Download Effects of hormone therapy on blood pressure

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
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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
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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
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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
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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
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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
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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
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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.
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