Hormone Replacement Therapy and Postmenopausal Cardiovascular Events: A Meta-Analysis

AUTHORS

Shirvan Salaminia 1 , Yousof Mohsenzadeh 2 , Morteza Motedayen 3 , * , Fatemeh Sayehmiri 4 , Majid Dousti 5

1 Department of Cardiac Surgery, Yasuj University of Medical Sciences, Yasuj, Iran

2 Department of Cardiology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran

3 Department of Cardiology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

4 Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

5 Department of Parasitology, Faculty of Medicine, Shiraz University of Medical Sciences, Fars, Iran

How to Cite: Salaminia S , Mohsenzadeh Y , Motedayen M , Sayehmiri F, Dousti M . Hormone Replacement Therapy and Postmenopausal Cardiovascular Events: A Meta-Analysis, Iran Red Crescent Med J. Online ahead of Print ; 21(2):e82298. doi: 10.5812/ircmj.82298.

ARTICLE INFORMATION

Iranian Red Crescent Medical Journal: 21 (2); e82298
Published Online: February 27, 2019
Article Type: Systematic Review
Received: July 17, 2018
Revised: September 28, 2018
Accepted: January 29, 2019
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Abstract

Context: Hormone replacement therapy (HRT) is widely used to control postmenopausal symptoms. This therapy is also used to prevent diseases such as osteoporosis and dementia. However, clinical trials suggest some negative effects regarding postmenopausal HRT. This study evaluates the effects of HRT on postmenopausal cardiovascular events.

Evidence Acquisition: We collected data from 32 articles by using valid keywords and searching databases of PubMed, Medlib, ScienceDirect, EmBase, Scopus, Index Copernicus, SID, and Iranmedex. Analysis was performed by comparing three groups of postmenopausal women: combined hormone therapy (estrogen + progesterone), estrogen alone treated group, and placebo-receiving group (control group). Data were analyzed using the random effect model meta-analysis by using R software and Stata software Version 11.2.

Results: Of the collected 32 studies between 1998 and 2016, there were 1277686 subjects with an average age of 60.6 years. The prevalence of myocardial infarction were (2.64%), coronary heart disease (1.7%), stroke (254%), cardiovascular death (1.54%), revascularization (3.26 %), and cerebrovascular disease (CVD) (2.78%) in the combined hormone therapy group. Also, in the estrogen-treated group were 2.95%, 3.41%, 2.49%, 2.8%, - , 3.14%, respectively. In the placebo-receiving group these events were 2.09%, 2.73%, 2.9%, 2.25%, 4.96%, and 11.92, respectively. The results showed that estrogen therapy could increase the incidence of stroke. Moreover, HRT could have positive effects on the serum lipid profile in postmenopausal women.

Conclusion: Postmenopausal HRT appears to be non-effective on coronary artery disease, revascularization, myocardial infarction, and cardiac-related deaths; however, it could play a role in increasing the stroke rate.

Keywords

Cardiovascular Hormone Therapy Meta-Analysis Postmenopausal

Copyright © 2019, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited

1. Introduction

Menopause is considered to be a stage in the life of a woman, which is associated with permanent menstrual cessation and lack of ovarian hormonal activity. Today with increased life expectancy, almost a third of a woman life is during the postmenopausal period. After cardiac disease, menopause is the leading cause of elapsed years of life with disabilities in the age group of 45 - 70 years old (1, 2). Following the menopause and the decrease of ovarian activity accompanied by estrogen reduction, there are several symptoms such as menstrual disorder, vasomotor instability, genital atrophy, painful intercourse, itching, urethral inflammation, cystitis, and urinary incontinence. In long-term, major problems resulting from estrogen deprivation such as cardiovascular disease and osteoporosis threaten the health of postmenopausal women (3). There are significant changes in the level of lipoproteins and lipids (increased total cholesterol and LDL (low-density lipoprotein) and reduced HDL (High-Density Lipoprotein). These changes increase the risk of cardiovascular diseases (4). Cardiovascular diseases seem to be related to the menopause and this condition is one of the major causes of death in women with low-risk coronary artery disease (5). One measure available to support postmenopausal women's health is the use of hormone replacement therapy (HRT) in which steroid hormones are prescribed in the form of estrogen with or without progesterone (6). Although the protective effect of HRT against Alzheimer's, osteoporosis and urogenital atrophic changes (7) is currently known, some studies revealed that this treatment might increase the incidence of diseases such as breast cancer (8).

The long-term use of HRT in postmenopausal women to lessen cardiovascular diseases is debatable. Some doctors believe that HRT should not be prescribed to reduce the risk of cardiovascular diseases (9). Pharmacological evaluations have shown that estrogen and progesterone have cytoprotective properties, and thus they can affect the severity and frequency of cardiovascular events (10, 11). Several studies have displayed that HRT is associated with a drop in the risk of coronary artery disease (4, 12, 13); however, in several other randomized controlled trials, HRT has increased the risk of cardiovascular events such as coronary artery disease, stroke, and thromboembolic events (14-16). According to Women’s Health Initiative (WHI), combined estrogen-progesterone therapy increased 31% the risk of stroke compared with placebo. In estrogen therapy alone, the risk of stroke was significantly increased compared with placebo (17).

Neglecting the characteristics and clinical differences of the case and control groups, small sample sizes of the studied groups, short duration of follow-up, and the methodological limitations of observational studies could be among the reasons for these discrepancies in the results.

With this regards, it is not easy to decide whether to or not to use HRT, which also may be affected by the individual characteristics and beliefs of women and their doctors. An earlier meta-analysis (18) failed to demonstrate the beneficial use of HRT on cardiovascular events and declared that HRT does not affect coronary events and myocardial infarction; however, it can raise the risk of stroke in postmenopausal women.

Over the past two decades, various controlled randomized studies evaluated the effects of HRT on cardiovascular events in postmenopausal women on a large scale. However, due to the lack of inconsistency between the findings from these studies and also a better understanding of the effect of HRT on cardiovascular events, it seems necessary to conduct a meta-analysis study to assess the effect of HRT on cardiovascular events among postmenopausal women. Over time, improvements in medical facilities, the increase in community awareness, and attitudes of physicians and patients could be changed; therefore, updating the results of studies is essential to understand the effects of HRT in postmenopausal women.

2. Objectives

This work clarified data from randomized controlled trials about the effect of HRT on cardiovascular events in postmenopausal women by a meta-analysis.

3. Materials and Methods

3.1. Data Sources and Search Strategies

The present study is a meta-analysis of all data resources considering the effect of hormone replacement therapy on cardiovascular events in postmenopausal women. Using the acronym PICO (participants or population [P], intervention or exposure [I], comparison or comparator [C], and outcome [O]), the main concepts of the study search question identified. Hence, “P” stands for postmenopausal women, “I” for hormone therapy, “C” for comparing to the placebo group, and “O” for coronary heart disease, stroke, myocardial infarction, death from these diseases, and the need for revascularization. The study was conducted by the review and meta-analysis of existing electronic resources between 1998 and 2016. All scientific journals, as well as all articles presented at seminars and conferences and also all databases, including PubMed, Medlib, ScienceDirect, EmBase, Scopus, Index Copernicus, SID, and Iranmedex, were reviewed. The search for articles was mainly done in a systematic approach and by using valid keywords such as postmenopausal women, stroke, cardiovascular disease, randomized controlled trial, and their possible English combinations. Our keywords standardized in Mesh and ultimately the search string of ((( (hormone replacement therapy) OR estrogen replacement therapy) OR estradiol) OR progesterone) OR HRT))) AND (((cardiovascular) OR lipid profile) OR low-density lipoprotein) OR high-density lipoprotein) OR Cholesterol) OR LDL) OR HDL) OR Triglyceride) OR TG))) AND (((woman) OR female) AND Humans [Mesh]))) was used. Furthermore, the reference lists and citations of the selected articles were screened for relevant studies.

3.2. Study Selection

At first, a list of titles and abstracts of all collected articles were prepared by two researchers to select the related topics independently. Inclusion criteria consisted of (1) randomized controlled trial studies, (2) reported cardiovascular events in postmenopausal women, (3) done in the past twenty years [to reduce the effect of time passage]. Exclusion criteria consisted of (1) qualitative studies, (2) studies with no control group [The lack of a placebo control group may increase the effect of other factors and deteriorate the results], and (3) studies published in non-English language publications. The related articles independently entered the research process. If the two researchers did not agree on the choice of a particular article, the judgment left to the third researcher.

3.3. Data Extraction

In the next step, after determining the relevant study titles, the abstracts of various selected articles were evaluated by the researcher using the Ottawa quality assessment scale and studies with a score of below 3 were deleted. In the first stage, 19570 articles were found that according to the criteria mentioned for entry and exit, in total 32 articles were selected to enter the meta-analysis stage (Figure 1). The selected articles were completely evaluated and all of their data were extracted in a previously designed format, then the data entered Excel software. The Excel data sheet transferred to the R and the Stata software. The collected data were the author’s name, year of publication, the sample size in each study, mean age of participants, follow-up duration, underlying illness, regimen, and the frequency of risk factors for cardiovascular events. The evaluated cardiovascular events included the frequencies of coronary artery disease (CHD), myocardial infarction (MI), stroke, revascularization, cardiovascular mortality, and cardiovascular disease (CVD). Serum lipid profiles, including Low-Density Lipoprotein, High-Density Lipoprotein, total cholesterol and triglyceride (TG) levels were also recorded.

3.4. Data Synthesis and Analysis

Data pooled and analyzed based on sample size, mean, and standard deviation. Weight in each study is proportional to its reverse of variance. For evaluation of heterogeneity, Q-test and I2 index were tested at α error level less than 10%. In cases of heterogeneity, we used a random effect model for analysis. A subgroup analysis performed based on the mean age (mean age < 65 years or > 65 years) and the number of patients (< 10,000 persons or > 10,000 persons) in each treatment group. The data were analyzed using both R Statistical software and Stata Version 11.2 software.

4. Results

After removal of duplicates and unrelated studies, 32 papers from different countries were selected and appraised for analysis (Table 1). Figure 1 shows the study selection flow-chart. All studies were cross-sectional analytical studies. In all of these studies, a census sampling method had been used to collect information from the hospital profile and questionnaires, which were completed by interview and observation. In this meta-analysis, the Q-Cochran test showed incongruity of the findings in the selected studies (I2 = 98.3%), hence the Random Effects model was used in all subsequent stages. The total sample size was 1277686 persons with an average age of 60.6 years and a follow-up period of 2 to 16 years (average; 5.2 years).

Table 1. General Characters of Entered Studies
First AuthorSample SizeYearMean Age, yFollow-Up, yConditionInterventionsEvents
Herrington (16)309200065.83.2Coronary artery disease0.625 mg of CEE; 0.625 mg of CEE plus 2.5 mg of MPACHD, MI, Stroke, death, Lipid Profile Revascularization
Hulley (15)2763199866.74.1Coronary artery disease0.625 mg of conjugated estrogen and 2.5 mg of MPACHD, MI, Stroke, death, Lipid Profile Revascularization
Simon (19)2763200166.74.1Coronary artery disease0.625 mg of conjugated estrogen and 2.5 mg of MPAStroke, Lipid Profile
Grady (20)2763200266.76.8Coronary artery disease0.625 mg of conjugated estrogen and 2.5 mg of MPACHD, MI, Stroke, death, Lipid Profile Revascularization
Waters (21)423200265.52.815% - 75% coronary stenosis0.625 mg of CEE plus 2.5 mg of MPACHD, MI, Stroke, death, Lipid Profile
Rossouw (22)16608200263.25.2Healthy women0.625 mg of CEE plus 2.5 mg of MPACHD, MI, Stroke, death
Wassertheil-Smoller (17)16608200363.25.6Healthy women0.625 mg of CEE plus 2.5 mg of MPAStroke, death
Manson (23)16608200263.25.2Healthy women0.625 mg of CEE plus 2.5 mg of MPACHD,MI, Revascularization
Viscoli (24)664200171.52.8Recently had an ischemic stroke or transient ischemic attack1 mg of estradiol-17βCHD, MI, Stroke, death
Anderson (25)10739200463.66.8Previous hysterectomy0.625 mg of CEECHD, MI, Stroke, death, CVD
Veerus (26)1778200658.73.4Healthy women0.625 mg of CEE plus 2.5 mg of MPACHD, MI, Stroke
Vickers (27)4385200762.83.8Healthy women0.625 mg of CEE; 0.625 mg of CEE plus 2.5 mg of MPACHD, MI, Stroke, death
Harman (28)727201452.74Healthy women50 mcg/d of transdermal 17β-estradiol plus 0.45 mg/d of Oral CEECHD, MI, Stroke, Lipid Profile
Manson (29)27374201363.35.6Healthy women0.625 mg of CEE; 0.625 mg of CEE plus 2.5 mg of MPACHD, MI, Stroke, death, CVD
Hodis (30)643201655.45Healthy women1 mg of estradiol-17βCHD,MI, Lipid Profile
Schierbeck (31)100620125016Healthy women2 mg 17-β-estradiol plus 1 mg orethisterone acetateMI, Stroke, Lipid Profile
Rossouw (32)273472007655Healthy women0.625 mg of CEE; 0.625 mg of CEE plus 2.5 mg of MPACHD, Stroke, death
Manson (33)1064200755.28.7Healthy women0.625 mg of CEECHD
Heiss (34)15730200863.37.8Healthy women0.625 mg of CEE plus 2.5 mg of MPACHD, MI, Stroke, death, CVD, Revascularization
Lacroix (35)10739201164.510.7Previous hysterectomy0.625 mg of CEECHD, MI, Stroke, death, CVD, Revascularization
Shufelt (36)93676201462.310.4Healthy women0.625 mg of CEE; 0.625 mg of CEE plus 2.5 mg of MPACHD, Stroke, death, CVD
Renoux (37)75668201070.36.68Healthy women0.625 mg of CEE plus 2.5 mg of MPAStroke
Hernan (38)345752008605.9Healthy women0.625 mg of CEE plus 2.5 mg of MPACHD
Toh (39)16608201064.65.6Healthy women0.625 mg of CEE plus 2.5 mg of MPACHD
Huang (40)2763200966.75Coronary artery disease0.625 mg of CEE plus 2.5 mg of MPACHD
Grodstein (41)1217002008644Healthy women0.625 mg of CEE; 0.625 mg of CEE plus 2.5 mg of MPAStroke
Tannen (42)29201200763.66.8Previous hysterectomy0.625 mg of CEE; 0.625 mg of CEE plus 2.5 mg of MPAMI, Stroke, death
Bassuk (43)273472016657.2Healthy women0.625 mg of CEE; 0.625 mg of CEE plus 2.5 mg of MPACHD, MI, Stroke, death, CVD, Revascularization
Løkkegaard (44)6980982008606Healthy women0.625 mg of CEE plus 2.5 mg of MPAMI
Canonico (45)15797201656.7320% Stroke50 µg/d of estrogensStroke, Lipid Profile
Cherry (46)1017200262.62Previous myocardial infarction2 mg of oestradiol valerateCHD, MI, Stroke, death
Hodis (47)222200161.22low-density lipoprotein cholesterol, levels of 3.37 mmol/L or greater1 mg of estradiol-17βCHD, MI, Stroke, Lipid Profile

Abbreviations: CEE, combined estrogen hormone therapy; CHD, coronary artery disease; CVD, cerebrovascular disease; MI, myocardial infarction; MPA, medroxyprogesterone acetate.

Of this 32 article, 24 (410253 postmenopausal women) reported the effect of combined estrogen hormone therapy (CEE) and medroxyprogesterone acetate (MPA) versus placebo or estrogen. In 16 studies (108499 postmenopausal women) the therapeutic effects of estrogen alone was reported compared with placebo. Considering medical history, 23 studies were conducted on healthy postmenopausal women, 7 on postmenopausal women with the previous cardiovascular disease, and 2 on high-risk postmenopausal women (history of any of the factors of high blood pressure, hyperlipidemia, diabetes, and smoking). In all studies, risk factors for cardiovascular events (such as the history of hypertension, diabetes, smoking, etc.) were the same between groups.

The prevalence of coronary artery disease was 1.70% in the combined hormone therapy group after sensitivity analysis and removal of outlier studies in the remaining studies.

The results of these studies showed that combined hormone therapy could increase coronary events; however, this increase was not statistically significant (Figure 2).

The rate of coronary heart diseases with combination therapy (95% CI, random effect model)
Figure 2. The rate of coronary heart diseases with combination therapy (95% CI, random effect model)

The single effect of estrogen therapy on CHD was 3.41 (Figure 3). The prevalence of myocardial infarction was 2.73% after sensitivity analysis. Overall, combined hormone therapy did not significantly alter the risk of myocardial infarction compared with placebo (Table 2). In addition, the single effect of estrogen therapy on myocardial infarction was studied in 14 studies (after sensitivity analysis) and the prevalence of heart attacks was 2.64% in this group. In general, there was no evidence of the effect of estrogen therapy on the increased risk of myocardial infarction.

Table 2. The Frequency of Reported Events
Event/InterventionPrevalence
CHD
Combined1.7
Estrogen3.41
Placebo2.73
MI
Combined2.64
Estrogen2.95
Placebo2.09
Stroke
Combined2.54
Estrogen2.49
Placebo2.90
Death
Combined1.54
Estrogen2.80
Placebo2.25
Revascularization
Combined3.26
Estrogen-
Placebo4.96
CVD
Combined2.78
Estrogen3.14
Placebo11.92

Abbreviations: CHD, coronary artery disease; CVD, cerebrovascular disease; MI, myocardial infarction.

The rate of coronary heart diseases with estrogen treatment (95% CI, random effect model)
Figure 3. The rate of coronary heart diseases with estrogen treatment (95% CI, random effect model)

The prevalence of stroke after sensitivity analysis was 2.54% in the remaining 15 studies. Overall, combined hormone therapy did not significantly change the risk of stroke compared with placebo (Figure 4).

Stroke rate with combination therapy (95% CI, random effect model)
Figure 4. Stroke rate with combination therapy (95% CI, random effect model)

Also, the effect of estrogen therapy alone on stroke was studied in 17 studies (after sensitivity analysis), and the prevalence of stroke was 2.49% in this group. Generally, estrogen therapy was associated with an increased risk of stroke (Figure 5).

Stroke rate with estrogen treatment (95% CI, random effect model)
Figure 5. Stroke rate with estrogen treatment (95% CI, random effect model)

The impact of hormone therapy (combination therapy or estrogen therapy alone) on the frequency of cardiovascular mortality, revascularization, and cerebrovascular diseases (CVDs) were presented in Table 2.

Interestingly, this study showed some important findings in the lipid profile of postmenopausal women. In comparison to the placebo group, combined hormone therapy reduced serum Low-Density Lipoprotein and total cholesterol levels meanwhile increased serum High-Density Lipoprotein and triglyceride concentrations. The study also showed that estrogen therapy increased serum triglycerides, High-Density Lipoprotein meanwhile decreased serum Low-Density Lipoprotein and total cholesterol levels compared with placebo. However, none of the changes were statistically significant (Table 3).

Table 3. Serum Lipoprotein Profile
InterventionLDL, mg/dLHDL, mg/dLTotal Cholesterol, mg/dLTG, mg/dL
Combined hormone133.253217.3160.1
Estrogen130.854.3217.1147.2
Placebo136.653.8217.6146.9

Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride.

To determine the effect of age on the onset of hormone therapy on cardiovascular events, studies were categorized into two groups based on population age (< 65-year old or > 65-year old). Twenty-two studies were in the group under 65 years and ten studies in the group over 65 years (Table 1). In the group more than the 65-year-old, the incidence of cardiovascular events was higher than those under 65-year old (Table 4). In a subgroup analysis of the study population (15 studies < 10,000 persons and 17 studies > 10,000 persons), the incidence of cardiovascular events was higher in subgroups below 10,000 persons (Table 4). According to the publication bias analysis, the effect of bias in these studies was not significant (P = 0.317).

Table 4. Hormone Replacement Therapy and Cardiovascular Events in Subgroup Analysis
Event/InterventionSubgroups
Mean Age > 65 yMean Age < 65 yStudy Population < 10000Study Population > 10000
CHD
Combined19.64.920.22.4
Estrogen108.7913.14.6
Placebo12.28.0716.93.2
MI
Combined7.22.84.43.3
Estrogen4.63.713.54.4
Placebo7.162.194.52.4
Stroke
Combined9.024.26.45.1
Estrogen10.63.58.54.3
Placebo7.62.15.62.7
Death
Combined5.11.66.22.07
Estrogen7.72.86.53.6
Placebo7.52.27.42.2
Revascularization
Combined8.459.910.53.3
Estrogen57.5-7.5
Placebo14.4316.36
CVD
Combined108.5--
Estrogen813.5--
Placebo1514--

Abbreviations: CHD, coronary artery disease; CVD, cerebrovascular disease; MI, myocardial infarction.

5. Discussion

The present meta-analysis was designed to evaluate all studies about the effect of postmenopausal hormone replacement therapy on cardiovascular diseases. This study revealed that combined hormone therapy is associated with an increased risk of stroke meanwhile did not affect the rate of coronary artery disease, cerebrovascular disease, revascularization, heart attacks, and cardiovascular mortality. We also found that estrogen therapy is associated with an increased stroke rate and a decreased revascularization rate, meanwhile did not affect the rate of coronary artery disease, myocardial infarction, and the death rate of cardiovascular or cerebrovascular disease events. Moreover, the evaluation of lipid profiles showed that hormone therapy could have a favorable effect on serum lipid profiles of postmenopausal women.

Interestingly, the findings of this study suggest that hormone therapy does not affect coronary heart disease (CHD), myocardial infarction (MI), cardiac death, revascularization, and cerebrovascular disease. Two other previous meta-analytic studies (18, 48) showed similar results. On the other hand, this study contrasted with that of many prior observational studies in evaluating cardiovascular events, suggesting that hormone therapy can reduce cardiovascular events (49-52).

Lack of significant difference in the incidence of coronary artery disease in women receiving HTR or placebo could be due to the protective effects of estrogen and progesterone on the lipid profile of postmenopausal women. Cardiovascular diseases are multifactorial but many studies have shown the association of serum lipid level with these diseases (53). Serum triglyceride level has a strong relationship with atherogenic properties of Low-Density Lipoprotein particles. This relationship may increase Low-Density Lipoprotein atherogenic properties and the risk of coronary artery disease up to three times (54). In an epidemiological study, there was an inverse association between the level of High-Density Lipoprotein and the incidence of atherosclerosis (55). The clearance of chylomicrons and also chylomicron residues is increased with hormone therapy, which can be a protective effect of estrogen against cardiovascular diseases (56). Nevertheless, estrogen has adverse physiological effects such as increased serum triglyceride and Low-Density Lipoprotein level, and also increased inflammatory factors such as C-reactive protein. These adverse effects could reduce estrogen’s cardiovascular protective effects (57, 58).

Moreover, this study revealed that the prevalence of coronary artery disease was higher in postmenopausal women who received combined hormone therapy in comparison to those of estrogen therapy alone (Table 2). The reason could be that the estrogen significantly reduces serum Low-Density Lipoprotein and total cholesterol levels while progesterone (MPA) positively moderated blood lipid levels (13, 59).

Remarkably, this review suggested that HRT in comparison to placebo leads to an increase in the incidence of stroke (Table 2). This rise presumably is due to the impact of hormones on coagulation pathways and inflammatory factors. The estrogen has an impact on the synthesis of some coagulation factors such as plasminogen, fibrinogen, and C-reactive protein (60-62). Estrogen increases the sensitivity of brain neurons to ischemic conditions (63), which could increase the stroke rate. There was no significant difference between the relative risk of myocardial infarction, cerebrovascular disease, and cardiovascular mortality of HRT and placebo groups (Table 2). The reason for this may be the fact that despite the positive effects of HRT on the cardiovascular system, coincidently HRT has a negative effect on the cardiovascular system through its effect on coagulation and inflammatory factors. Studies have shown that increasing the amount of coagulation and inflammatory factors (especially C-reactive protein) is responsible for the development of cardiovascular disease (64).

Data analysis based on the mean age as a mediating factor suggested an increase in the incidence of cardiovascular events with increased age. However, this was not an unexpected event considering the impact of higher age on cardiovascular events (65).

Overall, this study showed that HRT could have positive effects on serum lipoprotein levels in postmenopausal women, which is consistent with the results of previous studies (66-68) and this can justify part of the effects of HRT on cardiovascular events. As seen in the 5th paragraph of the discussion, this effect could be small in the case of combined hormone therapy.

5.1. Weaknesses and Strengths

The most important limitations to this study are as follow (1) Different period of tracking the effects of HRT in collected studies that may affect HRT regarding cardiovascular events. (2) Differences between reviewed articles such as dosage, HRT technique, and duration of HRT in postmenopausal women. (3) Based on the intrinsic character of our meta-analysis, our data were derived from the published articles or information provided by the authors, which resulted in our lack of access to the original data and consequently lack of comprehensive analysis of the source data. 4) The articles in this study did not address the socioeconomic status of women. The socioeconomic status of postmenopausal women could affect HRT regarding cardiovascular events (69).

This meta-analysis carried out on high-quality studies. Statistical findings did not show significant heterogeneity between the appraised studies and the similarities were more than the differences. However, small differences existed such as the hormone dosage, the method hormone received, and the racial differences of the subjects, which could affect the results. The important strength point of this article is the use of high-quality studies and comparable features. All studies were homogeneous, with a placebo-control group, and acceptable randomizations.

Despite these limitations, this study suggests that HRT is not recommended for the prevention of cardiovascular events in postmenopausal women. Menopausal women who have intolerable symptoms may benefit from HRT in relieving menopausal symptoms. HRT could also be useful in preventing osteoporosis and improving their quality of life; however, it increases the risk for certain diseases such as stroke. Hence, the balance between the advantages and disadvantages of HRT should be assessed individually by the physician for each patient.

Footnotes

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