High Blood Press Cardiovasc Prev DOI 10.1007/s40292-014-0050-7
REVIEW ARTICLE
Hypertension in Premenopausal Women: Is There Any Difference? Andrea Ferrucci • Giulia Pignatelli • Sebastiano Sciarretta • Giuliano Tocci
Received: 3 February 2014 / Accepted: 24 March 2014 Ó Springer International Publishing Switzerland 2014
Abstract Hypertension is one of the most important cardiovascular (CV) risk factor, and that lowering blood pressure levels reduces the incidence of CV morbidity and mortality. The higher incidence of hypertension in postmenopausal than in pre-menopausal women raises the attention on the pathophysiological mechanisms potentially involved in post-menopausal ones and outweigh those involved in pre-menopausal women. However, CV disease is one of the leading causes of death in reproductive-age women. Thus, improved awareness, early identification and prompt clinical management of hypertension should be key elements in order to prevent hypertension-related CV morbidity and mortality in pre-menopausal women. However, available data in this specific age group of women are relatively poor and inconsistent, so that the clinical management of young hypertensive women is still debated. The aim of this review is to assess whether there are clear evidences on differences between men and women in epidemiological data, pathophysiological mechanisms, diagnostic options and therapeutic interventions of hypertension and its prognosis, in order to establish the correct approach to this group of hypertensive patients. Keywords Hypertension Pre-menopausal women Post-menopausal women Cardiovascular prevention
A. Ferrucci (&) G. Pignatelli S. Sciarretta G. Tocci Hypertension Unit, Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University of Rome Sapienza, Sant’Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy e-mail: [email protected] S. Sciarretta G. Tocci IRCCS Neuromed, Pozzilli (IS), Italy
1 Introduction Hypertension is a well established determinant of cardiovascular disease (CVD) in both men and women. Epidemiological data demonstrating the adverse prognosis of hypertension, and that lowering blood pressure (BP) levels may effectively prevent CV morbidity and mortality, are equally relevant for both women and men [1–4]. However, observational studies and large epidemiological databases consistently reported that BP levels are higher in men than in women under 40 years; with aging, BP levels tend to rise steeply in women than in men until overcome their values [5]. In addition, over the last decade it has been observed in US population that prevalence of hypertension increased when compared with data before 2000 (Fig. 1) [6], as well as awareness and pharmacological treatment of young hypertensive women (Fig. 2) [2]. Although specific data reporting hypertension prevalence in pre-menopausal women in European Countries are lacking, similar proportions have been also reported in our database, in which prevalence of hypertension in women in non-pregnant reproductive age is relatively low compared with age-matched men (Fig. 3). The higher incidence of hypertension observed during the post-menopausal age led to focus the attention on the potential beneficial effect of sexual hormones, while the mechanisms of hypertension in young women remained to be further clarified. However, CVD is one of the leading causes of death in reproductive-age women. Moreover hypertension, as well as other CV risk factors, may have reproductive health consequences, including preeclampsia and other pregnancy disorders like preterm delivery [7]. So improved awareness, early identification and prompt management of this condition are key aspects, in order to prevent hypertension-related CV morbidity and mortality in this population. Available data in this regard, however,
A. Ferrucci et al. Fig. 1 Age-standardized prevalence rate of hypertension by race/ethnicity for women: NHANES III 1988–1994 and NHANES 1999–2004. Derived from reference num. 06
Fig. 2 Trend in the selfreported and actual rates of hypertension among nonpregnant reproductive-age women (20–49 years) in the NHANES 1999–2008. Derived from reference num. 02
are relatively poor and inconsistent, as such the clinical management of young hypertensive women is still debated. In this review, we aimed to analyse if there are any clear evidence on differences between men and women in epidemiology, pathophysiology of hypertension and prognosis, and if a different therapeutic approach is needed in this group of hypertensive women.
2 Gender Differences in Pathophysiological Mechanisms? Current opinion is that men have a higher prevalence of hypertension compared with women [1, 3], and several studies have reported this disparity. There is a wealth of evidence that estrogen has a vasodilatatory effects and may be responsible for the lower BP in younger women. Experimental models investigating the
biological effects of estrogen demonstrate that administration of estradiol promotes endothelium-dependent vasodilatation [8]. There is also evidence that loss of estrogen at any age contributes to endothelial dysfunction, which is common in individuals with hypertension. Endothelial dysfunction is typically characterized by reductions in NO. Estradiol stimulates NO production since estradiol acutely increases intracellular calcium, which activates endothelial NO synthase [9], which would promote vasodilation and thus reductions in BP [10]. Estradiol also upregulates superoxide dismutase, which removes superoxide and reduces oxidative stress. Superoxide binds to NO and renders NO unavailable for vasodilation. However, an intact NO system is necessary for antioxidants to reduce BP. Therefore, in situations of chronic hypertension when endothelial dysfunction is present and NO levels have been reduced for long periods, estradiol may not be able to reduce BP. In this regard, Taddei et al. [11] evaluated endothelial function by measuring forearm blood flow
Hypertension in Premenopausal Women Fig. 3 Age-standardized prevalence rate of hypertension for women included in our database, Hypertension Unit, Division of Cardiology, Sant’Andrea Hospital of Rome, Italy
modifications induced by intrabrachial acetylcholine and demonstrated diminished endothelium-dependent vasodilatation in menopausal women, suggesting a protective effect of endogenous estrogens on endothelial function. For several years, evidences have been accumulated demonstrating that the renin-angiotensin system (RAAS) is modulated by gender and sex hormones. First, the hypothesis was that estrogen activates the RAAS [12, 13]. In 1994 Sealey et al. [14] evaluated the relationship between estrogen, progesterone and RAAS modulation and demonstrated a marked increase in plasma renin paralleled by increased plasma estrogen and progesterone levels during ovarian stimulation and early pregnancy. Later, the evidence of lower BP levels in premenopausal women, associated with a lower risk of development and progression of CV disease and hypertension, compared with age-
matched men, suggested a protective role of estrogen [15, 16]. Nowadays, the exact pathophysiological mechanisms by which sex hormones contribute to the regulation of cardiovascular function and blood pressure are still being investigated. Recently, Rands et al. [17] studied the intrarenal gene expression and urinary excretion of angiotensinogen during angiotensin II-dependent hypertension and high-salt diet, and demonstrated that there is higher intrarenal RAAS activation in male rats than in females. Despite the beneficial effects of estrogen, whether the presence of estradiol protects against increases in BP levels in premenopausal women, and conversely, whether the lack of estradiol contributes to development and progression of hypertension in postmenopausal women is controversial and unknown [18]. Longitudinal studies have not documented an increase in BP with menopause [19]. The
A. Ferrucci et al.
principal clinical studies on hormone replacement therapy effect in postmenopausal women do not support this theory. In the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study I and II, hormone replacement therapy failed to protect postmenopausal women against primary [20] or secondary [21, 22] cardiovascular events, respectively. Exogenous hormone administration, such as oral contraceptives (OC), is another topic worthy of interest. Numerous large studies have been performed over the last years, and they all confirmed that OC can increase BP levels [23, 24]. The magnitude of the increase of BP levels is related in one hand to the dose of estrogen and progestin and in the other hand to the duration of use. Another factor that may influence the development of hypertension is patient predisposition. The mechanism is the stimulation by estrogen of angiotensinogen production by the liver. But other factors OC-induced may be involved, like increases in body weight, plasma volume, plasma insulin and insulin resistance [25, 26]. Recommendations are to have a prudent approach to oral contraceptive in hypertensive women, monitoring BP regularly. Discontinuation of therapy should be based on the degree of hypertension, the risk of pregnancy and the overall cardiovascular risk profile.
3 Differences in Prognosis? Epidemiological data do not support any difference in prognosis between hypertensive age-matched men and women [1, 2, 27]. It’s well known that BP levels are lower in women than in age-matched men under 50 years [28]. However, recent clinical studies reported some specific characteristics of the development of hypertension and involvement of organ damage in women compared with men. With aging, BP tends to increase more rapidly in women than in men [29, 30]. National Health and Nutrition Examination Survey III cohort with the National Health and Nutrition Examination Survey IV cohort showed that women were more likely to have poorly controlled hypertension than men [18–20]. Palatini et al. [31] studied the organ involvement in premenopausal hypertensive women, and demonstrated that they showed an increased risk of developing hypertensive organ damage compared with hypertensive men of similar age.
quantify the effects of BP-lowering treatment in each sex and to determine if there are important differences, do not show any difference based on patient’s gender [32]. Some minor studies showed poorer outcomes in some groups of women [33], however, BPLTTC analysis does not find any evidence of an interaction between sex and the effectiveness of BP lowering treatment for any CV outcome tested in the selected clinical trials. On the basis of the available evidence, current European guidelines do not propose specific recommendations for the management of hypertension in women, except for pregnant women, in who use of RAAS inhibiting drugs is strictly forbidden [34].
5 Conclusions Despite epidemiological studies documented a different prevalence on hypertension in men compared with women, nowadays there’s no evidence of a direct effect of estrogens on hypertension development and progression. This statement is also supported by the failure of hormone replacement therapy in protecting against primary and secondary cardiovascular events. Female hormones can affect the RAAS and other mechanisms involved in the physiological regulation of blood pressure, and so playing a ‘‘protective’’ role. However the lack of estrogen is not responsible of the onset and development of hypertension. Moreover, the lowering gap between two sexes in the last decade, may suggest a role of women’s lifestyle rather than their hormone profile, considering that women’s lifestyle is being more and more similar to men’s one. From a prognostic point of view prognosis, hypertension has the same adverse effects in men and in women. Indeed some study reported a worst trend of hypertension and its consequences in women than in men. Besides hypertension in women, like others CV risk factor, has reproductive health consequences. So a correct identification and approach of this disorder is necessary to prevent related morbidity and mortality. In view of the above considerations, hypertension in women should be promptly faced with the same considerations done for men. The only exception is pregnancy, argument over the goal of this review, during which drugs accepted are well documented. Conflict of interest disclosure There are no conflict of interest and no financial disclosure to disclose.
4 Differences in Therapy? Nowadays, there are no definite evidence of a benefit from different therapeutic approach in women than in men. The meta-analysis of the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC), which aimed to
References 1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension; analysis of worldwide data. Lancet. 2005;365:217–23.
Hypertension in Premenopausal Women 2. Laz TH, Rahman M, Berenson AB. Trends in serum lipids and hypertension prevalence among non-pregnant reproductive-age women: United-States Nation Health and Nutrition Examination Survey 1999–2008. Matern Child Health J. 2013;17(8):1424–31. 3. Costanzo S, Di Castelnuovo A, Zito F, Krogh V, Siani A, Arnout J, Cappuccio FP, Miller MA, Van Dongen M, De Lorgeril M, De Gaetano G, Donati MB, Iacoviello L; for the European collaborative group of the IMMIDIET Project. Prevalence, awareness, treatment and control of hypertension in healthy unrelated malefemale pairs of European Regions: the dietary habit profile in European communities with different risk of myocardial infarction—the impact of migration as a model of gene-environment interaction project. J Hypertens. 2008, 26:2303–11. 4. De Giusti M, Dito E, Pagliaro B, Burocchi S, Laurino FL, Tocci G, Volpe M, Rubattu S. A survey on blood pressure levels and hypertension control in a sample of the Italian general population. High Blood Press Cardiovasc Prev. 2012;19(3):129–35. 5. Lawes CMM, Vander Hoorn S, Law MR, Elliott P, MacMahon S, Rodgers A. Blood pressure and the global burden disease 2000. Part 1: estimates of blood pressure levels. J Hypertens. 2006; 24:413–22. 6. Cutler JA, Solrie PD, Wolz M, Thom T, Fields LE, Roccella EJ. Trends in hypertension prevalence, awareness, treatment and control rates in the United States adults between 1988–1994 and 1999–2004. Hypertension. 2008;52:818–27. 7. Rich-Edwards JW, McElrath TF, Karumanchi SA, Seely EW. Breathing life into the lifecourse approach: pregnancy history and cardiovascular disease in women. Hypertension. 2010; 56(3):331–4. 8. Lieberman EH, Gerhard MD, Uehata A, Walsh BW, Selwyn AP, Ganz P, Yeung AC, Creager MA. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med. 1994;121(12):936–41. 9. Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Moncada S. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA. 1994;91:5212–6. 10. Dubey RK, Oparil S, Imthurn B, Jackson EK. Sex hormones and hypertension. Cardiovasc Res. 2002;53:688–708. 11. Taddei S, Virdis A, Ghiadoni L, Mattei P, Sudano I, Bernini G, Pinto S, Salvetti A. Menopause is associated with endothelial dysfunction in women. Hypertension. 1996;28(4):576–82. 12. Laragh JH. Renin, angiotensin, aldosterone and hormonal regulation of arterial pressure and salt balance. Introductory remarks. Fed Proc. 1967;26:39–41. 13. Skinner SL, Lumbers ER, Symonds EM. Alteration by oral contraceptives of normal menstrual changes in plasma renin activity, concentration and substrate. Clin Sci. 1969;36:67–76. 14. Sealey JE, Itskovitz-Eldor J, Rubattu S, James GD, August P, Thaler I, Levron J, Laragh JH. Estradiol- and progesterone-related increases in the renin-aldosterone system: studies during ovarian stimulation and early pregnancy. J Clin Endocrinol Metab. 1994;79(1):258–64. 15. Chappell MC, Westwood BM, Yamaleyeva LM. Differential effects of sex steroids in young and aged female mRen2.Lewis rats: a model of estrogen and salt-sensitive hypertension. Gend Med. 2008;5(Suppl A):S65–75. 16. Yanes LL, Sartori-Valinotti JC, Iliescu R, et al. Testosteronedependent hypertension and upregulation of intrarenal angiotensinogen in Dahl salt-sensitive rats. Am J Physiol Renal Physiol. 2009;296:F771–9. 17. Rands VF, Dale MS, Kobori H, Prieto MC. Sexual dimorphism in urinary angiotensinogen excretion during chronic angiotensin II—salt hypertension. Gend Med. 2012;9:207–18.
18. Yanes LL, Reckelhoff JF. Postmenopausal hypertension. Am J Hypertens. 2011;24(7):740–9. 19. Hjortland MC, McNamara PM, Kannel WB. Some atherogenic concomitants of menopause: The Framingham Study. Am J Epidemiol. 1976;103(3):304–11. 20. Burry KA. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. Curr Women’s Health Rep. 2002;2:331–2. 21. Herrington DM. The HERS trial results: paradigms lost? Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 1999;131:463–6. 22. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N; HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49–7. 23. Dong W, Colhoun HM, Poulter NR. Blood pressure in women using oral contraceptives: results from the Health Survey for England 1994. J Hypertens. 1997;15:1063–8. 24. Chasan-Taber L, Willett WC, Manson JE, Spiegelman D, Hunter DJ, Curhan G, et al. Prospective study of oral contraceptives and hyper-tension among women in the United States. Circulation. 1996;94:483–9. 25. August P. Hypertension in women. Adv Chronic Kidney Dis. 2013;20(5):396–401. 26. The WHO multicentre trial of the vasopressors effects of combined oral contraceptives. Contraception. 1989; 40(2):147–6. 27. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–13. 28. Lawes CM, Vander Hoorn S, Law MR, Elliott P, MacMahon S, Rodgers A. Blood pressure and the global burden of disease 2000. Part 1: estimates of blood pressure levels. J Hypertens. 2006;24(3):413–22. 29. Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension. 2009;54:11–8. 30. Wiinberg N, Høegholm A, Christensen HR, Bang LE, Mikkelsen KL, Nielsen PE, Svendsen TL, Kampmann JP, Madsen NH, Bentzon MW. 24-Hambulatory blood pressure in 352 normal Danish subjects, related to age and gender. Am J Hypertens. 1995; 8:978–6. 31. Palatini P, Mos L, Santonastaso M, Saladini F, Benetti E, Mormino P, Bortolazzi A, Cozzio S. Premenopausal women have increased risk of hypertensive target organ damage compared with men of similar age. J Womens Health (Larchmt). 2011;20(8):1175–81. 32. Turnbull F, Woodward M, Neal B, Barzi F, Ninomiya T, Chalmers J, Perkovic V, Li N, MacMahon S, Blood Pressure Lowering Treatment Trialists’ Collaboration. Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials. Eur Heart J. 2008;29:2669–80. 33. Ong KL, Tso AW, Lam KS, Cheung BM. Gender difference in blood pressure control and cardiovascular risk factors in Americans with diagnosed hypertension. Hypertension. 2008;51:1142–8. 34. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2013 ESH/ESC Guidelines for the management of arterial hypertension. Eur Heart J. 2013;34:2159–219.
REVIEW ARTICLE
Hypertension in Premenopausal Women: Is There Any Difference? Andrea Ferrucci • Giulia Pignatelli • Sebastiano Sciarretta • Giuliano Tocci
Received: 3 February 2014 / Accepted: 24 March 2014 Ó Springer International Publishing Switzerland 2014
Abstract Hypertension is one of the most important cardiovascular (CV) risk factor, and that lowering blood pressure levels reduces the incidence of CV morbidity and mortality. The higher incidence of hypertension in postmenopausal than in pre-menopausal women raises the attention on the pathophysiological mechanisms potentially involved in post-menopausal ones and outweigh those involved in pre-menopausal women. However, CV disease is one of the leading causes of death in reproductive-age women. Thus, improved awareness, early identification and prompt clinical management of hypertension should be key elements in order to prevent hypertension-related CV morbidity and mortality in pre-menopausal women. However, available data in this specific age group of women are relatively poor and inconsistent, so that the clinical management of young hypertensive women is still debated. The aim of this review is to assess whether there are clear evidences on differences between men and women in epidemiological data, pathophysiological mechanisms, diagnostic options and therapeutic interventions of hypertension and its prognosis, in order to establish the correct approach to this group of hypertensive patients. Keywords Hypertension Pre-menopausal women Post-menopausal women Cardiovascular prevention
A. Ferrucci (&) G. Pignatelli S. Sciarretta G. Tocci Hypertension Unit, Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University of Rome Sapienza, Sant’Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy e-mail: [email protected] S. Sciarretta G. Tocci IRCCS Neuromed, Pozzilli (IS), Italy
1 Introduction Hypertension is a well established determinant of cardiovascular disease (CVD) in both men and women. Epidemiological data demonstrating the adverse prognosis of hypertension, and that lowering blood pressure (BP) levels may effectively prevent CV morbidity and mortality, are equally relevant for both women and men [1–4]. However, observational studies and large epidemiological databases consistently reported that BP levels are higher in men than in women under 40 years; with aging, BP levels tend to rise steeply in women than in men until overcome their values [5]. In addition, over the last decade it has been observed in US population that prevalence of hypertension increased when compared with data before 2000 (Fig. 1) [6], as well as awareness and pharmacological treatment of young hypertensive women (Fig. 2) [2]. Although specific data reporting hypertension prevalence in pre-menopausal women in European Countries are lacking, similar proportions have been also reported in our database, in which prevalence of hypertension in women in non-pregnant reproductive age is relatively low compared with age-matched men (Fig. 3). The higher incidence of hypertension observed during the post-menopausal age led to focus the attention on the potential beneficial effect of sexual hormones, while the mechanisms of hypertension in young women remained to be further clarified. However, CVD is one of the leading causes of death in reproductive-age women. Moreover hypertension, as well as other CV risk factors, may have reproductive health consequences, including preeclampsia and other pregnancy disorders like preterm delivery [7]. So improved awareness, early identification and prompt management of this condition are key aspects, in order to prevent hypertension-related CV morbidity and mortality in this population. Available data in this regard, however,
A. Ferrucci et al. Fig. 1 Age-standardized prevalence rate of hypertension by race/ethnicity for women: NHANES III 1988–1994 and NHANES 1999–2004. Derived from reference num. 06
Fig. 2 Trend in the selfreported and actual rates of hypertension among nonpregnant reproductive-age women (20–49 years) in the NHANES 1999–2008. Derived from reference num. 02
are relatively poor and inconsistent, as such the clinical management of young hypertensive women is still debated. In this review, we aimed to analyse if there are any clear evidence on differences between men and women in epidemiology, pathophysiology of hypertension and prognosis, and if a different therapeutic approach is needed in this group of hypertensive women.
2 Gender Differences in Pathophysiological Mechanisms? Current opinion is that men have a higher prevalence of hypertension compared with women [1, 3], and several studies have reported this disparity. There is a wealth of evidence that estrogen has a vasodilatatory effects and may be responsible for the lower BP in younger women. Experimental models investigating the
biological effects of estrogen demonstrate that administration of estradiol promotes endothelium-dependent vasodilatation [8]. There is also evidence that loss of estrogen at any age contributes to endothelial dysfunction, which is common in individuals with hypertension. Endothelial dysfunction is typically characterized by reductions in NO. Estradiol stimulates NO production since estradiol acutely increases intracellular calcium, which activates endothelial NO synthase [9], which would promote vasodilation and thus reductions in BP [10]. Estradiol also upregulates superoxide dismutase, which removes superoxide and reduces oxidative stress. Superoxide binds to NO and renders NO unavailable for vasodilation. However, an intact NO system is necessary for antioxidants to reduce BP. Therefore, in situations of chronic hypertension when endothelial dysfunction is present and NO levels have been reduced for long periods, estradiol may not be able to reduce BP. In this regard, Taddei et al. [11] evaluated endothelial function by measuring forearm blood flow
Hypertension in Premenopausal Women Fig. 3 Age-standardized prevalence rate of hypertension for women included in our database, Hypertension Unit, Division of Cardiology, Sant’Andrea Hospital of Rome, Italy
modifications induced by intrabrachial acetylcholine and demonstrated diminished endothelium-dependent vasodilatation in menopausal women, suggesting a protective effect of endogenous estrogens on endothelial function. For several years, evidences have been accumulated demonstrating that the renin-angiotensin system (RAAS) is modulated by gender and sex hormones. First, the hypothesis was that estrogen activates the RAAS [12, 13]. In 1994 Sealey et al. [14] evaluated the relationship between estrogen, progesterone and RAAS modulation and demonstrated a marked increase in plasma renin paralleled by increased plasma estrogen and progesterone levels during ovarian stimulation and early pregnancy. Later, the evidence of lower BP levels in premenopausal women, associated with a lower risk of development and progression of CV disease and hypertension, compared with age-
matched men, suggested a protective role of estrogen [15, 16]. Nowadays, the exact pathophysiological mechanisms by which sex hormones contribute to the regulation of cardiovascular function and blood pressure are still being investigated. Recently, Rands et al. [17] studied the intrarenal gene expression and urinary excretion of angiotensinogen during angiotensin II-dependent hypertension and high-salt diet, and demonstrated that there is higher intrarenal RAAS activation in male rats than in females. Despite the beneficial effects of estrogen, whether the presence of estradiol protects against increases in BP levels in premenopausal women, and conversely, whether the lack of estradiol contributes to development and progression of hypertension in postmenopausal women is controversial and unknown [18]. Longitudinal studies have not documented an increase in BP with menopause [19]. The
A. Ferrucci et al.
principal clinical studies on hormone replacement therapy effect in postmenopausal women do not support this theory. In the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study I and II, hormone replacement therapy failed to protect postmenopausal women against primary [20] or secondary [21, 22] cardiovascular events, respectively. Exogenous hormone administration, such as oral contraceptives (OC), is another topic worthy of interest. Numerous large studies have been performed over the last years, and they all confirmed that OC can increase BP levels [23, 24]. The magnitude of the increase of BP levels is related in one hand to the dose of estrogen and progestin and in the other hand to the duration of use. Another factor that may influence the development of hypertension is patient predisposition. The mechanism is the stimulation by estrogen of angiotensinogen production by the liver. But other factors OC-induced may be involved, like increases in body weight, plasma volume, plasma insulin and insulin resistance [25, 26]. Recommendations are to have a prudent approach to oral contraceptive in hypertensive women, monitoring BP regularly. Discontinuation of therapy should be based on the degree of hypertension, the risk of pregnancy and the overall cardiovascular risk profile.
3 Differences in Prognosis? Epidemiological data do not support any difference in prognosis between hypertensive age-matched men and women [1, 2, 27]. It’s well known that BP levels are lower in women than in age-matched men under 50 years [28]. However, recent clinical studies reported some specific characteristics of the development of hypertension and involvement of organ damage in women compared with men. With aging, BP tends to increase more rapidly in women than in men [29, 30]. National Health and Nutrition Examination Survey III cohort with the National Health and Nutrition Examination Survey IV cohort showed that women were more likely to have poorly controlled hypertension than men [18–20]. Palatini et al. [31] studied the organ involvement in premenopausal hypertensive women, and demonstrated that they showed an increased risk of developing hypertensive organ damage compared with hypertensive men of similar age.
quantify the effects of BP-lowering treatment in each sex and to determine if there are important differences, do not show any difference based on patient’s gender [32]. Some minor studies showed poorer outcomes in some groups of women [33], however, BPLTTC analysis does not find any evidence of an interaction between sex and the effectiveness of BP lowering treatment for any CV outcome tested in the selected clinical trials. On the basis of the available evidence, current European guidelines do not propose specific recommendations for the management of hypertension in women, except for pregnant women, in who use of RAAS inhibiting drugs is strictly forbidden [34].
5 Conclusions Despite epidemiological studies documented a different prevalence on hypertension in men compared with women, nowadays there’s no evidence of a direct effect of estrogens on hypertension development and progression. This statement is also supported by the failure of hormone replacement therapy in protecting against primary and secondary cardiovascular events. Female hormones can affect the RAAS and other mechanisms involved in the physiological regulation of blood pressure, and so playing a ‘‘protective’’ role. However the lack of estrogen is not responsible of the onset and development of hypertension. Moreover, the lowering gap between two sexes in the last decade, may suggest a role of women’s lifestyle rather than their hormone profile, considering that women’s lifestyle is being more and more similar to men’s one. From a prognostic point of view prognosis, hypertension has the same adverse effects in men and in women. Indeed some study reported a worst trend of hypertension and its consequences in women than in men. Besides hypertension in women, like others CV risk factor, has reproductive health consequences. So a correct identification and approach of this disorder is necessary to prevent related morbidity and mortality. In view of the above considerations, hypertension in women should be promptly faced with the same considerations done for men. The only exception is pregnancy, argument over the goal of this review, during which drugs accepted are well documented. Conflict of interest disclosure There are no conflict of interest and no financial disclosure to disclose.
4 Differences in Therapy? Nowadays, there are no definite evidence of a benefit from different therapeutic approach in women than in men. The meta-analysis of the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC), which aimed to
References 1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension; analysis of worldwide data. Lancet. 2005;365:217–23.
Hypertension in Premenopausal Women 2. Laz TH, Rahman M, Berenson AB. Trends in serum lipids and hypertension prevalence among non-pregnant reproductive-age women: United-States Nation Health and Nutrition Examination Survey 1999–2008. Matern Child Health J. 2013;17(8):1424–31. 3. Costanzo S, Di Castelnuovo A, Zito F, Krogh V, Siani A, Arnout J, Cappuccio FP, Miller MA, Van Dongen M, De Lorgeril M, De Gaetano G, Donati MB, Iacoviello L; for the European collaborative group of the IMMIDIET Project. Prevalence, awareness, treatment and control of hypertension in healthy unrelated malefemale pairs of European Regions: the dietary habit profile in European communities with different risk of myocardial infarction—the impact of migration as a model of gene-environment interaction project. J Hypertens. 2008, 26:2303–11. 4. De Giusti M, Dito E, Pagliaro B, Burocchi S, Laurino FL, Tocci G, Volpe M, Rubattu S. A survey on blood pressure levels and hypertension control in a sample of the Italian general population. High Blood Press Cardiovasc Prev. 2012;19(3):129–35. 5. Lawes CMM, Vander Hoorn S, Law MR, Elliott P, MacMahon S, Rodgers A. Blood pressure and the global burden disease 2000. Part 1: estimates of blood pressure levels. J Hypertens. 2006; 24:413–22. 6. Cutler JA, Solrie PD, Wolz M, Thom T, Fields LE, Roccella EJ. Trends in hypertension prevalence, awareness, treatment and control rates in the United States adults between 1988–1994 and 1999–2004. Hypertension. 2008;52:818–27. 7. Rich-Edwards JW, McElrath TF, Karumanchi SA, Seely EW. Breathing life into the lifecourse approach: pregnancy history and cardiovascular disease in women. Hypertension. 2010; 56(3):331–4. 8. Lieberman EH, Gerhard MD, Uehata A, Walsh BW, Selwyn AP, Ganz P, Yeung AC, Creager MA. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med. 1994;121(12):936–41. 9. Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Moncada S. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA. 1994;91:5212–6. 10. Dubey RK, Oparil S, Imthurn B, Jackson EK. Sex hormones and hypertension. Cardiovasc Res. 2002;53:688–708. 11. Taddei S, Virdis A, Ghiadoni L, Mattei P, Sudano I, Bernini G, Pinto S, Salvetti A. Menopause is associated with endothelial dysfunction in women. Hypertension. 1996;28(4):576–82. 12. Laragh JH. Renin, angiotensin, aldosterone and hormonal regulation of arterial pressure and salt balance. Introductory remarks. Fed Proc. 1967;26:39–41. 13. Skinner SL, Lumbers ER, Symonds EM. Alteration by oral contraceptives of normal menstrual changes in plasma renin activity, concentration and substrate. Clin Sci. 1969;36:67–76. 14. Sealey JE, Itskovitz-Eldor J, Rubattu S, James GD, August P, Thaler I, Levron J, Laragh JH. Estradiol- and progesterone-related increases in the renin-aldosterone system: studies during ovarian stimulation and early pregnancy. J Clin Endocrinol Metab. 1994;79(1):258–64. 15. Chappell MC, Westwood BM, Yamaleyeva LM. Differential effects of sex steroids in young and aged female mRen2.Lewis rats: a model of estrogen and salt-sensitive hypertension. Gend Med. 2008;5(Suppl A):S65–75. 16. Yanes LL, Sartori-Valinotti JC, Iliescu R, et al. Testosteronedependent hypertension and upregulation of intrarenal angiotensinogen in Dahl salt-sensitive rats. Am J Physiol Renal Physiol. 2009;296:F771–9. 17. Rands VF, Dale MS, Kobori H, Prieto MC. Sexual dimorphism in urinary angiotensinogen excretion during chronic angiotensin II—salt hypertension. Gend Med. 2012;9:207–18.
18. Yanes LL, Reckelhoff JF. Postmenopausal hypertension. Am J Hypertens. 2011;24(7):740–9. 19. Hjortland MC, McNamara PM, Kannel WB. Some atherogenic concomitants of menopause: The Framingham Study. Am J Epidemiol. 1976;103(3):304–11. 20. Burry KA. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. Curr Women’s Health Rep. 2002;2:331–2. 21. Herrington DM. The HERS trial results: paradigms lost? Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 1999;131:463–6. 22. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N; HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49–7. 23. Dong W, Colhoun HM, Poulter NR. Blood pressure in women using oral contraceptives: results from the Health Survey for England 1994. J Hypertens. 1997;15:1063–8. 24. Chasan-Taber L, Willett WC, Manson JE, Spiegelman D, Hunter DJ, Curhan G, et al. Prospective study of oral contraceptives and hyper-tension among women in the United States. Circulation. 1996;94:483–9. 25. August P. Hypertension in women. Adv Chronic Kidney Dis. 2013;20(5):396–401. 26. The WHO multicentre trial of the vasopressors effects of combined oral contraceptives. Contraception. 1989; 40(2):147–6. 27. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–13. 28. Lawes CM, Vander Hoorn S, Law MR, Elliott P, MacMahon S, Rodgers A. Blood pressure and the global burden of disease 2000. Part 1: estimates of blood pressure levels. J Hypertens. 2006;24(3):413–22. 29. Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension. 2009;54:11–8. 30. Wiinberg N, Høegholm A, Christensen HR, Bang LE, Mikkelsen KL, Nielsen PE, Svendsen TL, Kampmann JP, Madsen NH, Bentzon MW. 24-Hambulatory blood pressure in 352 normal Danish subjects, related to age and gender. Am J Hypertens. 1995; 8:978–6. 31. Palatini P, Mos L, Santonastaso M, Saladini F, Benetti E, Mormino P, Bortolazzi A, Cozzio S. Premenopausal women have increased risk of hypertensive target organ damage compared with men of similar age. J Womens Health (Larchmt). 2011;20(8):1175–81. 32. Turnbull F, Woodward M, Neal B, Barzi F, Ninomiya T, Chalmers J, Perkovic V, Li N, MacMahon S, Blood Pressure Lowering Treatment Trialists’ Collaboration. Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials. Eur Heart J. 2008;29:2669–80. 33. Ong KL, Tso AW, Lam KS, Cheung BM. Gender difference in blood pressure control and cardiovascular risk factors in Americans with diagnosed hypertension. Hypertension. 2008;51:1142–8. 34. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2013 ESH/ESC Guidelines for the management of arterial hypertension. Eur Heart J. 2013;34:2159–219.
