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Effects of Hormone Therapy on Blood Pressure

Effects of Hormone Therapy on Blood Pressure

Menopause: The Journal of The North American Society Vol. 22, No. 4, pp. 456/468 DOI: 10.1097/gme.0000000000000322 * 2014 by The North American Menopause Society

REVIEW ARTICLE Effects of 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 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 mech- anisms 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 [ from year 2000 to November 2013. Results: 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 had a beneficial effect on blood pressure in normotensive women and, at most, a neutral effect on hypertensive women. In general, and 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 modulators.

ypertension is a major risk factor for cardiovascu- in both sexes between ages 45 and 64 years, after which lar disease, which is the leading cause of mortality women took the lead.1 Hand morbidity in both men and women. In the Na- To date, the mechanisms underlying postmenopausal hy- tional Health and Nutrition Examination Survey for years pertension are not clear. The low estrogen state associated 2007-2010, hypertension was more common in men than in with menopause has been implicated as a suspect and is women younger than 45 years; the prevalence became equal 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- Received January 11, 2014; revised and accepted July 7, 2014. system (RAAS), sympathetic system, kinin-kallikrein system, From the 1Endocrine Division, American University of Beirut, Beirut, atrial natriuretic peptide (ANP), and inflammation. Transition 2 Lebanon; Endocrine Hypertension Division, Brigham and Women’s to menopause is also associated with a higher prevalence of Hospital, Harvard Medical School, Boston, MA; 3Endocrine Division, and Program, WHO Collaborating metabolic syndrome and changes in body composition, in- Center for Metabolic Disorders; and 4Scholars in Health Research cluding increase in weight and fat mass, which can impact Program, American University of Beirut, Beirut, Lebanon. BP.2 In this article, we review potential pathways for the Funding/support: None. effects of hormone therapy (HT) on BP and evidence from Financial disclosure/conflicts of interest: None reported. clinical studies for the effects of HT and selective estrogen Supplemental digital content is available for this article. Direct URL ci- receptor modulators (SERMs) on BP. tations 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, Cal- cium Metabolism and Osteoporosis Program, WHO Collaborating METHODS Center for Metabolic Bone Disorders, Division of Endocrinology, De- Search methodology partment of Internal , American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon. A comprehensive review of the literature was implemented E-mail: [email protected] in consultation with our medical librarian, an expert in the

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE construction of searches in various biomedical databases. The PHYSIOLOGIC EFFECTS OF ESTROGEN ON THE topic of interest was divided into three main concepts: hy- VASCULAR SYSTEM pertension, HT, and menopause. Each of these concepts was Estrogen can exert its effect on the heart and vessels searched on Ovid MEDLINE as such and also as synonyms or through its two receptor isoforms, estrogen receptor (ER)-> related terms to achieve a comprehensive literature review. and ER-A,4,5 which are expressed in vascular endothelial cells The Ovid MEDLINE interfaceVwhich allows MeSH terms, and vascular smooth muscle cells. The functional properties of explode functions, and keyword search in title, abstract, sub- ER-> and ER-A are different, and their effects can be medi- ject headings, adjacency, and publication types, in addition ated through genomic6 or nongenomic7 mechanisms (Fig.). to Boolean operators (and, or) and truncationVwas used to The genomic mechanism occurs during a relatively long pe- identify all relevant articles using the main terms and related riod and consists of binding of estrogen to ER elements on terms (for full details, see Appendix I, Supplemental Digital promoter regions of the target gene, thereby regulating the Content 1, http://links.lww.com/MENO/A107). To retrieve transcription of the target gene.9 The nongenomic mechanism articles describing the impact of SERMs, we entered the terms has been the subject of multiple studies in recent decades. BSERM[ and Bhypertension[ as MeSH terms, related terms, These so-called extranuclear actions are mediated through and key words, and we used the operation AND. The search ERs located at or near the plasma membrane, which, once conducted in this review was limited to years 2000-2013, al- activated, interact with some membrane-associated signaling though we also included major relevant randomized con- molecules such as channels, G-proteins, the tyrosine kinase trolled trials (RCTs) before year 2000, such as the Heart and c-Src, and the epidermal growth factor receptor, leading to the Estrogen/progestin Replacement Study (HERS), Postmeno- activation of a cascade involving mitogen-activated protein ki- pausal Estrogen/Progestin Interventions (PEPI) trial, and one nase, phosphatidylinositol 3-OH kinase, small GTPase RhoA, and trial on transdermal estrogen. Additional relevant studies and protein kinase A/C, which might cause different actions like vaso- reviews published before 2000 were identified from reference dilatation but also may affect gene expression through the so-called lists of retrieved articles, and those available in authors’ li- Btwo-step model of sex signaling.[10 ER-AYdeficient braries were also used. male and female mice have been shown to develop hypertension and exaggerated vasoconstrictor response to A adrenergic re- ceptor .11 Risk-of-bias assessment Certain polymorphisms in ER-A genes have been demon- We conducted a risk-of-bias assessment for randomized strated to correlate with BP elevations in both women and trials detailed in this review using The Cochrane Collabora- men. In a study of 187 healthy postmenopausal women, those tion’s risk of bias tool, which was designed to evaluate clinical who had at least one allele with 26 cytosine-adenine repeats trials and its six criteria: (1) random sequence generation on the ER-A gene had higher systolic BP (SBP), with a mean (selection bias); (2) allocation concealment (selection bias); difference of 10 mm Hg (P = 0.032), compared with those (3) blinding of participants, providers, data collectors, out- who did not.12 In the Framingham Heart Study, men with come adjudicators, and data analysts (performance bias and specific polymorphisms in the ER-> gene had higher SBP, detection bias); (4) incomplete outcome data (attrition bias); and those with variations in ER-> nuclear receptor coactivator (5) selective reporting (reporting bias); and (6) other sources 1 and genes had a higher pulse pressure than those of bias (eg, early termination of trial). who did not have these specific polymorphisms. Women with The assessment was independently conducted by two au- polymorphisms in ER->, aromatase, and nuclear receptor co- thors (Z.I. and M.R.) and reviewed again by the senior author activator 1 genes also had higher diastolic BP (DBP).13 (G.E.-H.F.). We judged the risk of bias for each criterion as A newly discovered seven-transmembrane spanning intra- Blow risk,[Bhigh risk,[ or Bunclear risk[ and evaluated indi- cellular G-proteinYcoupled ER (GPER), which is expressed vidual bias items as described in the Cochrane Handbook for throughout the cardiovascular system, may play an important 3 Systematic Reviews of Interventions. Additional details are role in BP modulation. The activation of this receptor was available in Appendix II-A (Supplemental Digital Content 2, shown to reduce BP in ovariectomized mice14 and, conversely, http://links.lww.com/MENO/A108). GPER-deficient mice had increased endothelial prostanoid- 15 mediated vasoconstriction. 17A- (E2) is a primary for GPER; thus, decreasing E2 levels in menopause POTENTIAL ROLE OF ESTROGEN may be implicated in the pathophysiology of hypertension IN BP REGULATION through this receptor.16 Estrogen’s effect on BP is complex and includes direct and The effect of estrogen on target cells and organs, including indirect effects through multiple signaling pathways that may the vascular system, is thus regulated by a complex interplay either lower or raise BP, depending on the pathway involved. of genomic and nongenomic signaling mechanisms, and the This section will mainly address the effects of estrogen and integrated action of these machineries has important functional progesterone on BP from a pathophysiologic point of view roles in a variety of pathophysiologic processes. Although there and is followed by a clinical section that discusses the main are various types of oral and transdermal estrogen preparations relevant RCTs that focus on this topic. that can activate the genomic and nongenomic pathways detailed

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. ISSA ET AL

FIG. The multifaceted mechanisms of estrogen involve (1) acting on estrogen receptor (ER)-> and ER-A to reduce synthesis of 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 (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 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 Short-term sublingual administration of 17A-E2 1 mg was have been conjugated equine (CEE) and the native shown to improve vasodilatory responses in eight mildly hy- natural molecule 17A-E2. pertensive postmenopausal women (mean age, 54.4 y) who had no other risk factors for .26 The effect of 17A-E2 2 mg/day, alone or combined with the progestin Mechanisms through which estrogen would lower BP acetate (MPA) 5 mg/day, on the function Estrogen and vascular tone and morphology of isolated resistance arteries was assessed in Menopause and its associated low estrogen state are char- a randomized placebo-controlled trial in 55 healthy postmen- acterized by endothelial dysfunction,17 which can thus pre- opausal women (mean age, 57 y) before and after 3-month 18 dispose to hypertension. A study of 952 apparently healthy therapy with 17A-E2, MPA acetate, and 17A-E2 plus MPA postmenopausal women (mean age, 53 y) followed for a acetate or placebo. E2 augmented artery flowYmediated dila- mean of 3.6 years demonstrated that endothelial dysfunction, tation, improved endothelial cell morphology, increased the assessed by flow-mediated dilatation, preceded and predicted expression and phosphorylation of the actin binding protein hypertension.19 Aging per se is associated with a decline in myosin and of the focal adhesion complex controller, induced endothelial function in normal humans, and this decline seems the rearrangement of cytoskeletal actin and vinculin fibers, to occur earlier in men than in women. However, in women, a promoted endothelial cell horizontal migration, and decreased steep decline occurs at around the time of menopause, consis- signs of endothelial apoptosis. Some of these beneficial effects tent with loss of a protective effect of estrogen on the arterial were preserved with the addition of MPA, whereas MPA alone wall.20 The postmenopausal state is indeed associated with a failed to augment artery flowYmediated dilatation and to im- significant reduction in nitric oxide activity,21 and vasodilata- prove endothelial cell morphology and apoptosis.27 tion is one of the most important effects of estrogen on arterial Healthy postmenopausal women receiving oral 17A-E2 vessels. Estrogen-induced vasodilation has been described in 2mg/daycombinedwithmicronizedprogesterone200mg/day animal models22 and clinical studies and occurs through acti- had improved carotid artery compliance.28 Similarly, in a vation of the endothelial nitric oxide synthase and release of 12-month RCT, transdermal E2, but not oral CEE therapy, had a nitric oxide through genomic and nongenomic signal trans- beneficial effect on arterial stiffnessbuthadnoeffectonBP.29 duction pathways.23 Other possible mechanisms that have been However, the beneficial effect of estrogen on flow-mediated implicated in the vasodilatory effect of estrogen are release of vasodilatation has not been consistent across studies.30 The prostaglandin 2, stimulation of neuronal nitric oxide synthase in discrepancy in the results may be related to differences in age, vascular smooth muscles cells,24 and inhibition of voltage- timing of initiation of estrogen after menopause, and prepara- dependent L-type calcium current in vascular smooth cells.25 tions of estrogen and progestins.

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE

Estrogen and the kinin-kallikrein system fall in renin and maintenance of angiotensin I levels modu- Increase in the activity of the kinin-kallikrein system leads lated by a negative feedback loop system. to lowering of BP, and HT may affect this system. HT in the Angiotensin I is converted into angiotensin II (the active form of oral 17A-E2 (2 mg), alone or combined with continuous peptide) by angiotensin-converting enzyme (ACE), which is MPA, increased urinary kallikrein in 39 normoten- present in the lung and other tissues. Oral estrogen has been sive postmenopausal women after 3 months of E2 (P G 0.001) demonstrated to lower ACE levels. However, in several studies, and E2 with MPA (P G 0.01), whereas it decreased nonsig- despite lower ACE levels, levels of angiotensin II were higher nificantly in the placebo group (P 9 0.06). Although there in the presence of estrogen,40,41 thus suggesting that conver- were no significant BP changes after 3 months of therapy, sion into angiotensin II may occur via non-ACE pathways. there was a significant negative correlation between urinary This increase in angiotensin II would be expected to increase kallikrein and mean arterial pressure and pulse pressure in the BP. However, whether oral estrogen increases BP may depend estrogen-alone arm.31 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 Estrogen and ANP Seely et al,41 21 normotensive and 10 hypertensive women E was shown to increase ANP, a molecule with a wide 2 received either oral CEE (0.635 mg) or (60 mg/d), array of cardiovascular and renal effects, including natriuresis, a SERM, for a period of 16 weeks. Oral CEE increased diuresis, and antagonism of the renin-angiotensin system and angiotensinogen levels, decreased active renin and ACE the sympathetic nervous system, which could lower BP.32 E 2 levels, and kept angiotensin I levels unchanged. Both CEE also decreased ANP clearance and reduced weight gain in and droloxifene significantly increased plasma-immunoreactive follitropin receptor knockout mice, an animal model for obe- angiotensin II levels without a change in BP. Other studies sity and hypertension.33 The increase in ANP induced by E 2 supported a fall in circulating ACE levels with oral estrogen.42 was accompanied by a reduction in BP in ovariectomized Although oral estrogen increases angiotensinogen levels, spontaneously hypertensive rats.34 transdermal estrogen does not. Transdermal E2 at a dose of 0.2 mg twice a week had no significant effect on plasma renin Estrogen and inflammation activity or aldosterone levels in healthy postmenopausal 43 Indirect evidence suggests that inflammation may modulate women. This neutral effect of transdermal E2 on the RAAS BP in animal models. Angiotensin IIYinduced hypertension was shown in multiple studies.44<46 was attenuated in interleukin-6 knockout mice.35 Similarly, in Angiotensin mediates its effects by binding to the angio- pregnant rats with elevated tumor necrosis factor-> levels, tensin type 1 receptor (AT1R). The effects of estrogen on AT1R etanercept, a tumor necrosis factor->Ysoluble receptor inhibi- are conflicting. Estrogen can induce a decrease in AT1R tor, significantly reduced BP.36 Estrogen has been shown to expression in kidneys and vessels associated with a fall in have a suppressive effect on E-selectin, cell adhesion mole- BP, with restoration of estrogen, in an ovariectomized animal cules, monocyte chemoattractant protein-1, and tumor necrosis model.47In contrast, in an animal model that was pretreated factor->; inconsistent effects on interleukin-6; and stimulatory with an inhibitor of nitric oxide, U-nitro-L-arginine-methyl-ester, effects on vasoprotective cytokines such as transforming growth to create a model of vascular Baging,[ administration of E2 to factor->,37 in addition to attenuating vascular expression of ovariectomized animals increased AT1R protein in the kid- inflammation-associated genes.38 Thus, estrogen may have ney, and this increase was positively associated with an in- BP-lowering effects through these mechanisms. crease 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 antag- Mechanisms through which estrogen would increase BP onize angiotensin II receptorYmediated growth-promoting ef- Estrogen and the RAAS fects on vascular smooth muscle cells.49 The RAAS has powerful effects on BP through multiple Estrogen’s effect on the RAAS is thus complex and in- mechanisms mediated by angiotensin II. These include the volves both stimulatory and inhibitory actions. Estrogen’s promotion of sodium and water reabsorption via stimulation effect on the RAAS results in changes in BP that may depend of aldosterone release, systemic arteriolar vasoconstriction, on the relative balance between these actions, the health of the promotion of endothelial dysfunction, stimulation of the sym- underlying vasculature, and the ability of other homeostatic pathetic nervous system, and decrease in vagal tone. In addition, systems to compensate for ensuing changes in RAAS activity. angiotensin II has direct powerful inotropic, chronotropic, and Given estrogen’s complex relationship with the RAAS, it is hypertrophic effects on the heart. Estrogen can regulate several no surprise that estrogen administration has been demon- of the components of the RAAS. strated to influence antihypertensive response to agents that Oral estrogens induce an increase in the hepatic production interrupt the RAAS. Garcı´aetal50 showed that in spontane- of angiotensinogen (renin substrate).39 However, not all the ously hypertensive rats, the antihypertensive effect of the effects of estrogen are stimulatory after this step. The rise in converting captopril was enhanced when oral angiotensinogen is typically associated with a compensatory E2 was added; the combinationVnot captopril aloneVinhibited

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. ISSA ET AL extracellular signalYregulated kinase 1/2 phosphorylation, which In summary, postmenopausal women are at increased risk mediates angiotensin IIYinduced arterial muscle proliferation. for sympathetic overactivity induced by obesity, increased The AT1R blocker candesartan given to normotensive post- leptin levels, and anxiety, an effect that may be counteracted menopausal women resulted in a further decrease in BP in the by estrogen therapy. 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 POTENTIAL ROLE OF PROGESTINS IN BP DBP in a higher percentage of hypertensive postmenopausal REGULATION women compared with irbesartan alone and in addition to a We evaluated studies investigating the effects of progestins significant decrease in aldosterone levels.52 on the vascular system and found conflicting results,60possibly owing to differences in the type of progestin used, the route of Estrogen and the sympathetic system administration (oral vs transdermal), and the vascular markers Activation of the sympathetic system can lead to hyper- determined, the clinical relevance of which is still controversial. tension by causing vasoconstriction and by increasing renal Indeed, different classes of progestins differ in their metabolic, tubular sodium reabsorption.53 Postmenopausal status is as- androgenic, , and antimineralocorticoid effects, sociated with increased sympathetic activity through several as detailed in Table. The class properties for each of the pro- mechanisms. First, obesity, which is common in postmeno- gestins detailed in Table (eg, androgenic, glucocorticoid, and pausal women, can increase sympathetic activity, which, in the ) were derived from different studies that used kidney, leads to increased renin release and vasoconstriction differing methodologies and are thus mostly qualitative and not that can contribute to hypertension.54 Increased leptin levels directly comparable between the compounds listed. found in obese women also activate the sympathetic system via Szmuilowicz et al62 studied pressor and renovascular re- activation of melanocortin receptors in the hypothalamus,55,56 sponses to infused angiotensin II, a potent vasoconstrictor, in and obese postmenopausal women have a greater predilec- 34 hypertensive postmenopausal women not on HT and off all tion for hypertension than lean postmenopausal women.57 antihypertensive therapies for at least 2 weeks. The vasocon- Furthermore, anxiety and depression, which are more com- strictor response to angiotensin II was blunted in women with mon in women than in men, can activate the sympathetic higher endogenous progesterone levels on low sodium bal- system and elevate BP58,59 mainly in individuals with meta- ance, an effect that was independent of age, body mass index, bolic syndrome and hypertension. Oral estrogen therapy may and E2 concentration. Therefore, the presence of endogenous decrease sympathetic nerve activity.30 progesterone in premenopausal women, with levels ranging

TABLE. Biological activities of natural progesterone and synthetic progestins

Progestin Progestogenic Antigonadotropic Antiestrogenic Estrogenic Androgenic Antiandrogenic Glucocorticoid Antimineralocorticoid Progesterone + + + jj T ++ + j + jj T j T + + + jj T jj 17>-Hydroxy derivatives +++jj ++ j acetate acetate + + + jj ++ + j acetate + + + j T ++ j Medroxyprogesterone +++j T j + j acetate 19-Norprogesterone derivatives acetate + + + jj T jj + + + jj j j j + + + jj T j T derivatives Drosperinone + + + jj + j + 19-Nortestosterone derivatives + + + + + jj j + + + + + jj j Norethinodrel T + T + T jj j + + + j + jj j + + + j + jj j 3-keto- + + + j + jj j + + + j + j ++ + + TTj + jj (+) Effective; (T) weakly effective; (j) not effective. Reprinted from Schindler et al61 with permission of the publisher. Copyright * 2008, Elsevier.

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE between 10 and 20 ng/dL, may blunt a predisposition to hy- for coronary artery disease.69 Furthermore, in contrast to MPA, 62 pertension, a protective effect that may be lost in menopause. dydrogesterone was shown to have a neutral effect on E2- MPA is the most commonly used progestin in studies induced positive effect on nitric oxide synthase activity and evaluating the impact of HT on cardiovascular outcomes. It is expression in human endothelial cells from the umbilical vein70 17>-hydroxyprogesterone derivative, which is weakly effec- and has favorable effects on inflammatory markers71<73 in post- tive as an antiandrogenic agent with no antimineralocorticoid menopausal women. Dydrogesterone (at a dose of 10 mg for 61 activity. The administration of MPA with estrogen has been 14 d of each 28-d cycle) given sequentially with E2 1 mg was shown to attenuate estrogen’s augmentation of endothelium- showntodecreaseambulatorySBPby5mmHgafter12months dependent vasodilation.63 In the PEPI trial,64 875 healthy of treatment, compared with no treatment, in healthy postmeno- postmenopausal women aged 45 to 64 years were randomly pausal women.74 Similarly, dydrogesterone 10 mg/day given assigned to five groups: placebo; CEE 0.625 mg/day; CEE sequentially with oral E2 1 mg caused significant falls in 0.625 mg/day plus cyclic MPA 10 mg/day for 12 days/month; both daytime and nighttime AmBP in 35 mildly to moderately CEE 0.625 mg/day plus consecutive MPA 2.5 mg/day; or CEE hypertensive postmenopausal women versus no treatment.75 0.625 mg/day plus cyclic micronized progesterone 200 mg/day These findings need to be confirmed in larger randomized studies. for 12 days/month. SBP, which was among the primary out- Furthermore, Honisett et al76 evaluated the effects of mi- comes, did not vary between the MPA arm and the micronized cronized progesterone (100 mg daily) for 6 weeks on vascular progesterone arm. function and BP in a randomized placebo-controlled trial of The addition of the oral progestin norethisterone to estrogen 20 healthy postmenopausal women. Micronized progesterone has been shown to antagonize the vasodilatory effects of estrogen did not affect vascular function (as assessed by flow-mediated in postmenopausal women, as measured by the prostacyclin dilation of the brachial artery, systemic arterial compliance, thromboxane quotient,65 a factor that is known to be crucial and cutaneous vascular reactivity), nor did it change BP. for the relationship of vasorelaxation to vasoconstriction. In summary, as progestins differ in their BP effects, studies A new derivative progesterone, drosperinone of the effects of combined HT on BP may be affected by the (DRSP), was found to have antimineralocorticoid and anti- progestin used. Endogenous progesterone, micronized progester- androgenic activities.61 The addition of DRSP 3 mg to oral one, dydrogesterone, and DRSP may have BP-lowering effects 77 17A-E2 1 mg in women with stage 1 hypertension resulted in a through both direct vascular actions and diuretic properties. 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 MENOPAUSAL TRANSITION, HT, AND BP ambulatory BP (AmBP) monitoring in a subset of women Menopausal transition has been associated with changes in with decrements of j8.5/j4.2 mm Hg with DRSP/E2 versus BP, and several studies evaluating the impact of HT on BP in j1.8/j1.6 mm Hg with placebo (P = 0.002 for SBP and postmenopausal women are described herein. P = 0.07 for DBP vs placebo).66 BP measurements reached The change in BP across menopause was evaluated in a their lower limits within 2 months of therapy, and there was large cross-sectional study (Study on Hypertension Prevalence no significant difference in potassium levels from baseline or in Menopause in the Italian Population) of 18,326 Italian in the incidence of hyperkalemia in the DRSP/E2 group women aged 46 to 59 years. SBP and DBP were significantly compared with placebo. These results were confirmed in higher (3.4 and 3.1 mm Hg, respectively) in postmenopausal another RCT67 that tested three doses of DRSP combined with women than in perimenopausal and premenopausal women at oral E2, oral E2 alone, and placebo in 750 postmenopausal the younger end of the age range even after adjustment for women with stage 1 to stage 2 hypertension (mean [SD] age, age, body mass index, and other confounding factors.78 57 [6] y). Mean (SD) systolic AmBP (j6.1 [11.2], P G 0.0001) The Multi-Ethnic Study of Atherosclerosis included 610 and diastolic AmBP (j3.5 [7.1], P G 0.0001) decreased sig- normotensive American postmenopausal women who were fol- nificantly versus placebo mainly in the DRSP 3 mg/E2 group. lowed to assess change in BP and development of incident Nevertheless, thromboembolic events remain a concern with hypertension during a mean follow-up of 4.8 years (maximum, the use of DRSP, as shown in a recent analysis from the 6.7 y). One hundred ninety-four women developed incident Danish cohort study, where the rate ratio (95% CI) of confirmed hypertension. Higher endogenous E2, , and dehy- venous thromboembolism for users of oral contraceptive pills droepiandrosterone levels and lower sex hormoneYbinding containing DRSP was 2.1 (1.6-2.8) compared with levonor- globulin levels were associated with a higher incidence of gestrel as reference.68 Whether these findings are applicable to hypertension and greater longitudinal rise in BP after adjust- the lower doses of DRSP/E2 in HT regimens is not known. ing for age, race/ethnicity, and lifestyle factors. Adjustment Dydrogesterone is a , which seems to be a for body mass index eliminated the associations for E2 and highly selective progestin with neutral activity in glucocorti- testosterone but only attenuated the associations for dehy- coid, , and aldosterone receptors.61 The addition of droepiandrosterone and sex hormoneYbinding globulin. The dydrogesterone to E2 did not affect the serum levels of associations for E2, testosterone, and endothelin (a potent vasoconstrictor) compared with E2 alone were therefore mostly explained by adiposity, whereas the as- in postmenopausal women with more than two risk factors sociation for sex hormoneYbinding globulin was independent

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. ISSA ET AL of measures of adiposity, insulin resistance, and systemic cause this variable was not measured as a primary outcome 79 inflammation. in the trial. HT (oral E2 2 mg with or without norethisterone Much of the concern with the impact of HT on BP origi- 1 mg, according to hysterectomy status) had no effect on office nates from data that relate oral contraceptives to hypertension SBP and DBP, which were measured as primary outcomes in in younger women, although the specific hormonal compounds the Danish Osteoporosis Prevention Trial, an open-label trial (be it estrogens and progestins) used for HT replacement differ evaluating 1,006 postmenopausal women.90 Similarly, there and may not have the same effects on BP. Specifically, ethinyl was no difference in office BP between the HT group (un- E2 is commonly used in oral contraceptives and has a very opposed oral 17A-E2 1 mg) and the placebo group at 2 years potent effect on hepatic production of angiotensinogen.80 in the Estrogen in the Prevention of Atherosclerosis Trial In the literature, there is significant variability in the effect (EPAT), which evaluated 222 healthy postmenopausal women of HT on BP. This inconsistency among studies could be at- with the primary endpoint being BP and with the overall rate of tributable to the different designs, sample sizes, types of HT, progression of subclinical atherosclerosis measured by carotid and methods used to measure BP; type of menopause (surgical artery intima-media thickness.91 Other smaller randomized vs natural); and participant characteristics, including phase in controlled studies using AmBP measurement as primary out- the menopausal transition and endogenous hormonal profile. come revealed similar neutral effects of oral HT on BP.41,92 For studies that specified BP as primary outcome in normo- HT in normotensive women tensive women on oral HT, the risk of bias was mostly concen- Studies evaluating the effect of HT on BP in normotensive trated between low risk and unclear risk (see Appendix II-B.1, postmenopausal women varied in design between case-control Supplemental Digital Content 3, http://links.lww.com/MENO/A109). studies, prospective studies, and RCTs. It was low for most bias criteria in EPAT and the PEPI In our literature review of case-control and prospective trial,64,92 unclear in one study,41 and ranged from low to high studies, there was variability in the estrogen-progesterone in the studies by Vestergaard et al90 and SLrensen et al.92 preparations used and in the means of BP measuring (ambu- Transdermal E may represent an attractive and safer option latory vs clinic BP). A neutral or lowering effect of HT on BP 2 < for postmenopausal women given its bypass of first he- was the main outcome of these studies.81 86 Likewise, a re- patic pass, which is associated with increased , view by Mueck and Seeger,87 which summarized comparative C-reactive protein, and activation of coagulation.93 Seely et al43 studies with 24-hour AmBP measurements in normotensive evaluated the effect of transdermal E (two 0.1-mg patches postmenopausal women from 1997 to 2002, revealed mainly a 2 twice a week), with or without progesterone (intravaginal significant BP-lowering effect of HT. However, this review micronized progesterone 300 mg/d added for 2 weeks), on included studies that were not all randomized with different BP in 15 healthy postmenopausal women. The duration of use HT preparations, with predominant use of transdermal E , 2 was 8 weeks for transdermal E and 10 weeks for E and which may be more beneficial than oral HT in relation to 2 2 progesterone. Nocturnal SBP, DBP, and mean BP decreased BP effects.77 significantly (P G 0.02) versus placebo. The high doses used Randomized trials in this study aimed at achieving levels similar to those seen in 64 In the PEPI trial, 875 healthy postmenopausal women premenopausal women. The E2 levels achieved were similar were randomly assigned to CEE (0.625 mg) alone or in com- to those of the early to middle follicular phases, and proges- bination with progestin/CEE 0.625 mg (cyclic or continuous terone levels were compatible with those seen in the luteal MPA, or cyclic micronized progesterone) versus placebo for phase. The addition of progesterone did not lead to any further 3 years. No significant difference in office SBP, a primary change in day or night BP beyond that seen with E2 alone. outcome, was seen between treatment groups and placebo. The Similarly, 12 postmenopausal women were randomly assigned Women’s Health Initiative (WHI) consisted of two parallel to CEE 0.625 mg, transdermal E2 (two 0.1-mg patches twice a clinical trials and an observational study designed to test the week, 200 Kg/d), or placebo in a single-blind cross-over design. effects of postmenopausal HT, diet modification, and calcium Although oral CEE did not result in a change in BP, transdermal 94 and vitamin D supplements on heart disease, fractures, E2 resulted in a decrease in DBP compared with placebo. This cancer, and colorectal cancer. In one trial, women received oral lowering of DBP was also evident in another randomized CEE 0.625 mg with MPA 2.5 mg versus placebo, whereas in studybyIchikawaetal45 in 22 postmenopausal women. the other trial, they received CEE alone 0.625 mg versus pla- The three transdermal E2 studies specified BP as a pri- cebo. The method for measuring BP was not specified. In the mary outcome, but they had a small number of participants HT combination arm, SBP was 1.5 mm Hg higher at 2 years (N = 24-30) and a wide range of risk-of-bias assessment (P value not available), whereas DBP remained unchanged.88 (see Appendix II-B.1, Supplemental Digital Content 3, In the estrogen-only arm, SBP increased by 1.1 mm Hg http://links.lww.com/MENO/A109). It ranged from low risk (P = 0.003) at 1 year compared with placebo, whereas DBP to unclear risk in two studies43,94 and from low risk to high did not change.89 The increased risk of cardiovascular and risk in the third study.45 cerebrovascular events observed in this trial had a major im- In summary, RCTs evaluating the effect of various oral HT pact on HT use by postmenopausal women, but whether this preparations on BP as a primary outcome, such as PEPI trial was directly related to an increase in BP is still unknown be- (CEE/MPA/micronized progesterone), Danish Osteoporosis

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE

Prevention Trial (17A-E2/norethisterone), EPAT (17A-E2), and standard-dose cyclic gestodene [oral gestodene 0.025 mg on 43 smaller trials by Seely et al (CEE/micronized progesterone) days 17-28 of each 4-wk cycle] or oral 17A-E2 1 mg with low- 92 and SLrensen et al (17A-E2/norethisterone), consistently re- dose gestodene [0.025-mg addition in each third cycle only]) vealed a neutral effect. Conversely, the WHI showed an in- or no treatment on the progression of atherosclerosis. Again, 103 crease in BP in the CEE/MPA and CEE-only arms; however, BP was not a primary outcome. BP was not specified as a primary outcome. An essentially It has been suggested that some women may paradoxically beneficial effect of transdermal E2 preparations on BP was manifest an increase in BP in response to oral estrogen ther- noted in smaller trials,43,45,94 where BP was a specified pri- apy. However, the only study to support such observation is mary outcome, but the risk of bias was suboptimal. HERS, and this may be explained by the fact that 40% of women were hypertensive at study entry. However, BP was HT in hypertensive women not measured as primary endpoint in HERS. HT use in women with hypertension represents another For studies that specified BP as primary outcome in hy- challenge in relation to controversial data and the lack of pertensive women on oral HT, the risk-of-bias assessment randomized studies with BP as the primary endpoint. Instead, spanned all ranges (see Appendix II-B.1, Supplemental Digi- data are available from cross-sectional studies. One of the tal Content 3, http://links.lww.com/MENO/A109). It was low largest cross-sectional studies, the Rancho Bernardo Study, risk for most bias criteria in EPAT,91 mixed in three studies consisted of two componentsVa cross-sectional study of (unclear risk to low risk99 and low risk to high risk29,75), and 100 1,044 participants and a 10-year prospective follow-up of 443 mainly unclear in one study. The risk of bias in the other womenVthat evaluated the association between postmeno- four large trials that did not have BP as primary outcome was 101 pausal oral estrogen therapy and BP, renal function, and pro- low in HERS and spanned from low to high in the WHI 88,89,103 teinuria.95 In the cross-sectional study, DBP was highest 2002, WHI 2004, and PHOREA trial. in never users (age-adjusted P = 0.07; multivariate-adjusted The effect of transdermal estrogen on BP as a primary P = 0.01), but SBP did not differ by postmenopausal estrogen outcome has also been investigated in hypertensive women; 29,104 status after adjustment for covariates (age, weight, smoking, unfortunately, the studies were small (N = 24-30 ). They and hypercholesterolemia). On prospective analysis, SBP did showed a neutral effect or a decrease in BP and differed in not differ in the past and current estrogen user groups, but their pattern of decrease (systolic vs diastolic, daytime vs 29,104 29 never users exhibited an age-adjusted increase in SBP across nighttime). The risk of bias was low to unclear in one 104 time (mean increase, 6 mm Hg; P = 0.02), and the difference and low to high in the other (see Appendix II-B.1, Supple- persisted after multivariate adjustment. DBP of never users mental Digital Content 3, http://links.lww.com/MENO/A109). 29,91,99,100 showed no significant age-adjusted change (P = 0.1), whereas In summary, four of five small RCTs evaluating past users (age-adjusted P G 0.0001) and current users (age- the impact of oral HT on BP as a primary outcome in hyper- adjusted P G 0.0001) showed similar declines in their DBP. tensive women revealed a neutral effect on BP, and one 75 Other observational studies showed either a neutral84,96 or a study that used AmBP revealed a beneficial effect. Con- beneficial97,98 effect of HT on BP. versely, two large RCTsVHERS (CEE/MPA) and PHOREA trial (17A-E2/gestodene)Vthat did not have BP as a specified Randomized trials primary outcome revealed opposing results. Similar to find- In a randomized trial by Kaya et al75 evaluating 66 post- ings in normotensive women, a beneficial effect of transder- menopausal women, AmBP, a primary outcome, fell signifi- mal E2 preparations on BP was noted in two small trials in cantly in the group of women treated with HT (micronized hypertensive women, where BP was a specified primary out- 29,104 17A-E2 1 mg/d sequentially combined with dydrogesterone come, but their associated risk of bias was suboptimal, 10 mg/d for 14 d of each 28-d cycle). Other randomized trials thus the need for large randomized trials assessing the impact showed mainly no effect of varying HT regimens on BP, which of transdermal and oral estrogen on BP in hypertensive women. was a primary outcome in all of these studies.29,91,99,100 The effect of HT (CEE and MPA) on the secondary pre- SERMS, TIBOLONE, AND BP vention of coronary heart disease (CHD) was evaluated in SERMs, or tissue-specific estrogens, act either as agonists HERS, a randomized placebo-controlled trial where 39% of women were hypertensive.101 For 4.2 years, office SBP in- or as antagonists on the ER, depending on the target tissue creased by 1 mm Hg (P G 0.0001), whereas office DBP where they act. This family of synthetic compounds is designed remained unchanged in HT-treated women (CEE 0.625 mg to preserve the beneficial effects of estrogens on menopausal and MPA 2.5 mg) compared with placebo. Similarly, mean symptoms and bone, incur protection against cardiovascular pulse pressure increased by 2 mm Hg (P = 0.04) in treated diseases, and exert no undesired effects on reproductive organs. women versus placebo; however, BP and pulse pressure were However, the search for the ideal SERM is still ongoing, as 105<108 not primary or secondary outcomes.102 In contrast, office DBP such compound remains elusive. decreased significantly in the HT groups compared with the control group in the Postmenopausal Hormone Replacement Raloxifene Against Atherosclerosis (PHOREA) trial, which was designed Raloxifene is a second-generation SERM and the only one to determine the effect of HT (oral 17A-E2 1 mg with approved by the Food and Administration for prevention

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. ISSA ET AL and treatment of postmenopausal osteoporosis and for reduc- The Postmenopausal Evaluation and Risk Reduction with tion of the risk of invasive in high-risk women. trial was a 5-year RCT comparing the effects of Raloxifene was shown to reduce the risk of vertebral frac- lasofoxifene 0.25 or 0.5 mg with those of placebo in post- tures, was associated with increased risks of venous thrombo- menopausal women with osteoporosis. BP changes were not embolism and fatal (but not stroke), and did not display reported.117 any other on cardiovascular diseases.109,110 In a study by Morgante et al,111 raloxifene 60 mg/day did Tibolone not affect the renin-angiotensin system or BP in 20 normoten- Tibolone, a selective tissue estrogenic activity regulator, sive postmenopausal women and 20 hypertensive postmeno- has been widely used in as a substitute for HT during pausal women (controlled with antihypertensive the menopausal transition because of its in reliev- for 6 mo; mean age, 57 y). Sumino et al112 investigated the ing menopausal symptoms and its beneficial effect on bone effects of raloxifene on components of the RAAS in 23 hy- mineral density, compared with placebo.106 But the increased pertensive and 18 normotensive postmenopausal women risk of stroke associated with its use remains a major concern (mean [SD] age, 64.7 [7.3] y) with osteoporosis or osteopenia, preventing its approval in many countries. who were divided into four groups. Eleven hypertensive and In small studies of normotensive postmenopausal women eight normotensive women received raloxifene (60 mg/d) for where BP was a primary outcome, tibolone had a neutral118,119 6 months, and 12 hypertensive and 10 normotensive women or lowering120 effect on BP. The significant improvement in did not receive raloxifene for 6 months. BP and all param- BP among younger postmenopausal women in the study by eters of interest remained unchanged. Finally, administration Vassalle et al who received tibolone may be explained by the of raloxifene 60 mg/day did not affect the 24-hour AmBP fact that they had menopausal symptoms, the relief of which measurement in a 4-month placebo-controlled trial of 32 healthy may result in a concomitant decrease in BP.120 Lloyd et al121 postmenopausal women with osteopenia.113 studied the effect of tibolone 2.5 mg on BP in 29 hypertensive The Multiple Outcomes of Raloxifene Evaluation trial109 postmenopausal women for 6 months using a 2:1 randomiza- was designed to determine the effect of raloxifene on bone tion protocol design. The mean (SD) SBP declined by mineral density and vertebral fractures. Hypertension, captured 5.30% (2.87%) versus 4.94% (3.37%), whereas DBP declined as an adverse event, occurred in 9% in the placebo group by 5.38% (2.65%) versus 0.85% (3.69%) with tibolone and compared with 6.9% in the raloxifene 60 mg group (P =0.01). placebo, respectively, but not significantly. The Raloxifene Use for The Heart (RUTH) trial110 studied In the Long-Term Intervention on Fractures with Tibolone 10,101 postmenopausal women randomized to raloxifene trial on 4,538 postmenopausal women, BP measurements were 60 mg versus placebo for 5.6 years, and 78% of the partici- not detailed.122 In the Osteoporosis Prevention and Arterial pants were hypertensive. Approximately half of the women effects of tiboLone study123 that included 866 healthy post- had CHD at baseline; the other half were enrolled based on menopausal women, BP, which was not a specified outcome, CHD risk score, but BP was not a specified primary outcome. was unchanged and did not differ between the three groups. The primary objective of the RUTH trial was to determine the It decreased by j0.5% in the tibolone (2.5 mg) group and effects of raloxifene versus placebo on the incidence of cor- by j0.7% in the CEE 0.625 mg/MPA2.5 mg group (placebo, onary events and invasive breast cancer. No significant dif- P = not significant). Therefore, none of the trialsVwhich ferences in SBP or DBP were observed between treatment were mostly conducted in older postmenopausal women, in- groups,114 but raloxifene use was associated with increased cluding one trial conducted in hypertensive womenVrevealed risks of fatal stroke and venous thromboembolism. The inci- any increments in BP with tibolone. Limitations of these studies dence of fatal stroke did not differ among subgroups, except include their relatively short duration, small sample size (with for an observed higher incidence of stroke associated with the exception of the Long-Term Intervention on Fractures raloxifene use among current smokers. The increase in the with Tibolone trial and the Osteoporosis Prevention and Ar- incidence of fatal stroke in the RUTH trial remains a major terial effects of tiboLone study, which did not measure BP concern in high-risk patients, and the lack of data relating as a primary outcome), and, thus, their low power to detect therapy to BP further increases this concern. 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 Bazedoxifene is a novel third-generation SERM that re- most trials. Only five studies specified BP as a primary outcome ceived European Agency approval for treatment of (two with raloxifene112,113 and three with tibolone118,119,121), postmenopausal osteoporosis in women at high risk for frac- with mixed results on risk-of-bias criteria for both raloxifene tures. BP was neither a measured endpoint nor a reported ad- and tibolone (see Appendix II-B.2, Supplemental Digital Con- verse event in the studies evaluating bazedoxifene.115,116 tent 3, http://links.lww.com/MENO/A109). Lasofoxifene In summary, data on the effect of SERMs and tibolone on Lasofoxifene is a third-generation SERM that received BP are rather limited and restricted to raloxifene and tibolone. European Medicines Agency approval for treatment of post- The effect was essentially neutral, regardless of trial size, menopausal osteoporosis in women at high risk for fractures. whether BP was a specified primary outcome, and whether

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Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EFFECTS OF HORMONE THERAPY ON BLOOD PRESSURE studies evaluated normotensive112,113,118,119 or hypertensive121 changes in BP, measured as a secondary outcome were ob- 126 women. The increased risk of fatal stroke in the RUTH trial, served in the oral CEE or transdermal E2 arms. although a concern, was not documented to be related to BP. Societies and medical organizations restrict recommenda- tions for the use of HT for the treatment of vasomotor symp- OTHER HORMONAL PREPARATIONS 127<132 toms of menopause and recommend against the use of Other hormonal preparations, such as transdermal testos- HT for the prevention of chronic conditions, including coro- terone and , have been studied to some extent nary artery disease and stroke. Despite the potential effects in postmenopausal women, but their discussion is beyond of HT on BP and the controversial results reported, many the scope of this review. The Food and Drug Administration guidelines do not include specific recommendations concern- has not approved any androgen formulation for hypoactive ing the use of HT in women with hypertension or the clinical sexual desire disorder pending long-term safety data (http:// follow-up of BP in women initiating HT. The American Col- www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4082B1_ lege of Obstetrician and Gynecologists underscores that several 02_B-FDA-Intrinsa-Medical-Review.pdf). The regulatory variables may alter the BP effects of HT and estrogen therapy, agencies in Europe have approved a testosterone patch including the choice of progestin, and state that, in contrast K (Intrinsa 300 g) for women who had had surgical menopause, to the vasoconstrictive effect of MPA, natural progesterone has but it is no longer being manufactured as per Lexi-Comp been shown to have either a neutral or a slightly salutary effect (accessed May 2014). on BP.133 The Royal Australian and College of Obstetricians and Gynecologists recommended avoidance CONCLUSIONS or discontinuation of HT in women with uncontrolled hyper- Hypertension is a major risk factor for cardiovascular dis- tension.134 The recently published Eighth Joint National Com- ease, and menopause by itself seems to be a risk factor for mittee did not address the effect of HT on BP or the effect of an increase in BP. The effect of estrogen, with or without menopause on BP.135 progesterone, has been studied in postmenopausal women There are some limitations to our review. It does not rep- through observational and randomized trials. These studies resent a systematic review, and the search started in 2000. varied in design, population, sample size, duration, and for- However, the search was quite extensive and was updated to mulations used, and on whether BP was a specified primary November 2013, and its methodology is similar to that of outcome. The data for oral preparations were most robust in systematic reviews as detailed in Appendix I (Supplemental normotensive women (where BP was specified as a primary Digital Content 1, http://links.lww.com/MENO/A107), albeit outcome and sample size was large) but had major limitations limited to one major database, namely, MEDLINE. Major in all other subgroups. trials before 2000 were also included. In comparison with In normotensive women, the effect of oral estrogen therapy previous reviews, advantages include the fact that it covers on BP was neutral. These findings can be accepted with con- pathophysiologic and clinical studies, covers both HT and fidence in view of the fact that they were consistent across SERMs, and addresses relevant parameters to help assess the studies that had specified BP as a primary outcome, includ- strength of the data available and to achieve confidence in the ing two major large trials that had a low risk of bias (namely, conclusions derived. Namely, it identifies whether BP was PEPI trial and EPAT). The effect of transdermal therapy on specified as a primary outcome, systematically assesses the BP was beneficial in normotensive women, whereas the effect risk of bias in each study using an accepted tool, separates of oral and transdermal therapy was mostly neutral in hyper- large from small trials, and allows the identification of tensive women. Progestin formulations differed in BP effects knowledge gap and research needs. among studies, but micronized progesterone, dydrogesterone, The body of evidence today, including RCTs, does not and DRSP seemed to have beneficial outcomes. However, the support a deleterious effect of HT on BP, either in normo- abovementioned assessments are to be interpreted with caution tensive or in hypertensive women. Transdermal estrogens and in view of the characteristics of the studies currently available natural progestational agents seem to have a beneficial effect. (namely, low number of relevant studies, small sample size, However, the currently available studies, except for those that and associated risk-of-bias limitations). studied the impact of oral therapy on normotensive women, Results from the ongoing Early versus Late Intervention have several limitations (outlined previously), including the Trial with Estradiol,124 a trial whose main aim is to examine fact that most large trials did not assess BP as a predefined the effects of oral 17A-E2 on the progression of early (sub- outcomeVa shortcoming that needs to be addressed in future clinical) atherosclerosis and cognitive decline in healthy post- trials. In the interim, decisions regarding the use of HT in menopausal women, are estimated to be released in spring postmenopausal women with vasomotor symptoms need to 125 2014. The Kronos Early Estrogen Prevention Study exam-˙ be tailored, taking into account a woman’s individual risk ined the effects of estrogen (CEE 0.45 mg or transdermal 17A- profile and age and the evidence presented herein, with careful E2 50 Hg/day) each with 200 mg of oral progesterone for 12 monitoring of BP when starting such therapy. days per month, or placebo for 48 months on the development of atherosclerosis in postmenopausal women when HT was Acknowledgments: We would like to thank Ms Aida Farha (medical initiated within 3 years of the menopausal transition. No information specialist, Saab Medical Library, American University

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