
 296.Pastore MB, Jobe SO, Ramadoss J, Magness RR. Estrogen receptor‐α and estrogen receptor‐β in the uterine vascular endothelium during pregnancy: Functional implications for regulating uterine blood flow. Semin Reprod Med 30: 46‐61, 2012.
 297.Paterakis TS, Diamanti‐Kandarakis E. Aspects of cardiometabolic risk in women with polycystic ovary syndrome. Curr Obes Rep 3: 377‐386, 2014.
 298.Patten RD, Pourati I, Aronovitz MJ, Baur J, Celestin F, Chen X, Michael A, Haq S, Nuedling S, Grohe C. 17β‐Estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho‐inositide‐3 kinase/Akt signaling. Circ Res 95: 692‐699, 2004.
 299.Pedram A, Razandi M, Lubahn D, Liu J, Vannan M, Levin ER. Estrogen inhibits cardiac hypertrophy: Role of estrogen receptor‐beta to inhibit calcineurin. Endocrinology 149: 3361‐3369, 2008.
 300.Pedram A, Razandi M, O'mahony F, Lubahn D, Levin ER. Estrogen receptor‐β prevents cardiac fibrosis. Mol Endocrinol 24: 2152‐2165, 2010.
 301.Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER. A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem 282: 22278‐22288, 2007.
 302.Perez‐Sepulveda A, Monteiro LJ, Dobierzewska A, Espana‐Perrot PP, Venegas‐Araneda P, Guzman‐Rojas AM, Gonzalez MI, Palominos‐Rivera M, Irarrazabal CE, Figueroa‐Diesel H, Varas‐Godoy M, Illanes SE. Placental aromatase is deficient in placental ischemia and preeclampsia. PLoS One 10: e0139682, 2015.
 303.Perusquía M, Herrera N, Ferrer M, Stallone JN. Antihypertensive effects of androgens in conscious, spontaneously hypertensive rats. J Steroid Biochem Mol Biol 167: 106‐114, 2017.
 304.Peters SA, van der Schouw YT, Wood AM, Sweeting MJ, Moons KG, Weiderpass E, Arriola L, Benetou V, Boeing H, Bonnet F, Butt ST, Clavel‐Chapelon F, Drake I, Gavrila D, Key TJ, Klinaki E, Krogh V, Kuhn T, Lassale C, Masala G, Matullo G, Merritt M, Molina‐Portillo E, Moreno‐Iribas C, Nost TH, Olsen A, Onland‐Moret NC, Overvad K, Panico S, Redondo ML, Tjonneland A, Trichopoulou A, Tumino R, Turzanski‐Fortner R, Tzoulaki I, Wennberg P, Winkvist A, Thompson SG, Di Angelantonio E, Riboli E, Wareham NJ, Danesh J, Butterworth AS. Parity, breastfeeding and risk of coronary heart disease: A pan‐European case‐cohort study. Eur J Prev Cardiol 23: 1755‐1765, 2016.
 305.Pirimoglu ZM, Arslan C, Buyukbayrak EE, Kars B, Karsidag YK, Unal O, Turan MC. Glucose tolerance of premenopausal women after menopause due to surgical removal of ovaries. Climacteric 14: 453‐457, 2011.
 306.Pleis JR, Ward BW, Lucas JW. Summary health statistics for U.S. adults: National Health Interview Survey, 2009. Vital Health Stat10: 1‐207, 2010.
 307.Pongkan W, Chattipakorn SC, Chattipakorn N. Chronic testosterone replacement exerts cardioprotection against cardiac ischemia‐reperfusion injury by attenuating mitochondrial dysfunction in testosterone‐deprived rats. PLoS One 10: e0122503, 2015.
 308.Pongkan W, Pintana H, Jaiwongkam T, Kredphoo S, Sivasinprasasn S, Chattipakorn SC, Chattipakorn N. Vildagliptin reduces cardiac ischemic‐reperfusion injury in obese orchiectomized rats. J Endocrinol 231: 81‐95, 2016.
 309.Rahman SA, Hingorani V, Laumas KR. Biosynthesis of oestrogens and their inter‐conversion in human placentae from normal and toxaemic pregnancies. Clin Endocrinol (Oxf) 4: 333‐341, 1975.
 310.Ramaekers D, Ector H, Aubert A, Rubens A, Van de Werf F. Heart rate variability and heart rate in healthy volunteers. Is the female autonomic nervous system cardioprotective? Eur Heart J 19: 1334‐1341, 1998.
 311.Ramirez FD, Motazedian P, Jung RG, Di Santo P, MacDonald ZD, Moreland R, Simard T, Clancy AA, Russo JJ, Welch VA, Wells GA, Hibbert B. Methodological rigor in preclinical cardiovascular studies: Targets to enhance reproducibility and promote research translation. Circ Res 120: 1916‐1926, 2017.
 312.Rautaharju P, Zhou S, Wong S, Calhoun H, Berenson G, Prineas R, Davignon A. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 8: 690‐695, 1992.
 313.Razandi M, Pedram A, Levin ER. Estrogen signals to the preservation of endothelial cell form and function. J Biol Chem 275: 38540‐38546, 2000.
 314.Regitz‐Zagrosek V, Brokat S, Tschope C. Role of gender in heart failure with normal left ventricular ejection fraction. Prog Cardiovasc Dis 49: 241‐251, 2007.
 315.Regitz‐Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev 97: 1‐37, 2017.
 316.Renoux C, Dell'aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: A nested case‐control study. BMJ 340: c2519, 2010.
 317.Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307: 1625‐1630, 2005.
 318.Ribeiro Junior RF, Ronconi KS, Jesus ICG, Almeida PWM, Forechi L, Vassallo DV, Guatimosim S, Stefanon I, Fernandes AA. Testosterone deficiency prevents left ventricular contractility dysfunction after myocardial infarction. Mol Cell Endocrinol 460: 14‐23, 2017.
 319.Riboldi P, Gerosa M, Luzzana C, Catelli L. Cardiac involvement in systemic autoimmune diseases. Clin Rev Allergy Immunol 23: 247‐261, 2002.
 320.Rich‐Edwards JW, Fraser A, Lawlor DA, Catov JM. Pregnancy characteristics and women's future cardiovascular health: An underused opportunity to improve women's health? Epidemiol Rev 36: 57‐70, 2014.
 321.Robbins CL, Hutchings Y, Dietz PM, Kuklina EV, Callaghan WM. History of preterm birth and subsequent cardiovascular disease: A systematic review. Am J Obstet Gynecol 210: 285‐297, 2014.
 322.Roberts JM, Hubel CA. Pregnancy: A screening test for later life cardiovascular disease. Womens Health Issues 20: 304‐307, 2010.
 323.Roger VL, Go AS, Lloyd‐Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie‐Rosett J. Heart disease and stroke statistics–2011 update: A report from the American Heart Association. Circulation 123: e18‐e209, 2011.
 324.Roghair RD, Wemmie JA, Volk KA, Scholz TD, Lamb FS, Segar JL. Maternal antioxidant blocks programmed cardiovascular and behavioural stress responses in adult mice. Clin Sci (Lond) 121: 427‐436, 2011.
 325.Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd‐Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y. Heart disease and stroke statistics–2008 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117: e25‐e146, 2008.
 326.Rosing U, Carlstrom K. Serum levels of unconjugated and total oestrogens and dehydroepiandrosterone, progesterone and urinary oestriol excretion in pre‐eclampsia. Gynecol Obstet Invest 18: 199‐205, 1984.
 327.Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, Writing Group for the Women's Health Initiative I. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial. JAMA 288: 321‐333, 2002.
 328.Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297: 1465‐1477, 2007.
 329.Ruamyod K, Watanapa WB, Shayakul C. Testosterone rapidly increases Ca2+‐activated K+ currents causing hyperpolarization in human coronary artery endothelial cells. J Steroid Biochem Mol Biol 168: 118‐126, 2017.
 330.Rubanyi GM, Freay AD, Kauser K, Sukovich D, Burton G, Lubahn DB, Couse JF, Curtis SW, Korach KS. Vascular estrogen receptors and endothelium‐derived nitric oxide production in the mouse aorta. Gender difference and effect of estrogen receptor gene disruption. J Clin Inves 99: 2429, 1997.
 331.Rubio‐Gayosso I, Sierra‐Ramirez A, Garcia‐Vazquez A, Martinez‐Martinez A, Munoz‐Garcia O, Morato T, Ceballos‐Reyes G. 17Beta‐estradiol increases intracellular calcium concentration through a short‐term and nongenomic mechanism in rat vascular endothelium in culture. J Cardiovasc Pharmacol 36: 196‐202, 2000.
 332.Rutkowski K, Sowa P, Rutkowska‐Talipska J, Kuryliszyn‐Moskal A, Rutkowski R. Dehydroepiandrosterone (DHEA): Hypes and hopes. Drugs 74: 1195‐1207, 2014.
 333.Ryan MJ. The pathophysiology of hypertension in systemic lupus erythematosus. Am J Physiol Regul Integr Comp Physiol 296: R1258‐R1267, 2009.
 334.Saarelainen H, Valtonen P, Punnonen K, Laitinen T, Raitakari OT, Juonala M, Heiskanen N, Lyyra‐Laitinen T, Viikari JS, Heinonen S. Flow mediated vasodilation and circulating concentrations of high sensitive C‐reactive protein, interleukin‐6 and tumor necrosis factor‐alpha in normal pregnancy–The Cardiovascular Risk in Young Finns Study. Clin Physiol Funct Imaging 29: 347‐352, 2009.
 335.Saarelainen H, Valtonen P, Punnonen K, Laitinen T, Raitakari OT, Juonala M, Heiskanen N, Lyyra‐Laitinen T, Viikari JS, Vanninen E, Heinonen S. Subtle changes in ADMA and l‐arginine concentrations in normal pregnancies are unlikely to account for pregnancy‐related increased flow‐mediated dilatation. Clin Physiol Funct Imaging 28: 120‐124, 2008.
 336.Sabio JM, Vargas‐Hitos JA, Navarrete‐Navarrete N, Mediavilla JD, Jimenez‐Jaimez J, Diaz‐Chamorro A, Jimenez‐Alonso J. Prevalence of and factors associated with hypertension in young and old women with systemic lupus erythematosus. J Rheumatol 38: 1026‐1032, 2011.
 337.Salpeter SR, Walsh JM, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta‐analysis: Effect of hormone‐replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 8: 538‐554, 2006.
 338.Sandberg K, Ji H, Hay M. Sex‐specific immune modulation of primary hypertension. Cell Immunol 294: 95‐101, 2015.
 339.Santoro N, Allshouse A, Neal‐Perry G, Pal L, Lobo RA, Naftolin F, Black DM, Brinton EA, Budoff MJ, Cedars MI, Dowling NM, Dunn M, Gleason CE, Hodis HN, Isaac B, Magnani M, Manson JE, Miller VM, Taylor HS, Wharton W, Wolff E, Zepeda V, Harman SM. Longitudinal changes in menopausal symptoms comparing women randomized to low‐dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause 24: 238‐246, 2017.
 340.Sarray S, Madan S, Saleh LR, Mahmoud N, Almawi WY. Validity of adiponectin‐to‐leptin and adiponectin‐to‐resistin ratios as predictors of polycystic ovary syndrome. Fertil Steril 104: 460‐466, 2015.
 341.Sasano H, Suzuki T. Localization of steroidogenesis and steroid receptors in human corpus luteum. Classification of human corpus luteum (CL) into estrogen‐producing degenerating CL, and nonsteroid‐producing degenerating CL. Semin Reprod Endocrinol 15: 345‐351, 1997.
 342.Sathishkumar K, Balakrishnan M, Chinnathambi V, Gao H, Yallampalli C. Temporal alterations in vascular angiotensin receptors and vasomotor responses in offspring of protein‐restricted rat dams. Am J Obstet Gynecol 206: 507.e501‐510, 2012.
 343.Saw J, Ricci D, Starovoytov A, Fox R, Buller CE. Spontaneous coronary artery dissection: prevalence of predisposing conditions including fibromuscular dysplasia in a tertiary center cohort. JACC Cardiovasc Interv 6: 44‐52, 2013.
 344.Saxena AR, Karumanchi SA, Brown NJ, Royle CM, McElrath TF, Seely EW. Increased sensitivity to angiotensin II is present postpartum in women with a history of hypertensive pregnancy. Hypertension 55: 1239‐1245, 2010.
 345.Schwarz EB, McClure CK, Tepper PG, Thurston R, Janssen I, Matthews KA, Sutton‐Tyrrell K. Lactation and maternal measures of subclinical cardiovascular disease. Obstet Gynecol 115: 41‐48, 2010.
 346.Schwarz EB, Ray RM, Stuebe AM, Allison MA, Ness RB, Freiberg MS, Cauley JA. Duration of lactation and risk factors for maternal cardiovascular disease. Obstet Gynecol 113: 974‐982, 2009.
 347.Seara FAC, Barbosa RAQ, de Oliveira DF, Gran da Silva DLS, Carvalho AB, Freitas Ferreira AC, Matheus Nascimento JH, Olivares EL. Administration of anabolic steroid during adolescence induces long‐term cardiac hypertrophy and increases susceptibility to ischemia/reperfusion injury in adult Wistar rats. J Steroid Biochem Mol Biol 171: 34‐42, 2017.
 348.Shao X, Liu Y, Liu M, Wang Y, Yan L, Wang H, Ma L, Li YX, Zhao Y, Wang YL. Testosterone represses estrogen signaling by upregulating miR‐22: A mechanism for imbalanced steroid hormone production in preeclampsia. Hypertension 69: 721‐730, 2017.
 349.Sharifzadeh F, Kashanian M, Fatemi F. A comparison of serum androgens in pre‐eclamptic and normotensive pregnant women during the third trimester of pregnancy. Gynecol Endocrinol 28: 834‐836, 2012.
 350.Sharkey SW, Maron BJ. Epidemiology and clinical profile of Takotsubo cardiomyopathy. Circ J 78: 2119‐2128, 2014.
 351.Shaw LJ, Shaw RE, Merz CN, Brindis RG, Klein LW, Nallamothu B, Douglas PS, Krone RJ, McKay CR, Block PC, Hewitt K, Weintraub WS, Peterson ED. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in‐hospital mortality in the American College of Cardiology‐National Cardiovascular Data Registry. Circulation 117: 1787‐1801, 2008.
 352.Sheikh AS, O'Sullivan M. Pregnancy‐related spontaneous coronary artery dissection: Two case reports and a comprehensive review of literature. Heart Views 13: 53‐65, 2012.
 353.Shen W, Zhang T, Li S, Zhang H, Xi B, Shen H, Fernandez C, Bazzano L, He J, Chen W. Race and sex differences of long‐term blood pressure profiles from childhood and adult hypertension: The Bogalusa Heart Study. Hypertension 70: 66‐74, 2017.
 354.Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 97: 2050‐2058, 2012.
 355.Simoncini T, Hafezi‐Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol‐3‐OH kinase. Nature 407: 538‐541, 2000.
 356.Simpson E, Santen RJ. Celebrating 75 years of oestradiol. J Mol Endocrinol 55: T1‐T20, 2015.
 357.Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K, Speed C, Jones M. Aromatase–a brief overview. Annu Rev Physiol 64: 93‐127, 2002.
 358.Skilton MR, Bonnet F, Begg LM, Juonala M, Kahonen M, Lehtimaki T, Viikari JS, Raitakari OT. Childbearing, child‐rearing, cardiovascular risk factors, and progression of carotid intima‐media thickness: The Cardiovascular Risk in Young Finns study. Stroke 41: 1332‐1337, 2010.
 359.Sliwa K, Hilfiker‐Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E, Regitz‐Zagrosek V, Schaufelberger M, Tavazzi L, van Veldhuisen DJ, Watkins H, Shah AJ, Seferovic PM, Elkayam U, Pankuweit S, Papp Z, Mouquet F, McMurray JJ, Heart Failure Association of the European Society of Cardiology Working Group on Peripartum C. Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: A position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail 12: 767‐778, 2010.
 360.Sliwa K, Petrie MC, Hilfiker‐Kleiner D, Mebazaa A, Jackson A, Johnson MR, van der Meer P, Mbakwem A, Bauersachs J. Long‐term prognosis, subsequent pregnancy, contraception and overall management of peripartum cardiomyopathy: Practical guidance paper from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy. Eur J Heart Fail 20: 951‐962, 2018.
 361.Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: A retrospective cohort study of 129,290 births. Lancet 357: 2002‐2006, 2001.
 362.Son BK, Akishita M, Iijima K, Ogawa S, Maemura K, Yu J, Takeyama K, Kato S, Eto M, Ouchi Y. Androgen receptor‐dependent transactivation of growth arrest‐specific gene 6 mediates inhibitory effects of testosterone on vascular calcification. J Biol Chem 285: 7537‐7544, 2010.
 363.Son BK, Kozaki K, Iijima K, Eto M, Nakano T, Akishita M, Ouchi Y. Gas6/Axl‐PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate‐induced calcification of vascular smooth muscle cells. Eur J Pharmacol 556: 1‐8, 2007.
 364.Stallone JN, Crofton JT, Share L. Sexual dimorphism in vasopressin‐induced contraction of rat aorta. Am J Physiol 260: H453‐H458, 1991.
 365.Stark MJ, Clifton VL, Wright IM. Sex‐specific differences in peripheral microvascular blood flow in preterm infants. Pediatr Res 63: 415‐419, 2008.
 366.Stein PK, Kleiger RE, Rottman JN. Differing effects of age on heart rate variability in men and women. Am J Cardiol 80: 302‐305, 1997.
 367.Stevenson DK, Verter J, Fanaroff AA, Oh W, Ehrenkranz RA, Shankaran S, Donovan EF, Wright LL, Lemons JA, Tyson JE, Korones SB, Bauer CR, Stoll BJ, Papile LA. Sex differences in outcomes of very low birthweight infants: The newborn male disadvantage. Arch Dis Child Fetal Neonatal Ed 83: F182‐F185, 2000.
 368.Stirone C, Chu Y, Sunday L, Duckles SP, Krause DN. 17β‐Estradiol increases endothelial nitric oxide synthase mRNA copy number in cerebral blood vessels: Quantification by real‐time polymerase chain reaction. Eur J Pharmacol 478: 35‐38, 2003.
 369.Stocco C. Tissue physiology and pathology of aromatase. Steroids 77: 27‐35, 2012.
 370.Stoner L, Faulkner J, Westrupp N, Lambrick D. Sexual differences in central arterial wave reflection are evident in prepubescent children. J Hypertens 33: 304‐307, 2015.
 371.Strehlow K, Werner N, Berweiler J, Link A, Dirnagl U, Priller J, Laufs K, Ghaeni L, Milosevic M, Bohm M, Nickenig G. Estrogen increases bone marrow‐derived endothelial progenitor cell production and diminishes neointima formation. Circulation 107: 3059‐3065, 2003.
 372.Stuebe AM, Michels KB, Willett WC, Manson JE, Rexrode K, Rich‐Edwards JW. Duration of lactation and incidence of myocardial infarction in middle to late adulthood. Am J Obstet Gynecol 200: 138.e131‐138, 2009.
 373.Sudhir K, Chou TM, Messina LM, Hutchison SJ, Korach KS, Chatterjee K, Rubanyi GM. Endothelial dysfunction in a man with disruptive mutation in oestrogen‐receptor gene. The Lancet 349: 1146‐1147, 1997.
 374.Sullivan JC, Rodriguez‐Miguelez P, Zimmerman MA, Harris RA. Differences in angiotensin (1‐7) between men and women. Am J Physiol Heart Circ Physiol 308: H1171‐H1176, 2015.
 375.Sundgren NC, Giraud GD, Schultz JM, Lasarev MR, Stork PJ, Thornburg KL. Extracellular signal‐regulated kinase and phosphoinositol‐3 kinase mediate IGF‐1 induced proliferation of fetal sheep cardiomyocytes. Am J Physiol Regul Integr Comp Physiol 285: R1481‐H1489, 2003.
 376.Sundgren NC, Giraud GD, Stork PJ, Maylie JG, Thornburg KL. Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes. J Physiol 548: 881‐891, 2003.
 377.Surawicz B, Parikh SR. Differences between ventricular repolarization in men and women: Description, mechanism and implications. Ann Noninvasive Electrocardiol 8: 333‐340, 2003.
 378.Svartberg J, von Muhlen D, Schirmer H, Barrett‐Connor E, Sundfjord J, Jorde R. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study. Eur J Endocrinol 150: 65‐71, 2004.
 379.Swaak AJ, van den Brink HG, Smeenk RJ, Manger K, Kalden JR, Tosi S, Domljan Z, Rozman B, Logar D, Pokorny G, Kovacs L, Kovacs A, Vlachoyiannopoulos PG, Moutsopoulos HM, Chwalinska‐Sadowska H, Kiss E, Cikes N, Anic B, Schneider M, Fischer R, Bombardieri S, Mosca M, Graninger W, Smolen JS. Systemic lupus erythematosus. Disease outcome in patients with a disease duration of at least 10 years: Second evaluation. Lupus 10: 51‐58, 2001.
 380.Sweetland S, Beral V, Balkwill A, Liu B, Benson VS, Canonico M, Green J, Reeves GK, Million Women Study C. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost 10: 2277‐2286, 2012.
 381.Szarka A, Rigo J, Jr., Lazar L, Beko G, Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol 11: 59, 2010.
 382.Takagi G, Asai K, Vatner SF, Kudej RK, Rossi F, Peppas A, Takagi I, Resuello RR, Natividad F, Shen YT, Vatner DE. Gender differences on the effects of aging on cardiac and peripheral adrenergic stimulation in old conscious monkeys. Am J Physiol Heart Circ Physiol 285: H527‐H534, 2003.
 383.Taylor AH, Al‐Azzawi F. Immunolocalisation of oestrogen receptor beta in human tissues. J Mol Endocrinol 24: 145‐155, 2000.
 384.Taylor KE, Vallejo‐Giraldo C, Schaible NS, Zakeri R, Miller VM. Reporting of sex as a variable in cardiovascular studies using cultured cells. Biol Sex Differ 2: 11, 2011.
 385.Thomas GN, Tam LS, Tomlinson B, Li EK. Accelerated atherosclerosis in patients with systemic lupus erythematosus: A review of the causes and possible prevention. Hong Kong Med J 8: 26‐32, 2002.
 386.Thomas P, Converse A, Berg HA. ZIP9, a novel membrane androgen receptor and zinc transporter protein. Gen Comp Endocrinol 257: 130‐136, 2017.
 387.Thomas RS, Sarwar N, Phoenix F, Coombes RC, Ali S. Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor‐alpha activity. J Mol Endocrinol 40: 173‐184, 2008.
 388.Thompson JA, Richardson BS, Gagnon R, Regnault TR. Chronic intrauterine hypoxia interferes with aortic development in the late gestation ovine fetus. J Physiol 589: 3319‐3332, 2011.
 389.Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Apple FS, Lindahl B, Morrow DA, Chaitman BR, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow JJ, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez‐Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck‐Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, Morais J, Aguiar C, Almahmeed W, Arnar DO, Barili F, Bloch KD, Bolger AF, Botker HE, Bozkurt B, Bugiardini R, Cannon C, de Lemos J, Eberli FR, Escobar E, Hlatky M, James S, Kern KB, Moliterno DJ, Mueller C, Neskovic AN, Oieske BM, Schulman SP, Storey RF, Taubert KA, Vranckx P, Wagner DR. Third universal definition of myocardial infarction. J Am Coll Cardiol 60: 1581‐1598, 2012.
 390.Tooher J, Thornton C, Makris A, Ogle R, Korda A, Hennessy A. All hypertensive disorders of pregnancy increase the risk of future cardiovascular disease. Hypertension 70: 798‐803, 2017.
 391.Torréns JI, Sutton‐Tyrrell K, Zhao X, Matthews K, Brockwell S, Sowers M, Santoro N. Relative androgen excess during the menopausal transition predicts incident metabolic syndrome in mid‐life women: SWAN. Menopause (New York, NY) 16: 257, 2009.
 392.Tostes RC, Carneiro FS, Carvalho MHC, Reckelhoff JF. Reactive oxygen species: Players in the cardiovascular effects of testosterone. Am J Physiol Regul Integr Comp Physiol 310: R1‐R14, 2016.
 393.Towfighi A, Zheng L, Ovbiagele B. Sex‐specific trends in midlife coronary heart disease risk and prevalence. Arch Intern Med 169: 1762‐1766, 2009.
 394.Townsley JD, Brodie HJ. Studies on the mechanism of estrogen biosynthesis. 3. The stereochemistry of aromatization of C19 and C18 steroids. Biochemistry 7: 33‐40, 1968.
 395.Tsokos GC. Systemic lupus erythematosus. N Engl J Med 365: 2110‐2121, 2011.
 396.Ueda K, Lu Q, Baur W, Aronovitz MJ, Karas RH. Rapid estrogen receptor signaling mediates estrogen‐induced inhibition of vascular smooth muscle cell proliferation. Arterioscler Thromb Vasc Biol 33: 1837, 2013.
 397.Ullrich ND, Krust A, Collins P, MacLeod KT. Genomic deletion of estrogen receptors ERalpha and ERbeta does not alter estrogen‐mediated inhibition of Ca2+ influx and contraction in murine cardiomyocytes. Am J Physiol Heart Circ Physiol 294: H2421‐H2427, 2008.
 398.Umetani K, Singer DH, McCraty R, Atkinson M. Twenty‐four hour time domain heart rate variability and heart rate: Relations to age and gender over nine decades. J Am Coll Cardiol 31: 593‐601, 1998.
 399.Vaccarino V, Krumholz HM, Yarzebski J, Gore JM, Goldberg RJ. Sex differences in 2‐year mortality after hospital discharge for myocardial infarction. Ann Intern Med 134: 173‐181, 2001.
 400.Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex‐based differences in early mortality after myocardial infarction. N Engl J Med 341: 217‐225, 1999.
 401.Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex‐based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 341: 217‐225, 1999.
 402.Van PL, Bakalov VK, Zinn AR, Bondy CA. Maternal X chromosome, visceral adiposity, and lipid profile. Jama 295: 1373‐1374, 2006.
 403.Vasudevan N, Pfaff DW. Non‐genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 29: 238‐257, 2008.
 404.Velasco L, Sánchez M, Rubín JM, Hidalgo A, Bordallo C, Cantabrana B. Intracellular cAMP increases during the positive inotropism induced by androgens in isolated left atrium of rat. Eur J Pharmacol 438: 45‐52, 2002.
 405.Ventura‐Clapier R, Dworatzek E, Seeland U, Kararigas G, Arnal JF, Brunelleschi S, Carpenter TC, Erdmann J, Franconi F, Giannetta E, Glezerman M, Hofmann SM, Junien C, Katai M, Kublickiene K, Konig IR, Majdic G, Malorni W, Mieth C, Miller VM, Reynolds RM, Shimokawa H, Tannenbaum C, D'Ursi AM, Regitz‐Zagrosek V. Sex in basic research: Concepts in the cardiovascular field. Cardiovasc Res 113: 711‐724, 2017.
 406.Vicencio JM, Ibarra C, Estrada M, Chiong M, Soto D, Parra V, Diaz‐Araya G, Jaimovich E, Lavandero S. Testosterone induces an intracellular calcium increase by a nongenomic mechanism in cultured rat cardiac myocytes. Endocrinology 147: 1386‐1395, 2006.
 407.Vigen R, O'Donnell CI, Baron AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. Jama 310: 1829‐1836, 2013.
 408.Vikan T, Johnsen SH, Schirmer H, Njolstad I, Svartberg J. Endogenous testosterone and the prospective association with carotid atherosclerosis in men: The Tromso study. Eur J Epidemiol 24: 289‐295, 2009.
 409.Voskuyl AE. The heart and cardiovascular manifestations in rheumatoid arthritis. Rheumatology (Oxford) 45(Suppl 4): iv4‐7, 2006.
 410.Vryonidou A, Papatheodorou A, Tavridou A, Terzi T, Loi V, Vatalas IA, Batakis N, Phenekos C, Dionyssiou‐Asteriou A. Association of hyperandrogenemic and metabolic phenotype with carotid intima‐media thickness in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 90: 2740‐2746, 2005.
 411.Wang M, Crisostomo PR, Markel T, Wang Y, Lillemoe KD, Meldrum DR. Estrogen receptor beta mediates acute myocardial protection following ischemia. Surgery 144: 233‐238, 2008.
 412.Wang Z, Huang Z, Lu G, Lin L, Ferrari M. Hypoxia during pregnancy in rats leads to early morphological changes of atherosclerosis in adult offspring. Am J Physiol Heart Circ Physiol 296: H1321‐H1328, 2009.
 413.Watts EL, Appleby PN, Albanes D, Black A, Chan JM, Chen C, Cirillo PM, Cohn BA, Cook MB, Donovan JL, Ferrucci L, Garland CF, Giles GG, Goodman PJ, Habel LA, Haiman CA, Holly JMP, Hoover RN, Kaaks R, Knekt P, Kolonel LN, Kubo T, Le Marchand L, Luostarinen T, MacInnis RJ, Maenpaa HO, Mannisto S, Metter EJ, Milne RL, Nomura AMY, Oliver SE, Parsons JK, Peeters PH, Platz EA, Riboli E, Ricceri F, Rinaldi S, Rissanen H, Sawada N, Schaefer CA, Schenk JM, Stanczyk FZ, Stampfer M, Stattin P, Stenman UH, Tjonneland A, Trichopoulou A, Thompson IM, Tsugane S, Vatten L, Whittemore AS, Ziegler RG, Allen NE, Key TJ, Travis RC. Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men. PLoS One 12: e0187741, 2017.
 414.Weil BR, Manukyan MC, Herrmann JL, Wang Y, Abarbanell AM, Poynter JA, Meldrum DR. Signaling via GPR30 protects the myocardium from ischemia/reperfusion injury. Surgery 148: 436‐443, 2010.
 415.Wells SM, Langille BL, Lee JM, Adamson SL. Determinants of mechanical properties in the developing ovine thoracic aorta. Am J Physiol 277: H1385‐H1391, 1999.
 416.Williams D. Pregnancy: A stress test for life. Curr Opin Obstet Gynecol 15: 465‐471, 2003.
 417.Worboys S, Kotsopoulos D, Teede H, McGrath B, Davis SR. Evidence that parenteral testosterone therapy may improve endothelium‐dependent and ‐independent vasodilation in postmenopausal women already receiving estrogen. J Clin Endocrinol Metab 86: 158‐161, 2001.
 418.Wu IC, Lin XZ, Liu PF, Tsai WL, Shiesh SC. Low serum testosterone and frailty in older men and women. Maturitas 67: 348‐352, 2010.
 419.Wu J, Hadoke PW, Mair I, Lim WG, Miller E, Denvir MA, Smith LB. Modulation of neointimal lesion formation by endogenous androgens is independent of vascular androgen receptor. Cardiovasc Res 103: 281‐290, 2014.
 420.Xiao D, Huang X, Xue Q, Zhang L. Antenatal hypoxia induces programming of reduced arterial blood pressure response in female rat offspring: role of ovarian function. PLoS One 9: e98743, 2014.
 421.Xiao D, Xu Z, Huang X, Longo LD, Yang S, Zhang L. Prenatal gender‐related nicotine exposure increases blood pressure response to angiotensin II in adult offspring. Hypertension 51: 1239‐1247, 2008.
 422.Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: A systematic review and meta‐analysis of placebo‐controlled randomized trials. BMC Med 11: 108, 2013.
 423.Yan L, Ge H, Li H, Lieber SC, Natividad F, Resuello RRG, Kim SJ, Akeju S, Sun A, Loo K, Peppas AP, Rossi F, Lewandowski ED, Thomas AP, Vatner SF, Vatner DE. Gender‐specific proteomic alterations in glycolytic and mitochondrial pathways in aging monkey hearts. J Mol Cell Cardiol 37: 921‐929, 2004.
 424.Yasui T, Matsui S, Tani A, Kunimi K, Yamamoto S, Irahara M. Androgen in postmenopausal women. J Med Invest 59: 12‐27, 2012.
 425.Yu J, Akishita M, Eto M, Koizumi H, Hashimoto R, Ogawa S, Tanaka K, Ouchi Y, Okabe T. Src kinase‐mediates androgen receptor‐dependent non‐genomic activation of signaling cascade leading to endothelial nitric oxide synthase. Biochem Biophys Res Commun 424: 538‐543, 2012.
 426.Yu J, Akishita M, Eto M, Ogawa S, Son B‐K, Kato S, Ouchi Y, Okabe T. Androgen receptor‐dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3‐kinase/akt pathway. Endocrinology 151: 1822‐1828, 2010.
 427.Yu S, Xia S, Yang D, Wang K, Yeh S, Gao Z, Chang C. Androgen receptor in human prostate cancer‐associated fibroblasts promotes prostate cancer epithelial cell growth and invasion. Med Oncol 30: 674, 2013.
 428.Yu X, Ma H, Barman SA, Liu AT, Sellers M, Stallone JN, Prossnitz ER, White RE, Han G. Activation of G protein‐coupled estrogen receptor induces endothelium‐independent relaxation of coronary artery smooth muscle. Am J Physiol Endocrinol Metab 301: E882‐E888, 2011.
 429.Yu X, Zhang Q, Zhao Y, Schwarz BJ, Stallone JN, Heaps CL, Han G. Activation of G protein‐coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1‐mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA. PLoS One 12: e0173085, 2017.
 430.Zhai P, Eurell TE, Cooke PS, Lubahn DB, Gross DR. Myocardial ischemia‐reperfusion injury in estrogen receptor‐α knockout and wild‐type mice. Am J Physiol Heart Circ Physiol 278: H1640‐H1647, 2000.
 431.Zhang Y. Cardiovascular diseases in American women. Nutr Metab Cardiovasc Dis 20: 386‐393, 2010.
 432.Zhu D, Hadoke PW, Wu J, Vesey AT, Lerman DA, Dweck MR, Newby DE, Smith LB, MacRae VE. Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification. Sci Rep 6: 24807, 2016.
 433.Zimmerman MA, Budish RA, Kashyap S, Lindsey SH. GPER–novel membrane oestrogen receptor. Clin Sci 130: 1005‐1016, 2016.
 434.Zumoff B, Strain GW, Kream J, O'Connor J, Levin J, Fukushima DK. Obese young men have elevated plasma estrogen levels but obese premenopausal women do not. Metabolism 30: 1011‐1014, 1981.

 

Teaching Material

S. Chaudhari, S. C. Cushen, O. Osikoya, P. A. Jaini, R. Posey, K. W. Mathis, S. Goulopoulou. Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling. Compr Physiol 9: 2019, 405-441.

Didactic Synopsis

Major Teaching Points:

  1. Understanding the role of estrogens and androgens in normal vascular and cardiac physiology is necessary to explain their contribution to sex disparities in cardiovascular disease.
  2. Estrogen receptors are expressed on cardiomyocytes, vascular endothelial and smooth muscle cells and mediate the cardioprotective effects of estrogen in women via genomic and nongenomic pathways.
  3. Physiological concentrations of testosterone are necessary for normal cardiac development, but low testosterone is associated with adverse cardiac effects in men, while high testosterone is correlated with increased risk of cardiovascular disease in men and women.
  4. Conditions unique to or predominant in women, such as pregnancy, menopause, and certain autoimmune diseases, are associated with alterations in sex hormone production and function and play a fundamental role in promoting cardiovascular disease in women.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 This figure illustrates that the number of women who participated in randomized control trials is low in relation to the number of women who suffer from cardiovascular disease. Underrepresentation of women in biomedical research hinders our understanding of the pathophysiology of various cardiovascular diseases in women as compared to men. Importantly, it delays the development of therapeutic interventions that can specifically target the female patients with cardiovascular disease.

Figure 2 This figure illustrates the age-related changes in systolic and diastolic blood pressure from early childhood to adulthood. Sex differences in blood pressure, with men having higher blood pressures compared to women, are observed after puberty. This sexual dimorphism is evident until menopause.

Figure 3 This figure illustrates that LV mass and volumes vary with age and sex. Left ventricular mass (LV) mass increases during adolescence and declines in adulthood. Adolescent and adult males have greater LV mass compared to age-matched females, even after adjusting for body size (body surface area, BSA). End-diastolic volume (EDV) calculated as the endocardial volume at end-diastole increases during adolescence and early adulthood in males and declines thereafter but this trend was not observed in females. There are no sex differences in EDV during adolescence, but adult males have greater EDV compared to adult females.

Figure 4 This figure illustrates sex differences in age-related changes in circulating total and bioavailable estrogen. Bioavailable estrogen has rapid access to target tissues, while total estrogen comprises the fractions of estrogen that are bound to sex hormone binding globulin (SHBG) and the bioavailable form. Understanding the normal temporal changes in bioavailable estrogen may provide insight into the correlation between estrogen deficiency and sex differences in cardiovascular function and disease. In men, there is a small decrease in total estrogen with age, while bioavailable estrogen declines by 47% between 25 and 85 years of age. In women, both total and bioavailable estrogen decline in a similar manner and there is a large drop in both forms around the time of menopause.

Figure 5 Teaching points: Estrogen can induce its actions via nongenomic pathways that do not involve activation of nuclear estrogen receptors. Estrogen signaling via nongenomic mechanisms is rapid, involves estrogen receptors that are located in small invaginations of the plasma membrane (i.e., caveolae) and various intracellular signaling molecules such as kinases and phosphatases. In endothelial cells, the nongenomic estrogen signaling induces activation of kinases that leads to endothelial nitric oxide synthase (eNOS) phosphorylation and NO production. These events promote endothelium-dependent relation, and proliferation and migration of endothelial cells. In vascular smooth muscle cells, the nongenomic estrogen signaling induces phosphatase-mediated kinase inhibition that reduces vascular smooth muscle proliferation and migration.

Figure 6 Teaching points: The nongenomic actions of estrogen can be executed not only through the ER receptors that are localized in the plasma membrane but also through an orphan G-protein-coupled receptor, GPR30, also known as G protein-coupled estrogen receptor 1 (GPER-1). Signaling through this novel estrogen receptor induces vasodilation in the vasculature. Several studies in coronary arteries have indicated two different mechanisms for this action. Panel A illustrates an endothelium-independent mechanism that is mediated by a large conductance calcium-activated potassium channel, BK channel, which is expressed in coronary smooth muscle. Panel B illustrates an endothelium-dependent mechanism that involves activation of endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) in vascular endothelial cells.

Figure 7 Teaching points: The presence of estrogen receptor subtypes, ERα and ERβ, has been demonstrated in male and female human hearts. Hearts from healthy men, however, have higher expression of ERβ mRNA as compared to age-matched healthy postmenopausal women. In aortic stenosis, there is upregulation of ERβ mRNA that is inversely correlated to factors causing hypertrophic responses. The percent increase of ERβ mRNA is greater in women as compared to men with aortic stenosis, indicating probably a better compensatory response in women.

Figure 8 This figure illustrates sex-related variation in the expression of 56 genes in mice with cardiomyocyte-specific deletion of ERα. These genes were associated with various transcriptional networks and receptor hubs like extracellular space and matrix, NOS signaling, relaxation of vascular smooth muscle cells, metabolic networks, and certain signaling pathways. That means ERα regulates these processes differentially in men and women.

Figure 9 Teaching points: Menopause and associated estrogen deficiency are considered risk factors of cardiovascular disease in women. Understanding the mechanism underlying the effects of estrogen on cardiac function after cardiac ischemia-reperfusion injury in animal models aids in the development of efficacious estrogen replacement interventions. In female mice that were ovariectomized, treatment with estradiol or an estrogen-dendrimer conjugate improved all cardiac recovery after ischemia-reperfusion injury.

Figure 10 Teaching points: Premenopausal women are less likely to suffer from coronary artery disease compared to age-matched men, potentially due to the protective effects of estrogen. This effect is lost after menopause. This figure illustrates that pre-treatment with estrogen potentiates coronary artery dilation in postmenopausal women with coronary artery disease but has no effect in age-matched men. Understanding the effects of exogenous estrogen on the coronary vasculature leads to development of better estrogen replacement strategies and provides insight into the differing responses to hormone replacement therapies between men and women.

Figure 11 This figure illustrates sex differences in age-related changes in circulating total and bioavailable testosterone. Bioavailable form of testosterone is either free or associated with albumin in the circulation and it has rapid access to target tissues. Understanding the temporal changes in bioavailable circulating testosterone is important because a decrease in total testosterone fails to explain the morbidities seen in men with advancing age. Notice that the decrease in total testosterone is only 29%, while that of bioavailable testosterone is twice (64%) in men with increasing age. On the other hand, the reductions in total and bioavailable testosterone are marginal in women with increasing age (15% and 28% respectively).

Figure 12 Teaching points: Hydrogen peroxide (H2S) is a gas that has vasodilatory effects. Testosterone-induced vasodilation, but not estrogen- and progesterone-induced dilation, involves H2S in aortic rings of male rats. These effects are associated with the ability of testosterone to promote H2S production.

Figure 13 This figure illustrates that women who had experienced a hypertensive disorder of pregnancy have a greater risk of developing cardiovascular disease later in life compared to women who had no complications during pregnancy. Understanding whether and how pregnancy complications lead to cardiovascular disease is important because it aids in early identification and management of women in high risk of developing cardiovascular complications later in life.

Figure 14 This figure illustrates that testosterone and estradiol differ between normal pregnant women and women with preeclampsia. In preeclampsia, a hypertensive disorder of pregnancy that is characterized by systemic inflammation, circulating testosterone is increased, estradiol is reduced, and the ratio of testosterone to estradiol is significantly higher compared to normal pregnancy. Expression of aromatase and 17β-HSD3, enzymes that facilitate the synthesis of estrogen and testosterone, respectively, differs between women with preeclampsia and women who experience preterm labor. Understanding the role of sex steroids in gestational complications, such as preeclampsia and preterm labor, will aid in the development of interventions to counteract or potentiate their effects.

Figure 15 This figure illustrates a nonlinear, J-shaped relationship, between number of live births and incident of death from cardiovascular disease. The risk of mortality from cardiovascular disease is exponentially increased in women who had experienced large number (> 6) of births. This risk is higher in women with no children as compared to women with two to five children; yet, it remains substantially lower compared to women with large parity.

 


Related Articles:

Architecture of the Vessel Wall
Mechanics of Vascular Smooth Muscle
Steroid Hormone Receptor Families
Cardiovascular System
Top downloaded articles of 2019

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling
 

How to Cite

Sarika Chaudhari, Spencer C. Cushen, Oluwatobiloba Osikoya, Paresh A. Jaini, Rachel Posey, Keisa W. Mathis, Styliani Goulopoulou. Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling. Compr Physiol 2018, 9: 375-411. doi: 10.1002/cphy.c180003