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Menopause: The Journal of The North American Menopause Society Vol. 22, No. 4, pp. 000/000 DOI: 10.1097/gme.0000000000000322 * 2014 by The North American Menopause Society REVIEW ARTICLE Effects of hormone therapy on blood pressure Zeinab Issa, MD,1 Ellen W. Seely, MD,2 Maya Rahme, MSc,3 and Ghada El-Hajj Fuleihan, MD, MPH3,4 Abstract Objective: Although hormone therapy remains the most efficacious option for the management of vasomotor symptoms of menopause, its effects on blood pressure remain unclear. This review scrutinizes evidence of the mechanisms of action of hormone therapy on signaling pathways affecting blood pressure and evidence from clinical studies. Methods: Comprehensive Ovid MEDLINE searches were conducted for the terms Bhypertension[ and either of the following Bhormone therapy and menopause[ or Bselective estrogen receptor modulator[ from year 2000 to November 2013. Results: In vitro and physiologic studies did not reveal a clear deleterious effect of hormone therapy on blood pressure. The effect of oral therapy was essentially neutral in large trials conducted in normotensive women with blood pressure as primary outcome. Results from all other trials had several limitations. Oral therapy had a neutral effect on blood pressure in hypertensive women. Transdermal estrogen and micronized progesterone had a beneficial effect on blood pressure in normotensive women and, at most, a neutral effect on hypertensive women. In general, tibolone and raloxifene had a neutral effect on blood pressure in both hypertensive and normotensive women. Conclusions: Large randomized trials are needed to assess the effect of oral hormone therapy on blood pressure as a primary outcome in hypertensive women and the effect of transdermal preparations on both normotensive and hypertensive women. Transdermal preparations would be the preferred mode of therapy for hypertensive women, in view of their favorable physiologic and clinical profiles. The decision regarding the use of hormone therapy should be individualized, and blood pressure should be monitored during the course of treatment. Key Words: Hormone treatment Y Hypertension Y Menopause Y Blood pressure Y Selective estrogen receptor modulators. H ypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality and morbidity in both men and women. In the National Health and Nutrition Examination Survey for years 2007-2010, hypertension was more common in men than in women younger than 45 years; the prevalence became equal Received January 11, 2014; revised and accepted July 7, 2014. From the 1Endocrine Division, American University of Beirut, Beirut, Lebanon; 2Endocrine Hypertension Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 3Endocrine Division, Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders; and 4Scholars in Health Research Program, American University of Beirut, Beirut, Lebanon. Funding/support: None. Financial disclosure/conflicts of interest: None reported. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website (www.menopause.org). Address correspondence to: Ghada El-Hajj Fuleihan, MD, MPH, Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon. E-mail: [email protected] in both sexes between ages 45 and 64 years, after which women took the lead.1 To date, the mechanisms underlying postmenopausal hypertension are not clear. The low estrogen state associated with menopause has been implicated as a suspect and is supported by growing evidence for the effects of estrogen and its receptors on multiple surrogate markers of blood pressure (BP), such as vascular tone, renin-angiotensin-aldosterone system (RAAS), sympathetic system, kinin-kallikrein system, atrial natriuretic peptide (ANP), and inflammation. Transition to menopause is also associated with a higher prevalence of metabolic syndrome and changes in body composition, including increase in weight and fat mass, which can impact BP.2 In this article, we review potential pathways for the effects of hormone therapy (HT) on BP and evidence from clinical studies for the effects of HT and selective estrogen receptor modulators (SERMs) on BP. METHODS Search methodology A comprehensive review of the literature was implemented in consultation with our medical librarian, an expert in the Menopause, Vol. 22, No. 4, 2015 Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 1 ISSA ET AL construction of searches in various biomedical databases. The topic of interest was divided into three main concepts: hypertension, HT, and menopause. Each of these concepts was searched on Ovid MEDLINE as such and also as synonyms or related terms to achieve a comprehensive literature review. The Ovid MEDLINE interfaceVwhich allows MeSH terms, explode functions, and keyword search in title, abstract, subject headings, adjacency, and publication types, in addition to Boolean operators (and, or) and truncationVwas used to identify all relevant articles using the main terms and related terms (for full details, see Appendix I, Supplemental Digital Content 1, http://links.lww.com/MENO/A107). To retrieve articles describing the impact of SERMs, we entered the terms BSERM[ and Bhypertension[ as MeSH terms, related terms, and key words, and we used the operation AND. The search conducted in this review was limited to years 2000-2013, although we also included major relevant randomized controlled trials (RCTs) before year 2000, such as the Heart and Estrogen/progestin Replacement Study (HERS), Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, and one trial on transdermal estrogen. Additional relevant studies and reviews published before 2000 were identified from reference lists of retrieved articles, and those available in authors’ libraries were also used. Risk-of-bias assessment We conducted a risk-of-bias assessment for randomized trials detailed in this review using The Cochrane Collaboration’s risk of bias tool, which was designed to evaluate clinical trials and its six criteria: (1) random sequence generation (selection bias); (2) allocation concealment (selection bias); (3) blinding of participants, providers, data collectors, outcome adjudicators, and data analysts (performance bias and detection bias); (4) incomplete outcome data (attrition bias); (5) selective reporting (reporting bias); and (6) other sources of bias (eg, early termination of trial). The assessment was independently conducted by two authors (Z.I. and M.R.) and reviewed again by the senior author (G.E.-H.F.). We judged the risk of bias for each criterion as Blow risk,[ Bhigh risk,[ or Bunclear risk[ and evaluated individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions.3 Additional details are available in Appendix II-A (Supplemental Digital Content 2, http://links.lww.com/MENO/A108). POTENTIAL ROLE OF ESTROGEN IN BP REGULATION Estrogen’s effect on BP is complex and includes direct and indirect effects through multiple signaling pathways that may either lower or raise BP, depending on the pathway involved. This section will mainly address the effects of estrogen and progesterone on BP from a pathophysiologic point of view and is followed by a clinical section that discusses the main relevant RCTs that focus on this topic. 2 Menopause, Vol. 22, No. 4, 2015 PHYSIOLOGIC EFFECTS OF ESTROGEN ON THE VASCULAR SYSTEM Estrogen can exert its effect on the heart and vessels through its two receptor isoforms, estrogen receptor (ER)-> and ER-A,4,5 which are expressed in vascular endothelial cells and vascular smooth muscle cells. The functional properties of ER-> and ER-A are different, and their effects can be mediated through genomic6 or nongenomic7 mechanisms (Fig.). The genomic mechanism occurs during a relatively long period and consists of binding of estrogen to ER elements on promoter regions of the target gene, thereby regulating the transcription of the target gene.9 The nongenomic mechanism has been the subject of multiple studies in recent decades. These so-called extranuclear actions are mediated through ERs located at or near the plasma membrane, which, once activated, interact with some membrane-associated signaling molecules such as ion channels, G-proteins, the tyrosine kinase c-Src, and the epidermal growth factor receptor, leading to the activation of a cascade involving mitogen-activated protein kinase, phosphatidylinositol 3-OH kinase, small GTPase RhoA, and protein kinase A/C, which might cause different actions like vasodilatation but also may affect gene expression through the so-called Btwo-step model of sex steroid signaling.[10 ER-AYdeficient male and female mice have been shown to develop hypertension and exaggerated vasoconstrictor response to A adrenergic receptor agonists.11 Certain polymorphisms in ER-A genes have been demonstrated to correlate with BP elevations in both women and men. In a study of 187 healthy postmenopausal women, those who had at least one allele with 26 cytosine-adenine repeats on the ER-A gene had higher systolic BP (SBP), with a mean difference of 10 mm Hg (P = 0.032), compared with those who did not.12 In the Framingham Heart Study, men with specific polymorphisms in the ER-> gene had higher SBP, and those with variations in ER-> nuclear receptor coactivator 1 and aromatase genes had a higher pulse pressure than those who did not have these specific polymorphisms. Women with polymorphisms in ER->, aromatase, and nuclear receptor coactivator 1 genes also had higher diastolic BP (DBP).13 A newly discovered seven-transmembrane spanning intracellular G-proteinYcoupled ER (GPER), which is expressed throughout the cardiovascular system, may play an important role in BP modulation. The activation of this receptor was shown to reduce BP in ovariectomized mice14 and, conversely, GPER-deficient mice had increased endothelial prostanoidmediated vasoconstriction.15 17A-Estradiol (E2) is a primary ligand for GPER; thus, decreasing E2 levels in menopause may be implicated in the pathophysiology of hypertension through this receptor.16 The effect of estrogen on target cells and organs, including the vascular system, is thus regulated by a complex interplay of genomic and nongenomic signaling mechanisms, and the integrated action of these machineries has important functional roles in a variety of pathophysiologic processes. Although there are various types of oral and transdermal estrogen preparations that can activate the genomic and nongenomic pathways detailed * 2014 The North American Menopause Society Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE FIG. The multifaceted mechanisms of estrogen involve (1) acting on estrogen receptor (ER)-> and ER-A to reduce synthesis of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase and to increase synthesis of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD), thereby decreasing superoxide and increasing nitric oxide (NO) production and bioavailability (genomic effect); (2) rapidly activating eNOS via a calcium (Ca)-mediated mechanism without altering gene expression (nongenomic effect), leading to NO/cyclic guanosine monophosphate release and vascular relaxation; (3) activating protein kinase B (AKT) via MAP kinase (MAPK)Yphosphatidylinositol 3-OH (PI3) kinase pathways, reducing apoptosis and enhancing cell survival; and (4) reducing nuclear factor JB (NF-JB) activation/translocation via P38>-mediated p53 phosphorylation and c-Jun N-terminal kinase (JNK) 1/2Ymediated signaling pathways, inhibiting chemokine/cytokine transcription and decreasing inflammation. In addition, estrogen acts on the membrane-bound and G-proteinYcoupled estrogen receptor GPR30 associated with transactivation of epidermal growth factor receptors (EGFR), which induces rapid signal transduction, including activation of MAPK, protein kinase A, and PI3 kinase, leading to cardiovascular protection. GSH3A, glutathione 3A. Reprinted from Yang and Reckelhoff8 with permission of the publisher. Copyright * 2011, Wolters Kluwer Health | Lippincott Williams & Wilkins. herein, the most extensively studied estrogenic compounds have been conjugated equine estrogens (CEE) and the native natural molecule 17A-E2. Mechanisms through which estrogen would lower BP Estrogen and vascular tone Menopause and its associated low estrogen state are characterized by endothelial dysfunction,17 which can thus predispose to hypertension.18 A study of 952 apparently healthy postmenopausal women (mean age, 53 y) followed for a mean of 3.6 years demonstrated that endothelial dysfunction, assessed by flow-mediated dilatation, preceded and predicted hypertension.19 Aging per se is associated with a decline in endothelial function in normal humans, and this decline seems to occur earlier in men than in women. However, in women, a steep decline occurs at around the time of menopause, consistent with loss of a protective effect of estrogen on the arterial wall.20 The postmenopausal state is indeed associated with a significant reduction in nitric oxide activity,21 and vasodilatation is one of the most important effects of estrogen on arterial vessels. Estrogen-induced vasodilation has been described in animal models22 and clinical studies and occurs through activation of the endothelial nitric oxide synthase and release of nitric oxide through genomic and nongenomic signal transduction pathways.23 Other possible mechanisms that have been implicated in the vasodilatory effect of estrogen are release of prostaglandin 2, stimulation of neuronal nitric oxide synthase in vascular smooth muscles cells,24 and inhibition of voltagedependent L-type calcium current in vascular smooth cells.25 Short-term sublingual administration of 17A-E2 1 mg was shown to improve vasodilatory responses in eight mildly hypertensive postmenopausal women (mean age, 54.4 y) who had no other risk factors for cardiovascular disease.26 The effect of 17A-E2 2 mg/day, alone or combined with the progestin medroxyprogesterone acetate (MPA) 5 mg/day, on the function and morphology of isolated resistance arteries was assessed in a randomized placebo-controlled trial in 55 healthy postmenopausal women (mean age, 57 y) before and after 3-month therapy with 17A-E2, MPA acetate, and 17A-E2 plus MPA acetate or placebo. E2 augmented artery flowYmediated dilatation, improved endothelial cell morphology, increased the expression and phosphorylation of the actin binding protein myosin and of the focal adhesion complex controller, induced the rearrangement of cytoskeletal actin and vinculin fibers, promoted endothelial cell horizontal migration, and decreased signs of endothelial apoptosis. Some of these beneficial effects were preserved with the addition of MPA, whereas MPA alone failed to augment artery flowYmediated dilatation and to improve endothelial cell morphology and apoptosis.27 Healthy postmenopausal women receiving oral 17A-E2 2 mg/day combined with micronized progesterone 200 mg/day had improved carotid artery compliance.28 Similarly, in a 12-month RCT, transdermal E2, but not oral CEE therapy, had a beneficial effect on arterial stiffness but had no effect on BP.29 However, the beneficial effect of estrogen on flow-mediated vasodilatation has not been consistent across studies.30 The discrepancy in the results may be related to differences in age, timing of initiation of estrogen after menopause, and preparations of estrogen and progestins. Menopause, Vol. 22, No. 4, 2015 Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 3 ISSA ET AL Estrogen and the kinin-kallikrein system Increase in the activity of the kinin-kallikrein system leads to lowering of BP, and HT may affect this system. HT in the form of oral 17A-E2 (2 mg), alone or combined with continuous MPA, increased urinary kallikrein excretion in 39 normotensive postmenopausal women after 3 months of E2 (P G 0.001) and E2 with MPA (P G 0.01), whereas it decreased nonsignificantly in the placebo group (P 9 0.06). Although there were no significant BP changes after 3 months of therapy, there was a significant negative correlation between urinary kallikrein and mean arterial pressure and pulse pressure in the estrogen-alone arm.31 Estrogen and ANP E2 was shown to increase ANP, a molecule with a wide array of cardiovascular and renal effects, including natriuresis, diuresis, and antagonism of the renin-angiotensin system and the sympathetic nervous system, which could lower BP.32 E2 also decreased ANP clearance and reduced weight gain in follitropin receptor knockout mice, an animal model for obesity and hypertension.33 The increase in ANP induced by E2 was accompanied by a reduction in BP in ovariectomized spontaneously hypertensive rats.34 Estrogen and inflammation Indirect evidence suggests that inflammation may modulate BP in animal models. Angiotensin IIYinduced hypertension was attenuated in interleukin-6 knockout mice.35 Similarly, in pregnant rats with elevated tumor necrosis factor-> levels, etanercept, a tumor necrosis factor->Ysoluble receptor inhibitor, significantly reduced BP.36 Estrogen has been shown to have a suppressive effect on E-selectin, cell adhesion molecules, monocyte chemoattractant protein-1, and tumor necrosis factor->; inconsistent effects on interleukin-6; and stimulatory effects on vasoprotective cytokines such as transforming growth factor->,37 in addition to attenuating vascular expression of inflammation-associated genes.38 Thus, estrogen may have BP-lowering effects through these mechanisms. Mechanisms through which estrogen would increase BP Estrogen and the RAAS The RAAS has powerful effects on BP through multiple mechanisms mediated by angiotensin II. These include the promotion of sodium and water reabsorption via stimulation of aldosterone release, systemic arteriolar vasoconstriction, promotion of endothelial dysfunction, stimulation of the sympathetic nervous system, and decrease in vagal tone. In addition, angiotensin II has direct powerful inotropic, chronotropic, and hypertrophic effects on the heart. Estrogen can regulate several of the components of the RAAS. Oral estrogens induce an increase in the hepatic production of angiotensinogen (renin substrate).39 However, not all the effects of estrogen are stimulatory after this step. The rise in angiotensinogen is typically associated with a compensatory 4 Menopause, Vol. 22, No. 4, 2015 fall in renin and maintenance of angiotensin I levels modulated by a negative feedback loop system. Angiotensin I is converted into angiotensin II (the active peptide) by angiotensin-converting enzyme (ACE), which is present in the lung and other tissues. Oral estrogen has been demonstrated to lower ACE levels. However, in several studies, despite lower ACE levels, levels of angiotensin II were higher in the presence of estrogen,40,41 thus suggesting that conversion into angiotensin II may occur via non-ACE pathways. This increase in angiotensin II would be expected to increase BP. However, whether oral estrogen increases BP may depend on the relative activation of the different components of the RAAS and on the intactness of compensatory mechanisms to compensate for an increase in angiotensin II. In a study by Seely et al,41 21 normotensive and 10 hypertensive women received either oral CEE (0.635 mg) or droloxifene (60 mg/d), a SERM, for a period of 16 weeks. Oral CEE increased angiotensinogen levels, decreased active renin and ACE levels, and kept angiotensin I levels unchanged. Both CEE and droloxifene significantly increased plasma-immunoreactive angiotensin II levels without a change in BP. Other studies supported a fall in circulating ACE levels with oral estrogen.42 Although oral estrogen increases angiotensinogen levels, transdermal estrogen does not. Transdermal E2 at a dose of 0.2 mg twice a week had no significant effect on plasma renin activity or aldosterone levels in healthy postmenopausal women.43 This neutral effect of transdermal E2 on the RAAS was shown in multiple studies.44<46 Angiotensin mediates its effects by binding to the angiotensin type 1 receptor (AT1R). The effects of estrogen on AT1R are conflicting. Estrogen can induce a decrease in AT1R expression in kidneys and vessels associated with a fall in BP, with restoration of estrogen, in an ovariectomized animal model.47In contrast, in an animal model that was pretreated with an inhibitor of nitric oxide, U-nitro-L-arginine-methyl-ester, to create a model of vascular Baging,[ administration of E2 to ovariectomized animals increased AT1R protein in the kidney, and this increase was positively associated with an increase in proteinuria.48 Therefore, the effect of estrogen on AT1R may depend on the state of the underlying vasculature. Furthermore, oral estrogen has also been suggested to antagonize angiotensin II receptorYmediated growth-promoting effects on vascular smooth muscle cells.49 Estrogen’s effect on the RAAS is thus complex and involves both stimulatory and inhibitory actions. Estrogen’s effect on the RAAS results in changes in BP that may depend on the relative balance between these actions, the health of the underlying vasculature, and the ability of other homeostatic systems to compensate for ensuing changes in RAAS activity. Given estrogen’s complex relationship with the RAAS, it is no surprise that estrogen administration has been demonstrated to influence antihypertensive response to agents that interrupt the RAAS. Garcı́a et al50 showed that in spontaneously hypertensive rats, the antihypertensive effect of the converting enzyme inhibitor captopril was enhanced when oral E2 was added; the combinationVnot captopril aloneVinhibited * 2014 The North American Menopause Society Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE extracellular signalYregulated kinase 1/2 phosphorylation, which mediates angiotensin IIYinduced arterial muscle proliferation. The AT1R blocker candesartan given to normotensive postmenopausal women resulted in a further decrease in BP in the group receiving oral HT (CEE and MPA) versus those not receiving any.51 Furthermore, the AT1R blocker irbesartan added to oral E2 caused a 5Ymm Hg decrease in both SBP and DBP in a higher percentage of hypertensive postmenopausal women compared with irbesartan alone and in addition to a significant decrease in aldosterone levels.52 Estrogen and the sympathetic system Activation of the sympathetic system can lead to hypertension by causing vasoconstriction and by increasing renal tubular sodium reabsorption.53 Postmenopausal status is associated with increased sympathetic activity through several mechanisms. First, obesity, which is common in postmenopausal women, can increase sympathetic activity, which, in the kidney, leads to increased renin release and vasoconstriction that can contribute to hypertension.54 Increased leptin levels found in obese women also activate the sympathetic system via activation of melanocortin receptors in the hypothalamus,55,56 and obese postmenopausal women have a greater predilection for hypertension than lean postmenopausal women.57 Furthermore, anxiety and depression, which are more common in women than in men, can activate the sympathetic system and elevate BP58,59 mainly in individuals with metabolic syndrome and hypertension. Oral estrogen therapy may decrease sympathetic nerve activity.30 In summary, postmenopausal women are at increased risk for sympathetic overactivity induced by obesity, increased leptin levels, and anxiety, an effect that may be counteracted by estrogen therapy. POTENTIAL ROLE OF PROGESTINS IN BP REGULATION We evaluated studies investigating the effects of progestins on the vascular system and found conflicting results,60possibly owing to differences in the type of progestin used, the route of administration (oral vs transdermal), and the vascular markers determined, the clinical relevance of which is still controversial. Indeed, different classes of progestins differ in their metabolic, androgenic, glucocorticoid, and antimineralocorticoid effects, as detailed in Table. The class properties for each of the progestins detailed in Table (eg, androgenic, glucocorticoid, and mineralocorticoid) were derived from different studies that used differing methodologies and are thus mostly qualitative and not directly comparable between the compounds listed. Szmuilowicz et al62 studied pressor and renovascular responses to infused angiotensin II, a potent vasoconstrictor, in 34 hypertensive postmenopausal women not on HT and off all antihypertensive therapies for at least 2 weeks. The vasoconstrictor response to angiotensin II was blunted in women with higher endogenous progesterone levels on low sodium balance, an effect that was independent of age, body mass index, and E2 concentration. Therefore, the presence of endogenous progesterone in premenopausal women, with levels ranging TABLE. Biological activities of natural progesterone and synthetic progestins Progestin Progestogenic Antigonadotropic Antiestrogenic Progesterone + + Dydrogesterone + j Medrogestone + + 17>-Hydroxy derivatives Chlormadinone + + acetate Cyproterone acetate + + Megestrol acetate + + Medroxyprogesterone + + acetate 19-Norprogesterone derivatives Nomegestrol acetate + + Promegestone + + Trimegestone + + Spirolactone derivatives Drosperinone + + 19-Nortestosterone derivatives Norethisterone + + Lynestrenol + + Norethinodrel T + Levonorgestrel + + Norgestimate + + 3-keto-Desogestrel + + Gestodene + + Dienogest + + (+) Effective; (T) weakly effective; (j) not effective. Reprinted from Schindler et al61 with permission of the publisher. Estrogenic Androgenic Antiandrogenic Glucocorticoid Antimineralocorticoid + + + j j j j j j T T T + j j + T j + j j + + j + + + j j j j T T ++ + j + + + j j j + + + j j j j j j T j T j j j j j T + j j + j + + + T + + + + T + + + j j j j T + + T + + + + j j j j j j j j + j j j j j j + j j j j j j j + j Copyright * 2008, Elsevier. Menopause, Vol. 22, No. 4, 2015 Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 5 ISSA ET AL between 10 and 20 ng/dL, may blunt a predisposition to hypertension, a protective effect that may be lost in menopause.62 MPA is the most commonly used progestin in studies evaluating the impact of HT on cardiovascular outcomes. It is 17>-hydroxyprogesterone derivative, which is weakly effective as an antiandrogenic agent with no antimineralocorticoid activity.61 The administration of MPA with estrogen has been shown to attenuate estrogen’s augmentation of endotheliumdependent vasodilation.63 In the PEPI trial,64 875 healthy postmenopausal women aged 45 to 64 years were randomly assigned to five groups: placebo; CEE 0.625 mg/day; CEE 0.625 mg/day plus cyclic MPA 10 mg/day for 12 days/month; CEE 0.625 mg/day plus consecutive MPA 2.5 mg/day; or CEE 0.625 mg/day plus cyclic micronized progesterone 200 mg/day for 12 days/month. SBP, which was among the primary outcomes, did not vary between the MPA arm and the micronized progesterone arm. The addition of the oral progestin norethisterone to estrogen has been shown to antagonize the vasodilatory effects of estrogen in postmenopausal women, as measured by the prostacyclin thromboxane quotient,65 a factor that is known to be crucial for the relationship of vasorelaxation to vasoconstriction. A new spironolactone derivative progesterone, drosperinone (DRSP), was found to have antimineralocorticoid and antiandrogenic activities.61 The addition of DRSP 3 mg to oral 17A-E2 1 mg in women with stage 1 hypertension resulted in a mean reduction in clinic BP to j14.1/j7.9 mm Hg with DRSP/E2 and j7.1/j4.3 mm Hg with placebo (P G 0.000 for both SBP and DBP). A similar pattern was noted on 24-hour ambulatory BP (AmBP) monitoring in a subset of women with decrements of j8.5/j4.2 mm Hg with DRSP/E2 versus j1.8/j1.6 mm Hg with placebo (P = 0.002 for SBP and P = 0.07 for DBP vs placebo).66 BP measurements reached their lower limits within 2 months of therapy, and there was no significant difference in potassium levels from baseline or in the incidence of hyperkalemia in the DRSP/E2 group compared with placebo. These results were confirmed in another RCT67 that tested three doses of DRSP combined with oral E2, oral E2 alone, and placebo in 750 postmenopausal women with stage 1 to stage 2 hypertension (mean [SD] age, 57 [6] y). Mean (SD) systolic AmBP (j6.1 [11.2], P G 0.0001) and diastolic AmBP (j3.5 [7.1], P G 0.0001) decreased significantly versus placebo mainly in the DRSP 3 mg/E2 group. Nevertheless, thromboembolic events remain a concern with the use of DRSP, as shown in a recent analysis from the Danish cohort study, where the rate ratio (95% CI) of confirmed venous thromboembolism for users of oral contraceptive pills containing DRSP was 2.1 (1.6-2.8) compared with levonorgestrel as reference.68 Whether these findings are applicable to the lower doses of DRSP/E2 in HT regimens is not known. Dydrogesterone is a retroprogesterone, which seems to be a highly selective progestin with neutral activity in glucocorticoid, androgen, and aldosterone receptors.61 The addition of dydrogesterone to E2 did not affect the serum levels of endothelin (a potent vasoconstrictor) compared with E2 alone in postmenopausal women with more than two risk factors 6 Menopause, Vol. 22, No. 4, 2015 for coronary artery disease.69 Furthermore, in contrast to MPA, dydrogesterone was shown to have a neutral effect on E2induced positive effect on nitric oxide synthase activity and expression in human endothelial cells from the umbilical vein70 and has favorable effects on inflammatory markers71<73 in postmenopausal women. Dydrogesterone (at a dose of 10 mg for 14 d of each 28-d cycle) given sequentially with E2 1 mg was shown to decrease ambulatory SBP by 5 mm Hg after 12 months of treatment, compared with no treatment, in healthy postmenopausal women.74 Similarly, dydrogesterone 10 mg/day given sequentially with oral E2 1 mg caused significant falls in both daytime and nighttime AmBP in 35 mildly to moderately hypertensive postmenopausal women versus no treatment.75 These findings need to be confirmed in larger randomized studies. Furthermore, Honisett et al76 evaluated the effects of micronized progesterone (100 mg daily) for 6 weeks on vascular function and BP in a randomized placebo-controlled trial of 20 healthy postmenopausal women. Micronized progesterone did not affect vascular function (as assessed by flow-mediated dilation of the brachial artery, systemic arterial compliance, and cutaneous vascular reactivity), nor did it change BP. In summary, as progestins differ in their BP effects, studies of the effects of combined HT on BP may be affected by the progestin used. Endogenous progesterone, micronized progesterone, dydrogesterone, and DRSP may have BP-lowering effects through both direct vascular actions and diuretic properties.77 MENOPAUSAL TRANSITION, HT, AND BP Menopausal transition has been associated with changes in BP, and several studies evaluating the impact of HT on BP in postmenopausal women are described herein. The change in BP across menopause was evaluated in a large cross-sectional study (Study on Hypertension Prevalence in Menopause in the Italian Population) of 18,326 Italian women aged 46 to 59 years. SBP and DBP were significantly higher (3.4 and 3.1 mm Hg, respectively) in postmenopausal women than in perimenopausal and premenopausal women at the younger end of the age range even after adjustment for age, body mass index, and other confounding factors.78 The Multi-Ethnic Study of Atherosclerosis included 610 normotensive American postmenopausal women who were followed to assess change in BP and development of incident hypertension during a mean follow-up of 4.8 years (maximum, 6.7 y). One hundred ninety-four women developed incident hypertension. Higher endogenous E2, testosterone, and dehydroepiandrosterone levels and lower sex hormoneYbinding globulin levels were associated with a higher incidence of hypertension and greater longitudinal rise in BP after adjusting for age, race/ethnicity, and lifestyle factors. Adjustment for body mass index eliminated the associations for E2 and testosterone but only attenuated the associations for dehydroepiandrosterone and sex hormoneYbinding globulin. The associations for E2, testosterone, and dehydroepiandrosterone were therefore mostly explained by adiposity, whereas the association for sex hormoneYbinding globulin was independent * 2014 The North American Menopause Society Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE of measures of adiposity, insulin resistance, and systemic inflammation.79 Much of the concern with the impact of HT on BP originates from data that relate oral contraceptives to hypertension in younger women, although the specific hormonal compounds (be it estrogens and progestins) used for HT replacement differ and may not have the same effects on BP. Specifically, ethinyl E2 is commonly used in oral contraceptives and has a very potent effect on hepatic production of angiotensinogen.80 In the literature, there is significant variability in the effect of HT on BP. This inconsistency among studies could be attributable to the different designs, sample sizes, types of HT, and methods used to measure BP; type of menopause (surgical vs natural); and participant characteristics, including phase in the menopausal transition and endogenous hormonal profile. HT in normotensive women Studies evaluating the effect of HT on BP in normotensive postmenopausal women varied in design between case-control studies, prospective studies, and RCTs. In our literature review of case-control and prospective studies, there was variability in the estrogen-progesterone preparations used and in the means of BP measuring (ambulatory vs clinic BP). A neutral or lowering effect of HT on BP was the main outcome of these studies.81<86 Likewise, a review by Mueck and Seeger,87 which summarized comparative studies with 24-hour AmBP measurements in normotensive postmenopausal women from 1997 to 2002, revealed mainly a significant BP-lowering effect of HT. However, this review included studies that were not all randomized with different HT preparations, with predominant use of transdermal E2, which may be more beneficial than oral HT in relation to BP effects.77 Randomized trials In the PEPI trial,64 875 healthy postmenopausal women were randomly assigned to CEE (0.625 mg) alone or in combination with progestin/CEE 0.625 mg (cyclic or continuous MPA, or cyclic micronized progesterone) versus placebo for 3 years. No significant difference in office SBP, a primary outcome, was seen between treatment groups and placebo. The Women’s Health Initiative (WHI) consisted of two parallel clinical trials and an observational study designed to test the effects of postmenopausal HT, diet modification, and calcium and vitamin D supplements on heart disease, fractures, breast cancer, and colorectal cancer. In one trial, women received oral CEE 0.625 mg with MPA 2.5 mg versus placebo, whereas in the other trial, they received CEE alone 0.625 mg versus placebo. The method for measuring BP was not specified. In the HT combination arm, SBP was 1.5 mm Hg higher at 2 years (P value not available), whereas DBP remained unchanged.88 In the estrogen-only arm, SBP increased by 1.1 mm Hg (P = 0.003) at 1 year compared with placebo, whereas DBP did not change.89 The increased risk of cardiovascular and cerebrovascular events observed in this trial had a major impact on HT use by postmenopausal women, but whether this was directly related to an increase in BP is still unknown be- cause this variable was not measured as a primary outcome in the trial. HT (oral E2 2 mg with or without norethisterone 1 mg, according to hysterectomy status) had no effect on office SBP and DBP, which were measured as primary outcomes in the Danish Osteoporosis Prevention Trial, an open-label trial evaluating 1,006 postmenopausal women.90 Similarly, there was no difference in office BP between the HT group (unopposed oral 17A-E2 1 mg) and the placebo group at 2 years in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), which evaluated 222 healthy postmenopausal women with the primary endpoint being BP and with the overall rate of progression of subclinical atherosclerosis measured by carotid artery intima-media thickness.91 Other smaller randomized controlled studies using AmBP measurement as primary outcome revealed similar neutral effects of oral HT on BP.41,92 For studies that specified BP as primary outcome in normotensive women on oral HT, the risk of bias was mostly concentrated between low risk and unclear risk (see Appendix II-B.1, Supplemental Digital Content 3, http://links.lww.com/MENO/A109). It was low for most bias criteria in EPAT and the PEPI trial,64,92 unclear in one study,41 and ranged from low to high in the studies by Vestergaard et al90 and SLrensen et al.92 Transdermal E2 may represent an attractive and safer option for postmenopausal women given its bypass of first hepatic pass, which is associated with increased triglycerides, C-reactive protein, and activation of coagulation.93 Seely et al43 evaluated the effect of transdermal E2 (two 0.1-mg patches twice a week), with or without progesterone (intravaginal micronized progesterone 300 mg/d added for 2 weeks), on BP in 15 healthy postmenopausal women. The duration of use was 8 weeks for transdermal E2 and 10 weeks for E2 and progesterone. Nocturnal SBP, DBP, and mean BP decreased significantly (P G 0.02) versus placebo. The high doses used in this study aimed at achieving levels similar to those seen in premenopausal women. The E2 levels achieved were similar to those of the early to middle follicular phases, and progesterone levels were compatible with those seen in the luteal phase. The addition of progesterone did not lead to any further change in day or night BP beyond that seen with E2 alone. Similarly, 12 postmenopausal women were randomly assigned to CEE 0.625 mg, transdermal E2 (two 0.1-mg patches twice a week, 200 Kg/d), or placebo in a single-blind cross-over design. Although oral CEE did not result in a change in BP, transdermal E2 resulted in a decrease in DBP compared with placebo.94 This lowering of DBP was also evident in another randomized study by Ichikawa et al45 in 22 postmenopausal women. The three transdermal E2 studies specified BP as a primary outcome, but they had a small number of participants (N = 24-30) and a wide range of risk-of-bias assessment (see Appendix II-B.1, Supplemental Digital Content 3, http://links.lww.com/MENO/A109). It ranged from low risk to unclear risk in two studies43,94 and from low risk to high risk in the third study.45 In summary, RCTs evaluating the effect of various oral HT preparations on BP as a primary outcome, such as PEPI trial (CEE/MPA/micronized progesterone), Danish Osteoporosis Menopause, Vol. 22, No. 4, 2015 Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 7 ISSA ET AL Prevention Trial (17A-E2/norethisterone), EPAT (17A-E2), and smaller trials by Seely et al43 (CEE/micronized progesterone) and SLrensen et al92 (17A-E2/norethisterone), consistently revealed a neutral effect. Conversely, the WHI showed an increase in BP in the CEE/MPA and CEE-only arms; however, BP was not specified as a primary outcome. An essentially beneficial effect of transdermal E2 preparations on BP was noted in smaller trials,43,45,94 where BP was a specified primary outcome, but the risk of bias was suboptimal. HT in hypertensive women HT use in women with hypertension represents another challenge in relation to controversial data and the lack of randomized studies with BP as the primary endpoint. Instead, data are available from cross-sectional studies. One of the largest cross-sectional studies, the Rancho Bernardo Study, consisted of two componentsVa cross-sectional study of 1,044 participants and a 10-year prospective follow-up of 443 womenVthat evaluated the association between postmenopausal oral estrogen therapy and BP, renal function, and proteinuria.95 In the cross-sectional study, DBP was highest in never users (age-adjusted P = 0.07; multivariate-adjusted P = 0.01), but SBP did not differ by postmenopausal estrogen status after adjustment for covariates (age, weight, smoking, and hypercholesterolemia). On prospective analysis, SBP did not differ in the past and current estrogen user groups, but never users exhibited an age-adjusted increase in SBP across time (mean increase, 6 mm Hg; P = 0.02), and the difference persisted after multivariate adjustment. DBP of never users showed no significant age-adjusted change (P = 0.1), whereas past users (age-adjusted P G 0.0001) and current users (ageadjusted P G 0.0001) showed similar declines in their DBP. Other observational studies showed either a neutral84,96 or a beneficial97,98 effect of HT on BP. Randomized trials In a randomized trial by Kaya et al75 evaluating 66 postmenopausal women, AmBP, a primary outcome, fell significantly in the group of women treated with HT (micronized 17A-E2 1 mg/d sequentially combined with dydrogesterone 10 mg/d for 14 d of each 28-d cycle). Other randomized trials showed mainly no effect of varying HT regimens on BP, which was a primary outcome in all of these studies.29,91,99,100 The effect of HT (CEE and MPA) on the secondary prevention of coronary heart disease (CHD) was evaluated in HERS, a randomized placebo-controlled trial where 39% of women were hypertensive.101 For 4.2 years, office SBP increased by 1 mm Hg (P G 0.0001), whereas office DBP remained unchanged in HT-treated women (CEE 0.625 mg and MPA 2.5 mg) compared with placebo. Similarly, mean pulse pressure increased by 2 mm Hg (P = 0.04) in treated women versus placebo; however, BP and pulse pressure were not primary or secondary outcomes.102 In contrast, office DBP decreased significantly in the HT groups compared with the control group in the Postmenopausal Hormone Replacement Against Atherosclerosis (PHOREA) trial, which was designed to determine the effect of HT (oral 17A-E2 1 mg with 8 Menopause, Vol. 22, No. 4, 2015 standard-dose cyclic gestodene [oral gestodene 0.025 mg on days 17-28 of each 4-wk cycle] or oral 17A-E2 1 mg with lowdose gestodene [0.025-mg addition in each third cycle only]) or no treatment on the progression of atherosclerosis. Again, BP was not a primary outcome.103 It has been suggested that some women may paradoxically manifest an increase in BP in response to oral estrogen therapy. However, the only study to support such observation is HERS, and this may be explained by the fact that 40% of women were hypertensive at study entry. However, BP was not measured as primary endpoint in HERS. For studies that specified BP as primary outcome in hypertensive women on oral HT, the risk-of-bias assessment spanned all ranges (see Appendix II-B.1, Supplemental Digital Content 3, http://links.lww.com/MENO/A109). It was low risk for most bias criteria in EPAT,91 mixed in three studies (unclear risk to low risk99 and low risk to high risk29,75), and mainly unclear in one study.100 The risk of bias in the other four large trials that did not have BP as primary outcome was low in HERS101 and spanned from low to high in the WHI 2002, WHI 2004, and PHOREA trial.88,89,103 The effect of transdermal estrogen on BP as a primary outcome has also been investigated in hypertensive women; unfortunately, the studies were small (N = 24-3029,104). They showed a neutral effect or a decrease in BP and differed in their pattern of decrease (systolic vs diastolic, daytime vs nighttime).29,104 The risk of bias was low to unclear in one29 and low to high in the other104 (see Appendix II-B.1, Supplemental Digital Content 3, http://links.lww.com/MENO/A109). In summary, four29,91,99,100 of five small RCTs evaluating the impact of oral HT on BP as a primary outcome in hypertensive women revealed a neutral effect on BP, and one study75 that used AmBP revealed a beneficial effect. Conversely, two large RCTsVHERS (CEE/MPA) and PHOREA trial (17A-E2/gestodene)Vthat did not have BP as a specified primary outcome revealed opposing results. Similar to findings in normotensive women, a beneficial effect of transdermal E2 preparations on BP was noted in two small trials in hypertensive women, where BP was a specified primary outcome, but their associated risk of bias was suboptimal,29,104 thus the need for large randomized trials assessing the impact of transdermal and oral estrogen on BP in hypertensive women. SERMS, TIBOLONE, AND BP SERMs, or tissue-specific estrogens, act either as agonists or as antagonists on the ER, depending on the target tissue where they act. This family of synthetic compounds is designed to preserve the beneficial effects of estrogens on menopausal symptoms and bone, incur protection against cardiovascular diseases, and exert no undesired effects on reproductive organs. However, the search for the ideal SERM is still ongoing, as such compound remains elusive.105<108 Raloxifene Raloxifene is a second-generation SERM and the only one approved by the Food and Drug Administration for prevention * 2014 The North American Menopause Society Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE and treatment of postmenopausal osteoporosis and for reduction of the risk of invasive breast cancer in high-risk women. Raloxifene was shown to reduce the risk of vertebral fractures, was associated with increased risks of venous thromboembolism and fatal stroke (but not stroke), and did not display any other adverse effect on cardiovascular diseases.109,110 In a study by Morgante et al,111 raloxifene 60 mg/day did not affect the renin-angiotensin system or BP in 20 normotensive postmenopausal women and 20 hypertensive postmenopausal women (controlled with antihypertensive medications for 6 mo; mean age, 57 y). Sumino et al112 investigated the effects of raloxifene on components of the RAAS in 23 hypertensive and 18 normotensive postmenopausal women (mean [SD] age, 64.7 [7.3] y) with osteoporosis or osteopenia, who were divided into four groups. Eleven hypertensive and eight normotensive women received raloxifene (60 mg/d) for 6 months, and 12 hypertensive and 10 normotensive women did not receive raloxifene for 6 months. BP and all parameters of interest remained unchanged. Finally, administration of raloxifene 60 mg/day did not affect the 24-hour AmBP measurement in a 4-month placebo-controlled trial of 32 healthy postmenopausal women with osteopenia.113 The Multiple Outcomes of Raloxifene Evaluation trial109 was designed to determine the effect of raloxifene on bone mineral density and vertebral fractures. Hypertension, captured as an adverse event, occurred in 9% in the placebo group compared with 6.9% in the raloxifene 60 mg group (P = 0.01). The Raloxifene Use for The Heart (RUTH) trial110 studied 10,101 postmenopausal women randomized to raloxifene 60 mg versus placebo for 5.6 years, and 78% of the participants were hypertensive. Approximately half of the women had CHD at baseline; the other half were enrolled based on CHD risk score, but BP was not a specified primary outcome. The primary objective of the RUTH trial was to determine the effects of raloxifene versus placebo on the incidence of coronary events and invasive breast cancer. No significant differences in SBP or DBP were observed between treatment groups,114 but raloxifene use was associated with increased risks of fatal stroke and venous thromboembolism. The incidence of fatal stroke did not differ among subgroups, except for an observed higher incidence of stroke associated with raloxifene use among current smokers. The increase in the incidence of fatal stroke in the RUTH trial remains a major concern in high-risk patients, and the lack of data relating therapy to BP further increases this concern. Bazedoxifene Bazedoxifene is a novel third-generation SERM that received European Medicines Agency approval for treatment of postmenopausal osteoporosis in women at high risk for fractures. BP was neither a measured endpoint nor a reported adverse event in the studies evaluating bazedoxifene.115,116 Lasofoxifene Lasofoxifene is a third-generation SERM that received European Medicines Agency approval for treatment of postmenopausal osteoporosis in women at high risk for fractures. The Postmenopausal Evaluation and Risk Reduction with Lasofoxifene trial was a 5-year RCT comparing the effects of lasofoxifene 0.25 or 0.5 mg with those of placebo in postmenopausal women with osteoporosis. BP changes were not reported.117 Tibolone Tibolone, a selective tissue estrogenic activity regulator, has been widely used in Europe as a substitute for HT during the menopausal transition because of its efficacy in relieving menopausal symptoms and its beneficial effect on bone mineral density, compared with placebo.106 But the increased risk of stroke associated with its use remains a major concern preventing its approval in many countries. In small studies of normotensive postmenopausal women where BP was a primary outcome, tibolone had a neutral118,119 or lowering120 effect on BP. The significant improvement in BP among younger postmenopausal women in the study by Vassalle et al who received tibolone may be explained by the fact that they had menopausal symptoms, the relief of which may result in a concomitant decrease in BP.120 Lloyd et al121 studied the effect of tibolone 2.5 mg on BP in 29 hypertensive postmenopausal women for 6 months using a 2:1 randomization protocol design. The mean (SD) SBP declined by 5.30% (2.87%) versus 4.94% (3.37%), whereas DBP declined by 5.38% (2.65%) versus 0.85% (3.69%) with tibolone and placebo, respectively, but not significantly. In the Long-Term Intervention on Fractures with Tibolone trial on 4,538 postmenopausal women, BP measurements were not detailed.122 In the Osteoporosis Prevention and Arterial effects of tiboLone study123 that included 866 healthy postmenopausal women, BP, which was not a specified outcome, was unchanged and did not differ between the three groups. It decreased by j0.5% in the tibolone (2.5 mg) group and by j0.7% in the CEE 0.625 mg/MPA2.5 mg group (placebo, P = not significant). Therefore, none of the trialsVwhich were mostly conducted in older postmenopausal women, including one trial conducted in hypertensive womenVrevealed any increments in BP with tibolone. Limitations of these studies include their relatively short duration, small sample size (with the exception of the Long-Term Intervention on Fractures with Tibolone trial and the Osteoporosis Prevention and Arterial effects of tiboLone study, which did not measure BP as a primary outcome), and, thus, their low power to detect subtle BP changes, if any. The risk-of-bias assessment for the 12 randomized trials that used SERMs ranged between low risk and unclear risk for most trials. Only five studies specified BP as a primary outcome (two with raloxifene112,113 and three with tibolone118,119,121), with mixed results on risk-of-bias criteria for both raloxifene and tibolone (see Appendix II-B.2, Supplemental Digital Content 3, http://links.lww.com/MENO/A109). In summary, data on the effect of SERMs and tibolone on BP are rather limited and restricted to raloxifene and tibolone. The effect was essentially neutral, regardless of trial size, whether BP was a specified primary outcome, and whether Menopause, Vol. 22, No. 4, 2015 Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 9 ISSA ET AL studies evaluated normotensive112,113,118,119 or hypertensive121 women. The increased risk of fatal stroke in the RUTH trial, although a concern, was not documented to be related to BP. OTHER HORMONAL PREPARATIONS Other hormonal preparations, such as transdermal testosterone and phytoestrogens, have been studied to some extent in postmenopausal women, but their discussion is beyond the scope of this review. The Food and Drug Administration has not approved any androgen formulation for hypoactive sexual desire disorder pending long-term safety data (http:// www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4082B1_ 02_B-FDA-Intrinsa-Medical-Review.pdf). The regulatory agencies in Europe have approved a testosterone patch (Intrinsa 300 Kg) for women who had had surgical menopause, but it is no longer being manufactured as per Lexi-Comp (accessed May 2014). CONCLUSIONS Hypertension is a major risk factor for cardiovascular disease, and menopause by itself seems to be a risk factor for an increase in BP. The effect of estrogen, with or without progesterone, has been studied in postmenopausal women through observational and randomized trials. These studies varied in design, population, sample size, duration, and formulations used, and on whether BP was a specified primary outcome. The data for oral preparations were most robust in normotensive women (where BP was specified as a primary outcome and sample size was large) but had major limitations in all other subgroups. In normotensive women, the effect of oral estrogen therapy on BP was neutral. These findings can be accepted with confidence in view of the fact that they were consistent across studies that had specified BP as a primary outcome, including two major large trials that had a low risk of bias (namely, PEPI trial and EPAT). The effect of transdermal therapy on BP was beneficial in normotensive women, whereas the effect of oral and transdermal therapy was mostly neutral in hypertensive women. Progestin formulations differed in BP effects among studies, but micronized progesterone, dydrogesterone, and DRSP seemed to have beneficial outcomes. However, the abovementioned assessments are to be interpreted with caution in view of the characteristics of the studies currently available (namely, low number of relevant studies, small sample size, and associated risk-of-bias limitations). Results from the ongoing Early versus Late Intervention Trial with Estradiol,124 a trial whose main aim is to examine the effects of oral 17A-E2 on the progression of early (subclinical) atherosclerosis and cognitive decline in healthy postmenopausal women, are estimated to be released in spring 2014. The Kronos Early Estrogen Prevention Study125 exam˙ ined the effects of estrogen (CEE 0.45 mg or transdermal 17AE2 50 Hg/day) each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months on the development of atherosclerosis in postmenopausal women when HT was initiated within 3 years of the menopausal transition. No 10 Menopause, Vol. 22, No. 4, 2015 changes in BP, measured as a secondary outcome were observed in the oral CEE or transdermal E2 arms.126 Societies and medical organizations restrict recommendations for the use of HT for the treatment of vasomotor symptoms of menopause127<132 and recommend against the use of HT for the prevention of chronic conditions, including coronary artery disease and stroke. Despite the potential effects of HT on BP and the controversial results reported, many guidelines do not include specific recommendations concerning the use of HT in women with hypertension or the clinical follow-up of BP in women initiating HT. The American College of Obstetrician and Gynecologists underscores that several variables may alter the BP effects of HT and estrogen therapy, including the choice of progestin, and state that, in contrast to the vasoconstrictive effect of MPA, natural progesterone has been shown to have either a neutral or a slightly salutary effect on BP.133 The Royal Australian and New Zealand College of Obstetricians and Gynecologists recommended avoidance or discontinuation of HT in women with uncontrolled hypertension.134 The recently published Eighth Joint National Committee did not address the effect of HT on BP or the effect of menopause on BP.135 There are some limitations to our review. It does not represent a systematic review, and the search started in 2000. However, the search was quite extensive and was updated to November 2013, and its methodology is similar to that of systematic reviews as detailed in Appendix I (Supplemental Digital Content 1, http://links.lww.com/MENO/A107), albeit limited to one major database, namely, MEDLINE. Major trials before 2000 were also included. In comparison with previous reviews, advantages include the fact that it covers pathophysiologic and clinical studies, covers both HT and SERMs, and addresses relevant parameters to help assess the strength of the data available and to achieve confidence in the conclusions derived. Namely, it identifies whether BP was specified as a primary outcome, systematically assesses the risk of bias in each study using an accepted tool, separates large from small trials, and allows the identification of knowledge gap and research needs. The body of evidence today, including RCTs, does not support a deleterious effect of HT on BP, either in normotensive or in hypertensive women. Transdermal estrogens and natural progestational agents seem to have a beneficial effect. However, the currently available studies, except for those that studied the impact of oral therapy on normotensive women, have several limitations (outlined previously), including the fact that most large trials did not assess BP as a predefined outcomeVa shortcoming that needs to be addressed in future trials. In the interim, decisions regarding the use of HT in postmenopausal women with vasomotor symptoms need to be tailored, taking into account a woman’s individual risk profile and age and the evidence presented herein, with careful monitoring of BP when starting such therapy. Acknowledgments: We would like to thank Ms Aida Farha (medical information specialist, Saab Medical Library, American University * 2014 The North American Menopause Society Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE of Beirut) for her advice and assistance in designing comprehensive and complex searches of various medical literature resources and for provision of select articles. REFERENCES 1. Centers for Disease Control and Prevention Website. High blood pressure facts. Available at: http://www.cdc.gov/bloodpressure/facts.htm. Accessed December 8, 2013. 2. Sutton-Tyrrell K, Zhao X, Santoro N, et al. Reproductive hormones and obesity: 9 years of observation from the Study of Women’s Health Across the Nation. Am J Epidemiol 2010;171:1203-1213. 3. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. West Sussex, England: John Wiley & Sons Ltd; 2009. Available at: http://www. cochrane-handbook.org. Accessed June 27, 2014. 4. Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA. Estrogenic hormone action in the heart: regulatory network and function. Cardiovasc Res 2002;53:709-719. 5. Xing D, Nozell S, Chen YF, Hage F, Oparil S. Estrogen and mechanisms of vascular protection. Arterioscler Thromb Vasc Biol 2009; 29:289-295. 6. Barkhem T, Nilsson S, Gustafsson JA. Molecular mechanisms, physiological consequences and pharmacological implications of estrogen receptor action. Am J Pharmacogenomics 2004;4:19-28. 7. Prossnitz ER, Barton M. The G-proteinYcoupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 2011;7:715-726. 8. Yang XP, Reckelhoff JF. Estrogen, hormonal replacement therapy and cardiovascular disease. Curr Opin Nephrol Hypertens 2011;20:133-138. 9. Simoncini T. Mechanisms of action of estrogen receptors in vascular cells: relevance for menopause and aging. Climacteric 2009; 12(suppl 1):6-11. 10. Simoncini T, Genazzani AR. Non-genomic actions of sex steroid hormones. Eur J Endocrinol 2003;148:281-292. 11. Zhu Y, Bian Z, Lu P, et al. Abnormal vascular function and hypertension in mice deficient in estrogen receptor A. Science 2002;295: 505-508. 12. Ogawa S, Emi M, Shiraki M, Hosoi T, Ouchi Y, Inoue S. Association of estrogen receptor A (ESR2) gene polymorphism with blood pressure. J Hum Genet 2000;45:327-330. 13. Peter I, Shearman AM, Zucker DR, et al. Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study. J Hypertens 2005;23:2193-2200. 14. Lindsey SH, Cohen JA, Brosnihan KB, Gallagher PE, Chappell MC. Chronic treatment with the G proteinYcoupled receptor 30 agonist G-1 decreases blood pressure in ovariectomized mRen2.Lewis rats. Endocrinology 2009;150:3753-3758. 15. Meyer MR, Amann K, Field AS, Hu C, Hathaway HJ, Kanagy NL. Deletion of G proteinYcoupled estrogen receptor increases endothelial vasoconstriction. Hypertension 2012;59:507-512. 16. O’Dowd BF, Nqyen T, Marchese A, et al. Discovery of three novel G-proteinYcoupled receptor genes. Genomics 1998;47:310-313. 17. Kublickiene K, Svedas E, Landgren BM, et al. Small artery endothelial dysfunction in postmenopausal women: in vitro function, morphology, and modification by estrogen and selective estrogen receptor modulators. J Clin Endocrinol Metab 2005;90:6113-6122. 18. Nuzzo A, Rossi R, Modena MG. Endothelial dysfunction in postmenopausal women and hypertension. Womens Health 2007;3:515-518. 19. Rossi R, Chiurlia E, Nuzzo A, Cioni E, Origliani G, Modena MG. Flow mediated vasodilatation and the risk of developing hypertension in healthy postmenopausal women. J Am Coll Cardiol 2004;44:1636-1640. 20. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994;24:471-476. 21. Majmudar NG, Robson SC, Ford GA. Effects of the menopause, gender, and estrogen replacement therapy on vascular nitric oxide activity. J Clin Endocrinol Metab 2000;85:1577-1583. 22. Smolders RG, van der Mooren MJ, Kenemans P, van der Linden PW, Stehouwer CD, Sipkema P. 17A Estradiol induces a rapid, endotheliumdependent, sex-specific vasodilatation in spontaneous constricted rat arterioles. Am J Obstet Gynecol 2002;187:375-381. 23. Ouyang P, Michos ED, Karas RH. Hormone replacement therapy and the cardiovascular system: lessons learned and unanswered questions. J Am Coll Cardiol 2006;47:1741-1753. 24. Han G, Ma H, Chintala R, et al. Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling. Am J Physiol Heart Circ Physiol 2007;293:H314-H321. 25. Nakajima T, Kitazawa T, Hamada E, Hazama H, Omata M, Kurachi Y. 17A-Estradiol inhibits the voltage-dependent L-type Ca2+ currents in aortic smooth muscle cells. Eur J Pharmacol 1995;294:625-635. 26. Lima SM, Aldrighi JM, Consolim-Colombo FM, et al. Acute administration of 17A-estradiol improves endothelium-dependent vasodilation in postmenopausal women. Maturitas 2005;50:266-274. 27. Kublickiene K, Fu XD, Svedas E, Landgren BM, Genazzani AR, Simoncini T. Effects in postmenopausal women of estradiol and MPA alone and combined on resistance artery function and endothelial morphology and movement. J Clin Endocrinol Metab 2008;93:1874-1883. 28. Bui MN, Arai AE, Hathaway L, Waclawiw MA, Csako G, Cannon RO III. Effect of hormone replacement therapy on carotid arterial compliance in healthy postmenopausal women. Am J Cardiol 2002;90:82-85. 29. Sumino H, Ichikawa S, Kasama S, et al. Different effects of oral conjugated estrogen and transdermal estradiol on arterial stiffness and vascular inflammatory markers in postmenopausal women. Atherosclerosis 2006;189:436-442. 30. Ashraf M, Vongpanatasin W. Estrogen and hypertension. Curr Hypertens Rep 2006;8:368-376. 31. Farag NH, Mahata M, Ziegler MG, O’Connor DT, Mills PJ. Hormone replacement therapy increases renal kallikrein excretion in healthy postmenopausal women. Life Sci 2003;72:1279-1288. 32. Levin ER, Gardner DG, Samson WK. Mechanisms of disease: natriuretic peptides. N Engl J Med 1998;339:321-327. 33. Belo NO, Sairam MR, Dos Reis AM. Impairment of the natriuretic peptide system in follitropin receptor knockout mice and reversal by estradiol: implications for obesity-associated hypertension in menopause. Endocrinology 2008;149:1399-1406. 34. Belo NO, Silva-Barra J, Carnio EC, Antunes-Rodrigues J, Gutkowska J, Dos Reis AM. Involvement of atrial natriuretic peptide in blood pressure reduction induced by estradiol in spontaneously hypertensive rats. Regul Pept 2004;117:53-60. 35. Lee DL, Sturgis LC, Labazi H, et al. Angiotensin II hypertension is attenuated in interleukin-6 knockout mice. Am J Physiol Heart Circ Physiol 2006;290:H935-H940. 36. LaMarca B, Speed J, Fournier L, et al. Hypertension in response to chronic reductions in uterine perfusion in pregnant rats: effect of tumor necrosis factor-> blockade. Hypertension 2008;52:1161-1167. 37. Georgiadou P, Sbarouni E. Effect of hormone replacement therapy on inflammatory biomarkers. Adv Clin Chem 2009;47:59-93. 38. Gao H, Liang M, Bergdahl A, et al. Estrogen attenuates vascular expression of inflammation associated genes and adhesion of monocytes to endothelial cells. Inflamm Res 2006;55:349-353. 39. Schunkert H, Danser AH, Hense HW, Derkx FH, Kürzinger S, Riegger GA. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation 1997;95:39-45. 40. Umeda M, Ichikawa S, Kanda T, Sumino H, Kobayashi I. Hormone replacement therapy increases plasma level of angiotensin II in postmenopausal hypertensive women. Am J Hypertens 2001;14:206-211. 41. Seely EW, Brosnihan KB, Jeunemaitre X, et al. Effects of conjugated oestrogen and droloxifene on the renin-angiotensin system, BP and renal blood flow in postmenopausal women. Clin Endocrinol 2004; 60:315-321. 42. Proudler AJ, Ahmed AI, Crook D, Fogelman I, Rymer JM, Stevenson JC. Replacement therapy and serum angiotensin-converting-enzyme activity in postmenopausal women. Lancet 1995;346:89-90. 43. Seely E, Walsh B, Gerhard M, Williams GH. Estradiol with or without progesterone and ambulatory BP in postmenopausal women. Hypertension 1999;33:1190-1194. 44. Ichikawa J, Sumino H, Ichikawa S, Ozaki M. Different effects of transdermal and oral hormone replacement therapy on the reninangiotensin system, plasma bradykinin level, and BP of normotensive postmenopausal women. Am J Hypertens 2006;19:744-749. 45. Ichikawa A, Sumino H, Ogawa T, Ichikawa S, Nitta K. Effects of longterm transdermal hormone replacement therapy on the renin-angiotensinaldosterone system, plasma bradykinin levels and BP in normotensive postmenopausal women. Geriatr Gerontol Int 2008;8:259-264. Menopause, Vol. 22, No. 4, 2015 Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 11 ISSA ET AL 46. Hassager C, Riis BJ, StrLm V, Guyene TT, Christiansen C. The longterm effect of oral and percutaneous estradiol on plasma renin substrate and blood pressure. Circulation 1987;76:753-758. 47. Harrison-Bernard LM, Schulman IH, Raij L. Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension 2003;42:1157-1163. 48. Oestreicher EM, Guo C, Seely EW, et al. Estradiol increases proteinuria and angiotensin II type 1 receptor in kidneys of rats receiving L-NAME and angiotensin II. Kidney Int 2006;70:1759-1768. 49. Takeda-Matsubara Y, Nakagami H, Iwai M, et al. Estrogen activates phosphatases and antagonizes growth-promoting effect of angiotensin II. Hypertension 2002;39:41-45. 50. Garcı́a MP, Giménez J, Serna M, et al. Effect of estrogen and angiotensinconverting enzyme inhibitor on vascular remodeling in ovariectomized spontaneously hypertensive rats. Menopause 2006;13:397-403. 51. Sumino H, Ichikawa S, Miya Y, Sakamaki T, Kurabayashi M. Angiotensin II plays an important role in maintaining blood pressure in postmenopausal women receiving hormone replacement therapy. Am J Hypertens 2005;18:1340-1346. 52. Mirza FS, Ong P, Collins P, et al. Effects of estradiol and the angiotensin II receptor blocker irbesartan on vascular function in postmenopausal women. Menopause 2008;15:44-50. 53. Yanes L, Reckelhoff J. Postmenopausal hypertension. Am J Hypertens 2011;7:740-749. 54. Rahmouni K, Correia ML, Haynes WG, Mark AL. Obesity-associated hypertension: new insights into mechanisms. Hypertension 2005;45:9-14. 55. Hall JE, da Silva AA, do Carmo JM, et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. J Biol Chem 2010;285:17271-17276. 56. Haynes WG, Morgan DA, Djalali A, Sivitz WI, Mark AL. Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension 1999;33:542-547. 57. Rapelli A. Hypertension and obesity in menopause. J Hypertens 2002; 20:S26-S28. 58. Steiner M, Dunn E, Born L. Hormones and mood: from menarche to menopause and beyond. J Affect Disord 2003;74:67-83. 59. Lambert E, Dawood T, Straznicky N, et al. Association between the sympathetic firing pattern and anxiety level in patients with the metabolic syndrome and elevated blood pressure. J Hypertens 2010;28:543-550. 60. Mueck A, Seeger H. Progestogens and target tissues: vascular systems. Maturitas 2009;62:356-361. 61. Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas 2008;61:171-180. 62. Szmuilowicz ED, Adler GK, Ricchiuti V, Hopkins PN, Seely EW. Relationships between endogenous sex hormone concentrations and vascular function in postmenopausal women. J Clin Endocrinol Metab 2007;92:4738-4741. 63. Kawano H, Motoyama T, Hirai N, et al. Effect of medroxyprogesterone acetate plus estradiol on endothelium-dependent vasodilation in postmenopausal women. Am J Cardiol 2001;87:238-240. 64. The Writing Group of the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208. 65. Seeger H, Mueck AO, Teichmann AT, Lippert TH. Effect of sequential estrogen/progestin treatment on biochemical vasoactive markers in postmenopausal women comparing oral and transdermal application. Clin Exp Obstet Gynecol 2000;27:17-20. 66. White WB, Pitt B, Preston RA, Hanes V. Antihypertensive effects of drospirenone with 17A-estradiol, a novel hormone treatment in postmenopausal women with stage 1 hypertension. Circulation 2005;112:1979-1984. 67. White WB, Hanes V, Pitt B, Chauhan V. Effects of a new hormone therapy, drospirenone and 17-A-estradiol, in postmenopausal women with hypertension. Hypertension 2006;48:246-253. 68. Lidegaard K, Nielsen LH, Skovlund CW, Skjeldestad FE, LLkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011;343:d6423. 69. Gambacciani M, Monteleone P, Vitale C, et al. Dydrogesterone does not reverse the effects of estradiol on endothelium-dependant vasodilation in postmenopausal women: a randomised clinical trial. Maturitas 2002;43:117-123. 70. Simoncini T, Caruso A, Giretti MS, et al. Effects of dydrogesterone and of its stable metabolite, 20-adihydrodydrogesterone, on nitric oxide 12 Menopause, Vol. 22, No. 4, 2015 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. synthesis in human endothelial cells. Fertil Steril 2006;86(suppl 4): 1235-1242. Kwok S, Charlton-Menys V, Pemberton P, McElduff P, Durrington PN. Effects of dydrogesterone and norethisterone, in combination with oestradiol, on lipoproteins and inflammatory markers in postmenopausal women. Maturitas 2006;53:439-446. Crook D, Godsland IF, Hull J, Stevenson JC. Hormone replacement therapy with dydrogesterone and 17A-oestradiol: effects on serum lipoproteins and glucose tolerance during 24 month follow up. Br J Obstet Gynaecol 1997;104:298-304. Gaspard UJ, Wery OJ, Scheen AJ, Jaminet C, Lefebvre PJ. Long-term effects of oral estradiol and dydrogesterone on carbohydrate metabolism in postmenopausal women. Climacteric 1999;2:93-100. Kaya C, Cengiz SD, Cengiz B, Akgun G. Long-term effects of low-dose 17A-estradiol plus dydrogesterone on 24-h ambulatory blood pressure in healthy postmenopausal women: a 1-year randomized, prospective study. Gynecol Endocrinol 2007;23(suppl 1):124-129. Kaya C, Din0er Cengiz S, Cengiz B, Akgün G. The long-term effects of low-dose 17A-estradiol and dydrogesterone hormone replacement therapy on 24-h ambulatory blood pressure in hypertensive postmenopausal women: a 1-year randomized, prospective study. Climacteric 2006;9:437-445. Honisett SY, Pang B, Stojanovska L, Sudhir K, Komesaroff PA. Progesterone does not influence vascular function in postmenopausal women. J Hypertens 2003;21:1145-1149. L’hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safer postmenopausal HT? A review. Maturitas 2008;60:185-201. Zanchetti A, Facchetti R, Cesana GC, et al. Menopause-related BP increase and its relationship to age and body mass index: the SIMONA epidemiological study. J Hypertens 2005;23:2269-2276. Wang L, Szklo M, Folsom AR, Cook NR, Gapstur SM, Ouyang P. Endogenous sex hormones, blood pressure change, and risk of hypertension in postmenopausal women: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2012;224:228-234. Boldo A, White W. Blood pressure effects of the oral contraceptive and postmenopausal hormone therapies. Endocrinol Metab Clin North Am 2011;40:419-432. Christ M, Seyffart K, Tillmann HC, Wehling M. Hormone replacement in postmenopausal women: impact of progestogens on autonomic tone and BP regulation. Menopause 2002;9:127-136. Prelevic GM, Kwong P, Byrne DJ, Jagroop IA, Ginsburg J, Mikhailidis DP. A cross-sectional study of the effects of hormone replacement therapy on the cardiovascular disease risk profile in healthy postmenopausal women. Fertil Steril 2002;77:945-951. Higashi Y, Sanada M, Sasaki S, et al. Effect of estrogen replacement therapy on endothelial function in peripheral resistance arteries in normotensive and hypertensive postmenopausal women. Hypertension 2001; 37:651-657. Sumino H, Ichikawa S, Kumakura H, et al. Effects of hormone replacement therapy on office and ambulatory blood pressure in Japanese hypertensive postmenopausal women. Hypertens Res 2003;26:369-376. Scuteri A, Bos AJ, Brant LJ, Talbot L, Lakatta EG, Fleg JL. Hormone replacement therapy and longitudinal changes in BP in postmenopausal women. Ann Intern Med 2001;135:229-238. Butkevich A, Abraham C, Phillips RA. Hormone replacement therapy and 24-hour BP profile of postmenopausal women. Am J Hypertens 2000;13:1039. Mueck A, Seeger H. Effect of hormone therapy on BP in normotensive and hypertensive postmenopausal women. Maturitas 2004;49:189-203. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333. Anderson GL, Limacher M, Assaf AR, et al. Effects of CEE in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712. Vestergaard P, Hermann AP, Stilgren L, et al. Effects of 5 years of HT on menopausal symptoms and blood pressureVa randomised controlled study. Maturitas 2003;46:123-132. Steiner AZ, Hodis HN, Lobo RA, Shoupe D, Xiang M, Mack WJ. Postmenopausal oral estrogen therapy and blood pressure in normotensive and hypertensive subjects: the Estrogen in the Prevention of Atherosclerosis Trial. Menopause 2005;12:728-733. * 2014 The North American Menopause Society Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE 92. SLrensen MB, Rasmussen V, Jensen G, Ottesen B. Temporal changes in clinic and ambulatory BP during cyclic post-menopausal hormone replacement therapy. J Hypertens 2000;18:1387-1391. 93. Modena MG, Sismondi P, Mueck AO, et al. New evidence regarding hormone replacement therapies is urgently required. Transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits. Maturitas 2005;52:1-10. 94. Vongpatanasin W, Tuncel M, Mansour Y, Arbique D, Victor RG. Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation 2001;103:2903-2908. 95. Fung MM, Poddar S, Bettencourt R, Jassal SK, Barrett-Connor E. A cross-sectional and 10-year prospective study of postmenopausal estrogen therapy and blood pressure, renal function, and albuminuria: the Rancho Bernardo Study. Menopause 2011;18:629-637. 96. Karalis I, Beevers G, Beevers M, Lip G. Hormone replacement therapy and arterial BP in postmenopausal women with hypertension. Blood Press 2005;14:38-44. 97. Szekacs B, Vajo Z, Acs N, et al. Hormone replacement therapy reduces mean 24 hour BP and its variability in postmenopausal women with treated hypertension. Menopause 2000;7:31-35. 98. Lee DY, Kim JY, Kim JH, et al. Effects of hormone therapy on ambulatory BP in postmenopausal Korean women. Climacteric 2011; 14:92-99. 99. Harvey P, Molloy D, Upton J, Wing LM. Dose response effect of conjugated equine estrogen on blood pressure in postmenopausal women with hypertension. Blood Press 2000;9:275-282. 100. Manhem K, Ghanoum B, Johansson M, Milsom I, Gustafsson H. Influence of chronic hormone replacement therapy on left ventricular mass and serum-ACE activity. Blood Press 2010;19:295-300. 101. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613. 102. Nair GV, Chaput LA, Vittinghoff E, Herrington DM; Heart and Estrogen/ progestin Replacement Study Investigators. Pulse pressure and cardiovascular events in postmenopausal women with coronary heart disease. Chest 2005;127:1498-1506. 103. Angerer P, Störk S, Schacky C. Influence of 17A estradiol on BP of postmenopausal women at high vascular risk. J Hypertens 2001;19: 2135-2142. 104. Affinito P, Palomba S, Bonifacio M, et al. Effects of hormonal replacement therapy in postmenopausal hypertensive patients. Maturitas 2001;40:75-83. 105. de Villiers TJ. Clinical issues regarding cardiovascular disease and selective estrogen receptor modulators in postmenopausal women. Climacteric 2009;12(suppl 1):108-111. 106. El-Hajj Fuleihan G. Tibolone and the promise of ideal hormonereplacement therapy. N Engl J Med 2008;359:753-755. 107. Riggs BL, Hartmann LC. Selective estrogen-receptor modulatorsV mechanisms of action and application to clinical practice. N Engl J Med 2003;348:618-629. 108. El-Hajj Fuleihan G. Tissue specific estrogens. The promise for the future. N Engl J Med 1997;337:1686-1687. 109. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999; 282:637-645. 110. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125-137. 111. Morgante G, Delia A, Musacchio MC, Severi FM, Petraglia F, De Leo V. Effects of raloxifene therapy on plasma renin and aldosterone levels and BP in postmenopausal women. Gynecol Endocrinol 2006;22:376-380. 112. Sumino H, Ichikawa S, Kasama S, et al. Effects of raloxifene on the renin-angiotensin-aldosterone system and BP in hypertensive and normotensive osteoporotic postmenopausal women. Geriatr Gerontol Int 2010;10:70-77. 113. Cagnacci A, Zanni AL, Volpe A. Administration of raloxifene does not influence 24-hour ambulatory BP of postmenopausal women with osteopenia: a double-blind placebo-controlled study. Am J Obstet Gynecol 2003;188:1278-1282. 114. Collins P, Mosca L, Geiger MJ, et al. Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation 2009;119:922. De Villiers TJ, Chines AA, Palacios S, et al. Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial. Osteoporos Int 2011;22:567-576. Pinkerton JV, Pickar JH, Racketa J, Mirkin S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric 2012;15:411-418. Cummings SR, Ensrud K, Delmas PD, et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 2010;362:686-696. Skouby SO, Sidelmann JJ, Nilas L, Gram J, Jespersen J. The effect of continuous combined CEE plus MPA and tibolone on cardiovascular metabolic risk factors. Climacteric 2008;11:489-497. Cagnacci A, Baldassari F, Arangino S, Alessandrini C, Volpe A, Administration of tibolone decreases 24 h heart rate but not BP of postmenopausal women. Maturitas 2004;15;48:155-160. Vassalle C, Cicinelli E, Lello S, Mercuri A, Battaglia D, Maffei S. Effects of menopause and tibolone on different cardiovascular biomarkers in healthy women. Gynecol Endocrinol 2001;27:163-169. Lloyd G, McGing E, Cooper A, et al. A randomised placebo controlled trial of the effects of tibolone on BP and lipids in hypertensive women. J Hum Hypertens 2000;14:99-104. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708. Bots ML, Evans GW, Riley W, et al. The effect of tibolone and continuous combined conjugated equine oestrogens plus MPA on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study. Eur Heart J 2006; 27:746-755. ELITE: Early versus Late Intervention Trial with Estradiol. Available at: http://clinicaltrials.gov/ct2/show/NCT00114517. Accessed June 27, 2014. Kronos Early Estrogen Prevention Study (KEEPS). Available at: http:// clinicaltrials.gov/ct2/show/NCT00154180. Accessed June 27, 2014. Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014;161:249-260. Moyer VA; US Preventive Services Task Force. Menopausal hormone therapy for the primary prevention of chronic conditions: US Preventive Services Task Force recommendation statement. Ann Intern Med 2013; 158:47-54. Wathen CN, Feig DS, Feightner JW, Abramson BL, Cheung AM; Canadian Task Force on Preventive Health Care. Hormone replacement therapy for the primary prevention of chronic diseases: recommendation statement from the Canadian Task Force on Preventive Health Care. CMAJ 2004;170:1535-1537. American Academy of Family Physicians Website. Hormone replacement therapy. Available at: http://www.aafp.org/patient-care/clinicalrecommendations/all/hrt.html. Accessed June 27, 2014. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in womenV2011 update: a guideline from the American Heart Association. Circulation 2011; 123:1243-1262. Santen RJ, Allred DC, Ardoin SP. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010;95(suppl 1):s1-s66. The North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012;19:257-271. The Society of Obstetricians and Gynaecologists of Canada Website. Menopause and osteoporosis update 2009. Available at: http://sogc.org/ wp content/uploads/2013/01/Menopause_JOGC-Jan_09.pdf. Accessed December 22, 2013. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists Website. Hormone replacement therapy advice. Available at: http://www.ranzcog.edu.au/doc/hormone-replacement-therapy-advice.html. Accessed December 21, 2013. James PA, Oparil S, Carter BL. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-520. Menopause, Vol. 22, No. 4, 2015 Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 13