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The effects of transdermal estrogens combined with Medroxyprogesterone Acetate on cardiovascular disease risk factors in postmenopausal women: a meta-analysis of randomized controlled trials

Diabetology & Metabolic Syndrome volume 17, Article number: 111 (2025) Cite this article

Abstract

Background

To date, no meta-analysis has reported on the role of transdermal estrogens combined with Medroxyprogesterone Acetate (MPA) in relation to cardiovascular disease (CVD) risk factors in postmenopausal women. To fill this knowledge gap, a meta-analysis of randomized controlled trials (RCTs) was conducted to assess the effects of transdermal estrogens and MPA on CVD risk factors in postmenopausal women.

Methods

A systematic literature search was conducted in major databases including PubMed/Medline, Web of Science, SCOPUS, and Embase, from inception to 12 February 2025. The combination of Medical Subject Headings (MeSH) and non-MeSH keywords was used.

Results

A total of 14 trials were included in the meta-analysis. The combined eligible trials found that transdermal estrogens combined with MPA significantly decreased total cholesterol (TC) (WMD: -13.37 mg/dL, 95% CI: -21.54 to -5.21, p = 0.001), low density lipoprotein cholesterol (LDL-C) (WMD: -12.17 mg/dL, 95% CI: -23.26 to -1.08, p = 0.031), and apolipoprotein B (ApoB) (WMD: -7.26 mg/dL, 95% CI: -11.48 to -3.03, p = 0.001) compared to the control. No statistically significant associations were observed between transdermal estrogens combined with MPA on triglyceride (TG), high density lipoprotein cholesterol (HDL-C), lipoprotein(a) (Lp(a)), and apolipoprotein A1 (ApoAI).

Conclusion

Based on the results of the current meta-analysis, transdermal estrogens combined with oral MPA administration had a beneficial effect on certain CVD risk factors in postmenopausal women, as evidenced by the significant reductions in TC, LDL-C, and ApoB.

Introduction

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, with one-third of global deaths attributed to it [1, 2]. The risk of CVD increases with menopause, as postmenopausal women experience a reduction in cardioprotective effects [3]. Globally, the prevalence of CVD risk rate inclined from 0.061 to 0.070% in 2019 compared to 2020, with women having the higher prevalence [4]. There is a 2.6 time increased incidence of CVD events in postmenopausal women compared to premenopausal women of similar age group [3]. Estrogen levels decrease during menopause, and studies have shown that estrogen plays a key role in cardioprotection [5]. Hormone replacement therapy (HRT) is commonly recommended for postmenopausal women to alleviate urogenital and vasomotor symptoms [6]. During menopause, the risk factors for CVD, including dyslipidemia, diabetes mellitus, and hypertension, also increase [7, 8].

Before menopause, men are more commonly affected by CVD than women, but women tend to develop CVD later in life compared to men [9]. Postmenopausal women are believed to be at a higher risk of CVD, as this risk typically increases during the perimenopausal stage [10]. This elevated risk is associated with changes in lipoprotein, lipid, and sex hormone levels [11]. These factors highlight the importance of monitoring CVD risk factors in postmenopausal women. Studies have shown that increased levels of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (ApoB) are directly correlated with an increased risk of CVD [12].

As estrogen levels decrease in postmenopausal women and given estrogen’s significant role in reducing CVD risk, HRT is recommended to mitigate this risk [13]. For example, transdermal HRT has been shown to reduce CVD risk in women. A randomized controlled trial (RCT) suggested that transdermal estrogen in combination with progestin may reduce the risk of CVD in women, by significantly decreasing the activity of factor VII [14]. A meta-analysis found that in postmenopausal women, total cholesterol (TC), LDL-C, and triglycerides (TG) were reduced with the combination of transdermal estradiol and norethisterone acetate [15]. Another meta-analysis demonstrated that lipoprotein(a) (Lp(a)) and ApoB levels were decreased in postmenopausal women treated with a combination of estradiol and norethisterone acetate [16]. The combination of estrogen and progestin was also found to have a beneficial impact on TC and LDL-C in postmenopausal women. The authors reported that transdermal estrogen combined with progestin had favorable effects on TC and LDL-C, suggesting its use in CVD risk reduction [17]. Similarly, TC and TG levels were reduced in women treated with medroxyprogesterone acetate (MPA) [18]. HRT has beneficial effects on lipoprotein concentrations, which could be the mechanism behind its cardioprotective effect, reducing the risk of CVD by 50% in postmenopausal women [19]. Moreover, transdermal estrogen with progestin had a beneficial impact on triglyceride and coagulation factors, compared to oral estrogen progestin combination [20].

To date, no meta-analysis has reported on the role of transdermal estrogens combined with oral MPA in relation to CVD risk factors in postmenopausal women. To address this gap in knowledge, a meta-analysis of RCTs was conducted to assess the effects of transdermal estrogens and oral MPA on CVD risk factors in postmenopausal women.

Methods

We applied the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to investigating the effects of transdermal Estrogens combined with Oral MPA on cardiovascular disease risk factors in postmenopausal women [21].

Search strategy

The systematic literature search was executed in main databases including PubMed/Medline, Web of Science, SCOPUS, and Embase from inception to 12 February 2025 without language or time restrictions. The combination of Medical Subject Headings (MeSH) and non-MeSH keywords was used as follows: (Medroxyprogesterone Acetate OR “Depo-Medroxyprogesterone Acetate” OR " Depo Medroxyprogesterone Acetate” OR Sayana” OR estrogen OR estrogen replacement therapy OR “Provera” OR " hormone replacement therapy OR estradiol OR progestin therapy OR progestin OR progestin OR *progesterone OR HRT OR medrogestone) AND transdermal AND (‘Clinical Trials’ OR ‘RCT’ OR ‘Trial’ OR ‘intervention’ OR ‘Intervention Studies’ OR ‘randomized’ OR ‘controlled trial’ OR ‘random’ OR ‘placebo’ OR ‘randomized’) (Supplementary Table 1). In addition, we searched reference lists from all the relevant articles to detect additional eligible papers.

Eligibility criteria

All original randomized controlled trials (RCTs) with parallel or crossover designs that evaluated the effects of transdermal estrogens combined with medroxyprogesterone acetate on apolipoprotein A1 (ApoAI), ApoB, lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), and met the following inclusion criteria, were included in this meta-analysis. Eligibility criteria for the search and meta-analysis were defined using the PICOS framework: (1) Population (P): Postmenopausal women. (2) Intervention (I): Transdermal estrogens combined with oral MPA. (3) Comparison (C): A control group. (4) Outcomes (O): Sufficient data on at least one outcome measure in both control and intervention groups. (5) Study design (S): Original RCTs.

Papers were excluded based on following items: (i) case-control studies/ series (ii) preclinical studies, (iii) letters, reviews, editorials or commentaries, (iv) duplicated studies (v) studies not measuring outcomes of interest; grey literature (theses, congress proceedings, and technical reports etc.) and (vi) studies investigating the impacts of transdermal Estrogens combined with Oral MPA in combination with other medications (e.g. drugs).

Data extraction

Data were collected independently by two investigators, moreover the discrepancies between were resolved by head author. Extracted data included the following: (i) study design, (ii) characteristics of the studied sample (age of in postmenopausal women, health status) (iii) study location, (iv) study details (sample size, name of the study first author, year of publication, trial duration), (iv) transdermal Estrogens combined with Oral MPA dosage and (v) mean and SD of the post-intervention outcome measures (biochemical parameters).

Quality assessment

The risk of bias in the included publications was assessed using the Cochrane ROB2 tool [22, 23]. This assessment considered bias arising from the randomization process, deviations from intended interventions, missing outcome data, outcome measurement bias, selection bias in reporting results, and overall bias. The overall quality of the papers was categorized as having low risk, some concerns, or high risk of bias based on the evaluation criteria mentioned. Additionally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the certainty of evidence, categorized as very low, low, moderate, or high [23].

Data synthesis and statistical analysis

Statistical analyses were conducted using STATA software (version 14; Stata Corporation, College Station, Texas, USA). The sample size, mean, and standard deviation (SD) for outcome measures pre- and post-intervention of transdermal estrogens combined with oral medroxyprogesterone acetate (MPA) were used to calculate the overall effect size, reported as weighted mean differences (WMDs) with 95% confidence intervals (CIs).

A random-effects model was employed to account for potential heterogeneity among studies, as variations in study populations, interventions, and methodologies were expected. The choice of this model over a fixed-effects model was based on the assumption that the true effect size may vary across studies rather than being identical. To assess heterogeneity, Higgins’ I2 statistic was calculated, with a p-value < 0.1 and I2 values above 50% indicating moderate to high heterogeneity.

When standard deviations were not reported in an appropriate form, standardized formulas were applied to derive the SD from available data (e.g., conversion from standard error of the mean (SEM), medians with ranges, or 95% CIs) [24, 25]. Publication bias was assessed using funnel plots and Egger’s regression test [26]. If publication bias was detected, the trim-and-fill method was applied to estimate the impact of potentially missing studies [27]. A sensitivity analysis was performed by systematically removing each study and recalculating the overall effect size. Statistical significance was set at p < 0.05.

Results

Study selection

Figure 1 demonstrated the flow diagram of the study selection process. Out of 8346 relevant papers that were initially retrieved in the systematic search, 2738 duplicate articles were removed. The remaining 5608 articles were reviewed, of which 5527 publications were excluded according on title and abstract. Afterward, 81 papers were selected for further examination of full texts. Of these records, 70 publications were excluded. Finally, a total of 11 articles with 14 arms were included in the meta-analyses [28,29,30,31,32,33,34,35,36,37,38].

Fig. 1
figure 1

Flow chart for study examined and included into the meta-analysis

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Study characteristics

The general characteristics of the 11 eligible RCTs are summarized in Table 1. The studies were published between 1993 and 2008 and conducted in Japan, USA, Norway, Switzerland, Sweden, Canada, Spain, and Italy. The studies comprising Postmenopausal women of varying age from 48 to 58.6 years. The study populations included healthy postmenopausal women, postmenopausal women with type 2 diabetes, overweight or obese postmenopausal women, postmenopausal women with coronary disease, surgically postmenopausal women following hysterectomy, and hypertensive postmenopausal women. Duration of transdermal Estrogens combined with Oral MPA intervention varied from 3 to 24 months.

Table 1 Characteristics of the eligible studies
Full size table

Daily dosages varied from 2.5 to 10 mg/day for MPA and from 36 mg/day to 50 mg/day for transdermal 17b-estradiol. The baseline BMI were varied between 24 and 34. Supplementary Table 2 provides information on the quality of the eligible studies.

Findings from Meta-analysis

Effects of transdermal estrogens combined with oral Medroxyprogesterone acetate on TG

Combined 9 eligible trials including 373 sample sizes (transdermal Estrogens combined with Oral MPA = 194, placebo = 179), discovered no significant impact of transdermal Estrogens combined with Oral MPA on TG compared to the control (WMD: -2.91 mg/dL, 95% CI: -11.66 to 5.83, P = 0.514), with significant heterogeneity among studies (I2 = 63.3%, p = 0.005) (Fig. 2).

Fig. 2
figure 2

Forest plot of the randomized controlled trials investigating the effects of transdermal Estrogens combined with Oral Medroxyprogesterone Acetate administration on TG

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Effects of transdermal estrogens combined with oral Medroxyprogesterone acetate on TC

Combined 9 eligible trials including 373 sample sizes (transdermal Estrogens combined with Oral MPA = 194, placebo = 179), discovered transdermal Estrogens combined with Oral MPA significantly decrease TC compared to the control (WMD: -13.37 mg/dL, 95% CI: -21.54 to -5.21, p = 0.001), with significant heterogeneity among studies (I2 = 62%, p = 0.007) (Fig. 3).

Fig. 3
figure 3

Forest plot of the randomized controlled trials investigating the effects of transdermal transdermal Estrogens combined with Medroxyprogesterone Acetate administration on TC

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Effects of transdermal estrogens combined with oral Medroxyprogesterone acetate on LDL-C

Combined 7 eligible trials including 290 sample sizes (transdermal Estrogens combined with Oral MPA = 149, placebo = 141), discovered transdermal Estrogens combined with Oral MPA significantly decrease LDL-C compared to the control (WMD: -12.17 mg/dL, 95% CI: -23.26 to -1.08, p = 0.031), with significant heterogeneity among studies (I2 = 62%, p = 0.013) (Fig. 4).

Fig. 4
figure 4

Forest plot of the randomized controlled trials investigating the effects of transdermal Estrogens combined with Oral Medroxyprogesterone Acetate administration on LDL-C

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Effects of transdermal estrogens combined with oral Medroxyprogesterone acetate on HDL-C

Combined 7 eligible trials including 290 sample sizes (transdermal Estrogens combined with Oral MPA = 149, placebo = 141), discovered transdermal Estrogens combined with Oral MPA not significantly decrease HDL-C compared to the control (WMD: 0.96 mg/dL, 95% CI: -2.42 to 4.35, p = 0.576), with significant heterogeneity among studies (I2 = 55.5%, p = 0.028) (Fig. 5).

Fig. 5
figure 5

Forest plot of the randomized controlled trials investigating the effects of transdermal Estrogens combined with Medroxyprogesterone Acetate administration on HDL-C

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Effects of transdermal estrogens combined with oral Medroxyprogesterone acetate on Lp(a)

Combined 2 eligible trials including 62 sample sizes (transdermal Estrogens combined with Oral MPA = 24, placebo = 38), discovered transdermal Estrogens combined with Oral MPA not significantly decrease Lp(a) compared to the control (WMD: -2.75 mg/dL, 95% CI: -9.94 to 4.43, p = 0.453), without significant heterogeneity among studies (I2 = 0.0%, p = 0.604).

Effects of transdermal estrogens combined with oral Medroxyprogesterone acetate on ApoAI

Combined 4 eligible trials including 206 sample sizes (transdermal Estrogens combined with Oral MPA = 109, placebo = 97), discovered transdermal Estrogens combined with Oral MPA not significantly increase ApoAI compared to the control (WMD: 0.93 mg/dL, 95% CI: -8.56 to 10.43, p = 0.847), with significant heterogeneity among studies (I2 = 78%, p = 0.003).

Effects of transdermal estrogens combined with oral Medroxyprogesterone acetate on ApoB

Combined 4 eligible trials including 206 sample sizes (transdermal Estrogens combined with Oral MPA = 109, placebo = 97), discovered transdermal Estrogens combined with Oral MPA significantly decrease ApoB compared to the control (WMD: -7.26 mg/dL, 95% CI: -11.48 to -3.03, p = 0.001), without significant heterogeneity among studies (I2 = 0.0%, p = 0.791).

Sensitivity analysis

The direction and magnitude of the overall pooled estimates was not considerably influenced by removing a single study each time, denoting that the data were not excessively influenced by each study.

Publication bias

Visual inspection of funnel plots and Egger’s linear regression test revealed no evidence of publication bias in the meta-analysis of transdermal Estrogens combined with Oral MPA effects on ApoAI, ApoB, lipoprotein(a), LDL-C, TC, TG, and HDL-C (Fig. 6).

Fig. 6
figure 6

Funnel plot of the weighted mean difference (WMD) versus the standard error (s.e.) of the WMD

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Discussion

Despite optimistic outcomes, the effects of transdermal estrogens combined with oral MPA on CVD risk factors in postmenopausal women remain debatable. This meta-analysis of RCTs aimed to collate all available information on the effects of this combination on feasible CVD risk factors in postmenopausal women. Data from 11 articles with 14 study arms were included in this meta-analysis, based on the inclusion and exclusion criteria. The analysis focused on postmenopausal women who were either healthy, had type 2 diabetes, were overweight or obese, had coronary disease, had undergone hysterectomy, or were hypertensive. The current review found that transdermal estrogens combined with oral MPA significantly reduced TC, LDL-C, and ApoB levels.

Our study demonstrated a significant effect of transdermal estrogens combined with oral MPA on LDL-C and TC, but not on TG and HDL-C. Similar and conflicting results have been reported in other studies. For instance, oral conjugated equine estrogen was shown to decrease TC and LDL-C while increasing TG and HDL-C, whereas transdermal estradiol had minimal impact on the lipid profile [39]. A meta-analysis reported that a combination of transdermal 17β-estradiol and norethisterone acetate decreased TC and LDL-C without affecting TG and HDL-C [15]. Another clinical trial found that a combination of estrogen and progestogen decreased TC and HDL-C [40]. Additionally, a meta-analysis indicated that MPA administration reduced TC and HDL-C but increased LDL-C, although this increase was not statistically significant [18]. The discrepancies in these results are likely due to differences in the routes of administration. A meta-analysis of RCTs illustrated that every 1 mmol/L decrease in LDL-C could reduce the CVD risk by 23% [41]. In our study, there was 12.17 mg/dL decrease in LDL-C which is equivalent to 0.7 mmol/l reduction in LDL-C, which definitely has an impact in reducing the CVD risk. Our study specifically assessed the effects of transdermal estrogens combined with oral MPA. The transdermal route offers several benefits, including avoiding first-pass metabolism, which increases drug bioavailability [42]. Oral drug administration has been associated with a rise in HDL-C, whereas transdermal administration has not [43]. In our study, transdermal estrogens combined with oral MPA resulted in a non-significant increase in HDL-C and a non-significant decrease in TG.

Our meta-analysis also revealed a significant decrease in ApoB, a non-significant increase in ApoAI, and a non-significant decrease in Lp(a). A recent meta-analysis reported that estradiol and norethisterone acetate significantly reduced Lp(a) concentrations [16]. However, that meta-analysis focused solely on oral estrogen administration, whereas our analysis examined transdermal estrogen administration. The route of administration significantly impacts the effect of HRT on Lp(a). The oral route has been shown to reduce Lp(a) concentrations [44], in contrast to transdermal administration [45]. Similarly, previous studies have shown a reduction in Lp(a) levels with HRT [46], but these studies did not include progesterone.

Consistent with our findings, a meta-analysis reported that estradiol and norethisterone acetate significantly decreased ApoB levels without significantly affecting ApoAI [16]. A clinical trial also found that a combination of estrogens and progestins enhanced the reduction of ApoB compared to unopposed estrogens [47]. Preclinical studies have suggested that coronary arteries can locally synthesize estrogen, enhancing the anti-atherogenic properties of HRT. However, it should be noted that aging in women downregulates estrogen receptors [48].

Overall, the alterations in lipoprotein concentrations observed with this combination of transdermal estrogens and oral MPA are generally favorable, given the significant reductions in TC, LDL-C, and ApoB levels. Non-HDL-C and ApoB are recognized markers of CVD risk [49], and various studies have suggested that ApoB is a reliable predictor of CVD risk [50]. A meta-analysis reported that 10 mg/dL decrease in ApoB causes 6% decline in major CVD risk and 9% decline in the risk of coronary heart disease [51]. Our study showed a 7.26 mg/dL decrease in ApoB, which causes 4.4% decrease in CVD risk.

In clinical practice, transdermal estrogens combined with oral MPA can be recommended for postmenopausal women at high risk of CVD. However, it is crucial that the regimen be personalized, with healthcare professionals considering the cumulative dose of combined transdermal estrogens and oral MPA when making clinical judgments and prescribing for women with CVD risk.

Strengths and limitations

A notable strength of this study is that it is the first meta-analysis of RCT data to assess the effects of transdermal estrogens combined with oral MPA on CVD risk factors in postmenopausal women. The risk of bias was evaluated using the Cochrane ROB2 tool, and publication bias was assessed through funnel plots and Egger’s regression statistics, which provided noteworthy results.

The major limitation of this meta-analysis is the considerable heterogeneity among the trials, due to difference in regimens, doses, duration, population setting, and the study population, which may have affected the validity of study results. Another drawback is the inability to perform subgroup analyses regarding the duration and dosage of the drug due to insufficient data. Majority of studies included in the meta-analysis originated from the Western countries, and hence extrapolation of these results to Eastern populations is questionable. Most of the included RCTs possess significant sources of bias and the results should be interpreted with caution. There were only 4 arms on ApoA-I, 4 arms on ApoB, and 2 on lipoprotein (a), and hence the evidence to support these variables is low.

Conclusion

Based on the results of this meta-analysis, the administration of transdermal estrogens combined with oral MPA had a beneficial effect on certain CVD risk factors in postmenopausal women, as evidenced by significant reductions in TC, LDL-C, and ApoB. Since these parameters play a significant role in reducing CVD risk, treatment with transdermal estrogens combined with oral MPA could be recommended for postmenopausal women at high risk of CVD. However, the regimen should be personalized, and healthcare professionals should consider the cumulative dose of the combined treatment when making clinical judgments and prescribing for women with CVD risk.

Data availability

All data generated or analyzed during this study are included in this published article, and you can find these data in references.

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Authors and Affiliations

  1. Laboratory of Molecular Medicine, Puren Hospital, No. 1 Benxi St, Qingshan Dist, Wuhan City, 430080, China

    Fan Zhou

  2. Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia

    Kousalya Prabahar

  3. Department of Reproductive Medicine, Puren Hospital, No. 1 Benxi St, Qingshan Dist, Wuhan City, 430080, China

    Jiao Shu

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The authors’ contributions were as follows: F.Z, J.S, and K.P carried out the research, data analysis, and statistical assessment. F.Z, J.S, and K.P were involved in writing and structuring the manuscript. All authors reviewed and approved the final version of the manuscript.

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Zhou, F., Prabahar, K. & Shu, J. The effects of transdermal estrogens combined with Medroxyprogesterone Acetate on cardiovascular disease risk factors in postmenopausal women: a meta-analysis of randomized controlled trials. Diabetol Metab Syndr 17, 111 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-025-01664-1

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Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

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