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. 2020 Mar 10;14:157. doi: 10.3389/fnins.2020.00157

The Effect of Estrogen Replacement Therapy on Alzheimer's Disease and Parkinson's Disease in Postmenopausal Women: A Meta-Analysis

Yu-jia Song 1, Shu-ran Li 1, Xiao-wan Li 1, Xi Chen 1, Ze-xu Wei 1, Qing-shan Liu 1,*, Yong Cheng 1,*
PMCID: PMC7076111  PMID: 32210745

Abstract

Background: Estrogen replacement therapy (ERT) is a common treatment method for menopausal syndrome; however, its therapeutic value for the treatment of neurological diseases is still unclear. Epidemiological studies were performed, and the effect of postmenopausal ERT on treating neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), was summarized through a meta-analysis.

Methods: Twenty-one articles were selected using a systematic searching of the contents listed on PubMed and Web of Science before June 1, 2019. Epidemiological studies were extracted, and relevant research data were obtained from the original articles based on the predefined inclusion criteria and data screening principles. The Comprehensive Meta-Analysis Version 2 software was used to pool effective size, test heterogeneity, conduct meta-regression and subgroup analysis, and to calculate publication bias.

Results: Our results showed that ERT significantly decreased the risk of onset and/or development of AD [odds ratio (OR): 0.672; 95% CI: 0.581–0.779; P < 0.001] and PD (OR: 0.470; 95% CI: 0.368–0.600; P < 0.001) compared with the control group. A subgroup and meta-regression analysis showed that study design and measure of effect were the source of heterogeneity. Age, sample size, hormone therapy ascertainment, duration of the treatment, or route of administration did not play a significant role in affecting the outcome of the meta-analysis.

Conclusion: We presented evidence here to support the use of estrogen therapy for the treatment of AD and PD.

Keywords: estrogen replacement therapy, Alzheimer's disease, Parkinson's disease, meta-analysis, systematic review

Introduction

Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the sustained cell cycle arrest and production of a continuous senescence-associated secretory phenotype due to structural and functional changes in neurons (Kritsilis et al., 2018). According to global epidemiological data, between 2000 and 2013, death from AD increased by 71% (Prince et al., 2013). Next to AD in terms of incidence, PD is the second most common neurodegenerative disease and is characterized by the progressive damage of mesencephalic dopaminergic (DA) neurons of the substantia nigra (SN) and the striatal projections. The prevalence rate of PD was 100–200 per 100,000 people, and the annual incidence was 15 per 100,000 people in the United States (Ascherio and Schwarzschild, 2016). Neurodegenerative diseases often persist in the brain, making their pathogenesis difficult to study. Thus, it is urgent to develop effective prevention and treatment methods for the disease.

Some researches indicated that the risk of AD development and the severity differed significantly between men and women. The incidence of AD was two to three times higher among women than men, and premature menopause would increase the risk of onset and/or developing AD (Pike, 2017). PD was consistently observed to occur at a lesser frequency in women than in men at an approximate ratio of 1:1.5. During the progression of PD, female patients were usually associated with a more benign phenotype, suggesting the possible beneficial effect of estrogen (Picillo et al., 2017). The data suggest that perimenopause may increase the patient's vulnerability of developing neurological diseases, thus it may be a good window to perform menopausal hormone therapy for beneficial effects on patient's cognitive function.

A number of research reviews and in vivo and in vitro experiments with meta-analysis have been conducted to normalize clinical data due to individual differences in the link between estrogen replacement therapy (ERT) and its treatment effect on AD and PD. Several studies demonstrated that AD-related cognitive decline was improved and a lower risk of onset and/or developing AD was observed following the menopausal hormone therapy (Hogervorst et al., 2000; Bagger et al., 2005; Yesufu et al., 2007). However, controversial results have been reported. Other studies did not show significant differences between ERT and AD (Yaffe et al., 1998; Mulnard et al., 2000). Moreover, two studies advised that ERT should not be used for AD prevention (Shumaker et al., 2003; O'Brien et al., 2014). For PD, some investigations showed that there was an association between postmenopausal ERT and a lower risk of PD (Ragonese et al., 2004), while others did not observe such association (Rugbjerg et al., 2013). There has been no systematic meta-analysis for the connection between ERT and the risk of onset and/or developing PD.

In general, previous reviews relied mainly on qualitative analyses. The existing meta-analysis cannot reach a unified conclusion on whether there is a correlation between ERT, AD, and PD. Therefore, to address the inconsistent data, we included relevant scientific data prior to June 2019 and conducted a systematic and comprehensive analysis of the relationship between ERT and the risk of onset and/or developing AD and PD.

Methods

Study Selection and Data Collection

Relevant foreign literature was searched by two independent researchers from databases including PubMed and Web of Science. The following keywords were used as search input: estrogen therapy, ERT, hormone therapy, hormone replacement therapy, Alzheimer's disease, AD, Parkinson's disease, and PD. There was no year restriction applied. Additional articles were selected from the reference section of certain publications. Only full-text journal articles with accessible data for analysis were included.

The initial search yielded 3,668 records from PubMed and 3,201 records from Web of Science. After the screening of titles and abstracts, 6,758 records were excluded because they were not related to our present subject. The remaining 111 articles were selected for full-text scrutiny. Ninety studies were excluded due to no usable data (n = 50), no control group (n = 21), meta-analyses studies (n = 13), or repeated analysis with some documents (n = 6). Therefore, a total of 21 studies with 1,266 patient cases and 3,845 control cases were included in this meta-analysis. A flowchart of the selection process was presented in Figure 1.

Figure 1.

Figure 1

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Flowchart describing the approach used to identify eligible studies. We conducted a systematic search on Medline (via PubMed and Web of Science) and covering all articles up until June 1, 2019.

Data Extraction

For each selected study, the following data were extracted: study design, number of participants, number of AD case, number of control case, participants' ages, method for collecting data on hormone use, follow-up time, year of publication, measure of effect, diagnostic criteria, classifications and frequencies of hormone therapy application (e.g., timing of use, duration of use, route of administration, formulation, or any available information) and model, or other covariates.

Age was provided in the form of the mean value, unless otherwise stated. Nearly all the studies included adjusted odds ratio (OR)/relative risk (RR)/hazard risk (HR) values because there were some differences in covariates among the studies.

Statistical Analysis

The Comprehensive Meta-Analysis Version 2 software (Biostat, Englewood, NJ, USA) was used for all the statistical analyses. We grouped study findings on the basis of how hormone therapy was categorized (e.g., any vs. never used) and included a summary for measure of effect and 95% CIs in the tables. These summaries were calculated based on random-effects models which involved a weighting scheme.

Cochran Q test was applied to evaluate the statistical difference of heterogeneity across different studies. It was considered statistically significant when P < 0.05. I2 index was used to determine the inconsistency across different studies to evaluate the impact of heterogeneity. We used 25, 50, and 75% of I2 to define low, medium, and high levels of heterogeneity. The Egger's test was used to determine the significance of a statistical test for publication bias to assess the degree of asymmetry in the funnel plot.

Meta regression was conducted among factors that might lead to heterogeneity in order to identify the main factors. A predefined subgroup analysis was used to assess the impact of various factors in the study. The following subgroups were defined in the AD group: case >500 vs. case ≤500, case-control study vs. prospective cohort, publishing year ≤1995 vs. 1996–2005 vs. 2006–2019, women age ≤70 vs. 71–79 vs. age ≥80, measure of effect: OR vs. HR vs. RR, hormone therapy ascertainment by interview vs. questionnaires vs. prescription database vs. medical records, duration of the treatment <5 years vs. 5–10 years vs. treatment >10 years. It was considered as statistically significant if P < 0.05. Meanwhile, the change in I2 was compared before and after the introduction of covariates into the regression model.

Results

Characteristics of Included Studies

We found 111 potentially relevant articles. Among these articles, a total of 21 eligible studies were pooled together for analyses (Figure 1). The Newcastle–Ottawa Scale (NOS) scores of eligible articles were between 7 and 8, with an average of 7.57. Baseline characteristics of included studies are shown in Tables 1–3.

Table 1.

Characteristics of studies included.

References Country Study design Type of disease No. Start time Interval over which disease was assessed Age* Hormone therapy ascertainment Diagnostic criteria Effect measure** NOS score
Broe et al., 1990 Australia A case-control study AD 170 1986 1986–1988 79 Interview NINCDS-ADRDA OR 8
Graves et al., 1990 America A case-control study AD 260 1980 1980–1985 64.9 Questionnaires NINCDS-ADRDA OR 8
Brenner et al., 1994 America A case-control study AD 227 1987 1987–1992 77.59 Prescription database DSM-III-R, NINCDS-ADRDA OR 8
Paganini-Hill and Henderson, 1994 America A case-control study AD 355 1981 1981–1992 86.74 Questionnaire NINCDS-ADRDA OR 8
Mortel and Meyer, 1995 America A case-control study AD 241 NR NR 73.2 Medical records DSM-III-R, NINCDS-ADRDA OR 7
Tang et al., 1996 America Prospective cohort AD 1,124 NR 5 years 74.2 Prescription database DSM-III-R, NINCDS-ADRDA RR 7
Kawas et al., 1997 America Prospective cohort AD 472 1978 16 years 61.5 Multidisciplinary evaluations DSM-III-R, NINCDS-ADRDA RR 7
Slooter et al., 1999 Netherlands A case-control study AD 228 1980 1980–1987 58.06 Questionnaires NINCDS-ADRDA OR 8
Waring et al., 1999 America A case-control study AD 444 1980 1980–1984 82 Medical records DSM-III-R, NINCDS-ADRDA OR 7
Seshadri et al., 2001 United Kingdom A case-control study AD 280 1990 1990–1998 65.52 Prescription database NINCDS-ADRDA OR 8
Lindsay et al., 2002 America Prospective cohort AD 2,079 1991 1991–1996 73.3 Questionnaires DSM-IV, NINCDS-ADRDA OR 8
Zandi et al., 2002 America Prospective cohort AD 1,866 1998 1998–2000 74.4 Interview NINCDS-ADRDA HR 7
Henderson et al., 2005 America A case-control study AD 971 NR 6 months 50 Medical records NR OR 7
Roberts et al., 2006 America A case-control study AD 486 1985 1985–1989 84 Medical records DSM-IV, NINCDS-ADRDA OR 8
Lau et al., 2010 America Cross-sectional study AD 4,087 2005 2005–2007 77.1 Questionnaires NPI-Q OR 8
Shao et al., 2012 America Prospective cohort AD 1,768 1995 1995–2006 74.6 Questionnaires NINCDS-ADRDA HR 8
Imtiaz et al., 2017 Finland A case-control study AD 8,195 1999 1999–2009 72.3 Questionnaires DSM-IV, NINCDS-ADRDA HR 8
Fernandez and Lapane, 2000 America Cross-sectional study PD 10,145 1992 1992–2005 65 Medical records MDS-UPDRS OR 8
Martignoni et al., 2003 Italy A case-control study PD 442 NR 8.7 years 66.57 Questionnaires MDS-UPDRS Mean (SD) 7
Currie et al., 2004 America A case-control study PD 140 1999 NR 68.43 Interview MDS-UPDRS OR 7
Nicoletti et al., 2007 NR Cross-sectional study PD 11 NR 14 weeks 68.4 Clinical observation MDS-UPDRS Mean (SD) 7
Park et al., 2018 America A case-control study PD 300 2006 2006–2013 68.7 Questionnaires MDS-UPDRS OR 8
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NR, not reported; OR, odds ratio; RR, relative risk; HR, hazard ratio; AD, Alzheimer's disease; PD, Parkinson's disease; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; MDS-UPDRS, Movement Disorder Society-Sponsored Revision Unified Parkinson's Disease Rating Scale; NOS, Newcastle–Ottawa Scale.

*

The age provided is the value of the mean, unless otherwise stated.

**

Nearly all studies included adjusted OR/RR values because there were some differences in covariates among the studies.

Table 3.

Summaryof results–estrogen replacement therapy and Parkinson's disease risk.

References Study design No. Covariates Sample Size (PD/Con) OR/RR/HR 95% CI Outcome
Fernandez and Lapane, 2000 Cross-sectional study 10,145 Age, race, and motor impairment 23/96 NR NR Shorter duration of estrogen use was associated with a modestly increased risk of Alzheimer's disease, and longer duration with a weakly decreased risk.
Martignoni et al., 2003 A case-control study 442 Age, mode, premenopausal menstrual irregularities, presence of climacteric symptoms 55/78 0.52 0.30–0.92 Estrogen's potential beneficial effects on PD motor and cognitive functions.
Currie et al., 2004 A case-control study 140 Age 4/6 0.99 0.27–3.57 The existence of a qualitative relationship between PD and reproductive events.
Nicoletti et al., 2007 Cross-sectional study 11 NR 17/36 0.33 0.16–0.68 Postmenopausal estrogen therapy may be associated with a reduced risk of PD in women.
Park et al., 2018 A case-control study 300 Ethnicity, education, smoking duration, disease 195/NR 0.475 0.31–0.72 Estrogen replacement therapy has a possible benefit on dyskinesias in postmenopausal women with PD.
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NR, not reported; OR, odds ratio; RR, relative risk; HR, hazard ratio; PD, Parkinson's disease; Con, control group.

Table 2.

Summary of results–estrogen replacement therapy and Alzheimer's disease risk.

References Study design No. Covariates Sample size (AD/Con) OR/RR/HR 95% CI Outcome
Broe et al., 1990 A case-control study 170 Age, sex 11/24 0.34 0.12–0.94 Identified four risk factors for AD, there is no estrogen treatment.
Graves et al., 1990 A case-control study 260 NR 52/58 1.1 0.60–1.80 No statistically significant differences were observed between the two groups.
Brenner et al., 1994 A case-control study 227 Education, marital status, ethnicity, smoking or progestogen use 0/18 0.78 0.39–1.56 Provide no evidence that estrogen replacement therapy has an impact on the risk of Alzheimer's disease in women.
Paganini-Hill and Henderson, 1994 A case-control study 355 Age, weight, stroke, blood pressure, medication use 23/21 1.15 0.50–2.64 The increased incidence of Alzheimer's disease in older women may be due to estrogen deficiency and that it may be useful for preventing or delaying dementia.
Mortel and Meyer, 1995 A case-control study 241 Age 87/192 0.70 0.51–0.95 ERT may eventually prove to be a useful prophylactic agent for reducing risk of DAT and IVD among postmenopausal women.
Tang et al., 1996 Prospective cohort 1,124 Education, ethnicity, Apo E genotype 28/137 0.67 0.38–1.17 Estrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimer's disease.
Kawas et al., 1997 Prospective cohort 472 Age, education, age at menarche/menopause 9/221 0.46 0.21–0.99 Support for a protective influence of estrogen in AD.
Slooter et al., 1999 A case-control study 228 Age, education, Apo E genotype 372/324 0.53 0.39–0.73 Estrogen use is beneficial to Alzheimer's disease with early onset.
Waring et al., 1999 A case-control study 444 Age, education 4/121 1.37 0.48–3.95 Estrogen replacement therapy is associated with a reduced risk of AD in postmenopausal women.
Seshadri et al., 2001 A case-control study 280 Age, smoking, BMI, physician's practice 10/29 1.82 0.86–3.84 The use of HRT in women after the onset of menopause was not associated with a reduced risk of developing AD.
Lindsay et al., 2002 Prospective cohort 2,079 Age, education 28/25 1.10 0.63–1.93 No statistically significant association was found for estrogen replacement therapy can reduce risk of Alzheimer's disease.
Zandi et al., 2002 Prospective cohort 1,866 Age, education, Apo E genotypes 15/53 1.18 0.59–2.37 Prior HRT use is associated with reduced risk of AD, but there is no apparent benefit with current HRT use unless such use has exceeded 10 years.
Henderson et al., 2005 A case-control study 971 Age, education, race 87/1018 0.80 0.58–1.09 HT may protect younger women from AD or reduce the risk of early onset forms of AD, or that HT used during the early postmenopause may reduce AD risk.
Roberts et al., 2006 A case-control study 486 Age at menarche/ menopause, type of menopause, duration of fertile life, hypertension, diabetes, smoking, nonsteroidal anti-inflammatory drugs, education 9/148 0.50 0.25–0.90 Do not confirm a significant association between ET and AD.
Lau et al., 2010 Cross-sectional study 4,087 Age, sex, ethnicity, education, marital status and living arrangement 211/202 0.48 0.22–1.01 Number of medications used is associated with PIRx among ADC's community-dwelling elderly patients with and without dementia, polypharmacy increasing the risk of PIRx.
Shao et al., 2012 Prospective cohort 1,768 Education, alcohol or tobacco use, self-rated health status. 26/1038 0.59 0.36–0.96 Although possibly beneficial if taken during a critical window near menopause, HT initiated in later life may be associated with increased risk.
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NR, not reported; OR, odds ratio; RR, relative risk; HR, hazard ratio; AD, Alzheimer's disease; Con, control group; Apo E, apolipoprotein E; BMI, body mass index; DAT, dementia of the Alzheimer's type; IVD, ischemic vascular dementia; HRT, hormone replacement therapy; HT, hormone therapy; ET, estrogen therapy; PIRx, potentially inappropriate prescription medication; ADC, Alzheimer's disease center.

Stratification of the study: 13 were case-control studies, five were prospective cohort studies, and three were cross-sectional studies. Stratification of the location: 15 studies were conducted in America, three in Europe (one in the UK, one in Italy, and one in Netherlands), and two other countries (one in Canada, one in Australia). In the AD group, there were 13 studies in America, two in Europe (one in the UK and one in Netherlands), and one in other countries. Stratification of neurological disorders: five cases evaluated the impact of ERT on PD and 16 cases on AD. All studies were collected on the use of hormone therapy either by self-report (e.g., interview or questionnaire) at the start of the study, by electronic prescription database, or by medical records. Furthermore, all studies were included in this review except one reported using standard criteria to diagnose AD and dementia [e.g., National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA); Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R); Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV); or Movement Disorder Society-Sponsored Revision Unified PD Rating Scale (MDS-UPDRS)].

Association of AD and PD With ERT

We used random-effects meta-analysis to assess the association between ERT and neurological diseases. Our results showed that ERT decreased risks of developing AD (OR: 0.672; 95% CI: 0.581–0.779; P < 0.001) and PD (OR: 0.470; 95% CI: 0.368–0.600; P < 0.001) in patients compared with the control (Figure 2), suggesting that estrogen therapy had a greater impact on PD.

Figure 2.

Figure 2

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Forest plot displaying random-effects meta-analysis results for the association between Alzheimer's disease (AD) (A) and Parkinson's disease (PD) (B) and estrogen replacement therapy (ERT).

Investigation of Heterogeneity

Further subgroup analyses by disease outcome, 16 studies also had small heterogeneity in AD (I2 = 24.140; P = 0.181), but five studies of PD showed no heterogeneity (I2 = 0.000; P = 0.558). Since the data of PD were not enough, we only performed meta-regression analysis on the AD group. Study design (P = 0.01) and effect measure (P = 0.03) might be the sources of heterogeneity in the AD group, but number of cases (P = 0.172), age (P = 0.986), publication year (P = 0.712), hormone therapy ascertainment (P = 0.494), and duration of the treatment (P = 0.217) had no moderating effects on the significant association between hormone replacement therapy (HRT) and AD incidence (P > 0.05 in these studies) (Table 4).

Table 4.

Summary of the subgroups analysis results.

Analysis N Fix-effects model Random-effects model Heterogeneity Meta regression
OR (95% CI) P OR (95% CI) P I2 (%) P P
All studies of AD 16 0.681 (0.612–0.759) 0.000 0.672 (0.581–0.779) 0.000 24.140 0.181 –
All studies of PD 5 0.470 (0.368–0.600) 0.000 0.470 (0.368–0.600) 0.000 0.000 0.558 –
Subgroup 1 in AD group
Case > 500 6 0.653 (0.577–0.740) 0.000 0.627 (0.528–0.744) 0.000 26.755 0.234 0.17045
Case ≤ 500 10 0.771 (0.623–0.955) 0.017 0.758 (0.594–0.967) 0.026 19.734 0.261
Subgroup 2 in AD group
Case-control study 10 0.767 (0.641–0.920) 0.004 0.770 (0.633–0.936) 0.009 9.109 0.358 0.00867
Prospective cohort 5 0.519 (0.413–0.653) 0.000 0.519 (0.413–0.653) 0.000 0.000 0.635
Subgroup 3 in AD group
Year ≤ 1995 5 0.816 (0.607–1.096) 0.177 0.814 (0.602–1.101) 0.183 2.710 0.391 0.71219
1996–2005 8 0.608 (0.497–0.742) 0.000 0.592 (0.468–0.749) 0.000 17.281 0.294
2006–2019 3 0.692 (0.601–0.797) 0.000 0.699 (0.534–0.915) 0.009 55.305 0.107
Subgroup 4 in AD group
Age ≤ 70 5 0.725 (0.574–0.915) 0.007 0.727 (0.527–1.003) 0.052 33.396 0.199 0.98581
Age 71–79 7 0.658 (0.578–0.749) 0.000 0.621 (0.500–0.770) 0.000 38.876 0.133
Age ≥ 80 3 0.744 (0.548–1.093) 0.145 0.769 (0.524–1.12) 0.180 17.911 0.296
Subgroup 5 in AD group
Measure = OR 14 0.733 (0.650–0.827) 0.000 0.733 (0.650–0.827) 0.000 0.000 0.485 0.02941
Measure = HR 2 0.562 (0.432–0.732) 0.000 0.562 (0.432–0.732) 0.000 0.000 0.819
Measure = RR 2 0.372 (0.221–0.624) 0.000 0.372 (0.221–0.624) 0.000 0.000 0.473
Subgroup 6 in AD group
Treatment < 5 Y 6 0.707 (0.619–0.808) 0.000 0.707 (0.619–0.808) 0.000 0.000 0.593 0.21689
Treatment 5–10 Y 6 0.745 (0.565–0.983) 0.037 0.705 (0.455–1.094) 0.119 58.180 0.035
Treatment > 10 Y 3 0.571 (0.443–0.737) 0.000 0.571 (0.443–0.737) 0.000 0.000 0.637
Subgroup 7 in AD group
Interview 2 0.576 (0.355–0.934) 0.025 0.576 (0.355–0.934) 0.025 0.000 0.577 0.49442
Questionnaires 6 0.678 (0.593–0.775) 0.000 0.672 (0.572–0.788) 0.000 9.612 0.354
Prescription database 3 0.762 (0.535–1.084) 0.130 0.714 (0.340–1.496) 0.372 76.373 0.015
Medical records 4 0.711 (0.557–0.907) 0.006 0.709 (0.534–0.942) 0.018 14.937 0.317
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Furthermore, according to the results of subgroup analyses in the AD group, heterogeneity came from data measure. Two of the interaction terms of the predefined subgroups showed statistical significance: study design (P = 0.01) and measure of effect (P = 0.03). Estimated pooled differences among each subgroup are presented in Figure 3. For the stratified analyses among studies of AD, different measure of effects are the source of heterogeneity, but the root cause is different in effect design, suggesting that we should classify different research types before statistical analysis in meta-analysis. Forest plot displayed random-effects meta-analysis results for different effect designs in the AD subgroups (Figure 4). When only prospective cohort studies were included, we observed an increased effective size for AD studies (OR: 0.519; 95% CI: 0.413–0.653; P < 0.001), adding more proof that ERT is indeed beneficial for treating AD.

Figure 3.

Figure 3

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The following subgroups were defined in the Alzheimer's disease (AD) group: case >500 vs. case ≤500,case-control study vs. prospective cohort, publish year ≤ 1995 vs. 1996–2005 vs. 2006–2019, women age ≤70 vs. 71–79 vs. age ≥80, measure of effect = odds ratio (OR) vs. hazard ratio (HR) vs. relative risk (RR), hormone therapy ascertainment by interview vs. questionnaires vs. prescription database vs. medical records, duration of the treatment <5 years vs. 5–10 years vs. treatment >10 years.

Figure 4.

Figure 4

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Forest plot displaying random-effects meta-analysis results for the impact of different research types, which were case-control study (A) and prospective cohort (B).

Sensitivity Analyses

Sensitivity analysis demonstrated that none of the individual studies could induce statistical bias regarding the association between ERT and incidence of AD or PD, indicating that our findings were statistically reliable (Figure 5).

Figure 5.

Figure 5

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The outcome of the sensitivity analysis in Alzheimer's disease (AD) (A) and Parkinson's disease (PD) (B), with the exclusion of one study.

Publication Biases

Funnel plots were used to assess publication biases. We did not find an obvious asymmetry of funnel plots in any of the comparisons, which suggested that our findings were unlikely to be impacted by severe publication biases (Figure 6).

Figure 6.

Figure 6

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The funnel plot was symmetrical in Alzheimer's disease (AD) (A) and Parkinson's disease (PD) (B), suggesting that there was no publication bias in the current analysis.

Discussion

In this review, we presented results from a series of data on postmenopausal hormone therapy in relation to the risk of onset and/or developing AD and PD. Given the results of meta-analysis and subgroup analysis of our collected data, ERT shows a positive effect on the treatment of AD. The situation is similar in the case of ERT and PD. ERT induces some heterogeneity in the study of AD and can be attributed to the study design. Age, year of publication, number of cases, hormone therapy ascertainment, duration of the treatment, and route of administration do not significantly affect the outcome of the meta-analysis.

Multifactorial Bias and Time Limit

ERT and neurodegenerative disease performance were related to factors such as age, country, socioeconomic status, and health status. It was not feasible to eliminate these factors from the epidemiological study. Such confounding factors can be the source of some analysis bias. First, there was a big challenge in selecting data since most studies did not report effects in a manner that allowed their results to be used for meta-analyses. There are differences in the determination of estrogen treatment results, treatment duration, or disease interval evaluation in the included articles. We added meta-regression analysis, which showed they were minimally relevant to the result in these subgroups. However, it would indeed become a source of limitation. Second, many of the observational studies showed a clear time-dependent pattern. The data included in this article have a large time span, thus the diagnostic criteria may change. To avoid this bias, we adopted NINCDS-ADRDA diagnostic criteria in AD studies and MDS-UPDRS in PD studies. Compared with other diagnostic criteria, they have been applied for more than 20 years since it was established. At the same time, we also used meta-regression to evaluate whether the diagnostic criteria have a trend of change with time, and the regression result is non-existent. The large controlled studies currently underway will hopefully address this time limit. Third, determining the history of hormone therapy use was a concern in studies that relied on self-report (e.g., interview or questionnaire). Pathological cognitive changes had been a big challenge to recall the memory of hormone therapy use. We included several studies with hospital records or multidisciplinary evaluations on top of patient's self-report to reduce the chance of recall bias.

Discussion of Subgroup and Regression Analysis

Different researchers used appropriate study designs to study the relationship between ERT and AD and PD. Meta-regression results showed that the study design was indeed the heterogeneous source of meta-analysis (P = 0.01). Therefore, we classified the articles into case-control study and prospective cohort study according to different study designs and then re-conducted meta-analysis. When only prospective cohort studies were included, we observed an increased effective size for AD studies (OR: 0.519; 95% CI: 0.413–0.653; P < 0.001), adding more proof that ERT is indeed beneficial for treating AD (Figure 4). Therefore, we believe that this study design is more reasonable and effective in the epidemiological study of ERT and neurodegenerative diseases. We call on researchers to be more inclined to choose this research design in future epidemiological studies.

Some literature suggests that the role of ERT may depend on the age of menopause and the therapeutic intervention used. The time window of estrogen therapy is associated with the risk of onset and/or developing neurodegenerative disease, and early treatment performed 10 years after menopause can decrease the risk (Yaffe et al., 1998). Regression analysis for age (P = 0.98581 > 0.05) showed no statistical significance. According to the subgroup analysis among age ≤70 (I2 = 33.396, P = 0.199), age 71–79 (I2 = 38.876, P = 0.133), and age ≥80 (I2 = 17.911, P = 0.296), there was no evidence indicating that age was associated with the risk of disease development.

What requires further investigation is the relationship between the route of administration of estrogen therapy and the risk of onset and/or developing neurodegenerative disease. Four studies differentiated the use by route of administration (oral vs. transdermal), as shown in Table 5. Meta-analysis results of the oral route were OR: 0.925, 95% CI: 0.618–1.385, and P = 0.707. Results of the transdermal drug delivery were OR: 0.975, 95% CI: 0.731–1.299, and P = 0.861. There was no statistical significance between the use of oral estrogens and transdermal estrogens. However, our sample size of only four studies might cause a bias in the result. There was a lack of evidence from large and randomized clinical trials that examine the efficacy and safety of alternative hormone therapy for the route of administration.

Table 5.

Summary of results–route of administration and Alzheimer's disease risk.

References Study design No. Covariates Route of administration OR/RR/HR 95% CI
Brenner et al., 1994 A case-control study 227 Education, marital status, ethnicity, smoking or progestogen use Oral
Transdermal		 0.70
1.30		 0.10–1.50
0.70–2.30
Paganini-Hill and Henderson, 1994 A case-control study 355 Age, weight, stroke, blood pressure, medication use Oral 0.70 0.50–0.98
Transdermal 0.48 0.24–0.94
Seshadri et al., 2001 A case-control study 280 Age, smoking, BMI, physician's practice Oral 0.89 0.35–2.30
Transdermal 0.73 0.15–3.57
Imtiaz et al., 2017 A case-control study 8,195 Age, education Oral 1.14 1.10–1.18
Transdermal 1.07 0.86–1.34
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OR, odds ratio; RR, relative risk; HR, hazard ratio; BMI, body mass index.

Mechanism of Estrogen Therapy

Through different regulatory mechanisms, estrogen affects the conduction of nerve signals and tissue changes in the brain. At the same time, genes associated with neurodegenerative diseases are also shown to be regulated by estrogen (Nilsson et al., 2011; Xing et al., 2013), and these results are in agreement with the results of our meta-analysis. It has been reported that estrogen decreases reactive oxygen leak and diffusion lipid peroxidation coupled with oxidative stress and endogenous oxidative damage by increasing electron transport chain complex IV and mitochondrial reactivity (Irwin et al., 2008). Brain-derived neurotrophic factor (BDNF) gene contains an estrogen response element (ERE), which confirms that ERβ affects the maturation and plasticity of synapses through the BDNF-TrkB signaling pathway (Zhao et al., 2011). We have shown that there is an important interaction between the apolipoprotein E (Apo E) gene and the risk of onset and/or developing AD (Liu et al., 2013). ERE presents on the Apo E gene, which can modify the expression of the Apo E gene in the cerebral cortex by 17β-estradiol (Struble, 2003). PD is a neurodegenerative disease caused by substantia nigra degeneration or loss of dopaminergic neurons. It has been found that estrogen can convert D2 DA receptors from a high affinity state to a low affinity state in monkeys with different dyskinesias. An important interaction between the brain renin-angiotensin system (RAS) and effects of 17β-estradiol in models of PD, the RAS enhances the progression of dopaminergic degeneration by intensifying neuroinflammation, and estrogen protects dopaminergic neurons by inhibition of RAS (Labandeira-Garcia et al., 2016). In the PD model, 17β-estradiol is a negative regulator of the RAS, which inhibits its function and reduces neuroinflammation and DA degeneration. Estrogen rapidly and directly acts on striatum and nucleus accumbens, via a G-protein-coupled external membrane receptor, to enhance DA releases and DA-mediated behaviors (Becker, 1999). At the same time, 17β-estradiol is found to inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced DA depletion under a dosing regimen (repeated daily administration) (Ramirez et al., 2003). At present, DA agonists are one of the main drugs for symptomatic treatment of PD. It is determined that the beneficial effects of estrogen on DA receptors can delay the progression of PD.

In conclusion, a meta-analysis was conducted with regard to the long-standing debate about whether ERT protects cognition and reduces the risk of neurodegenerative disease. First, different diseases were classified. In the case of AD, more research data were included, beneficial conclusions were thus obtained, which also verified the clinical observation data. Meta-analysis in the estrogen therapy and the risk of PD were first conducted, the results showed that estrogen therapy significantly reduced the risk of PD. These data can help with the development of new therapeutic ideas and preventative measures for future clinical application regarding the development AD and PD.

Some of the minor issues that have been experienced so far with estrogen use were addressed. The results of studies and meta-analysis indicated that estrogen therapy does have beneficial effects on neurodegenerative diseases such as AD and PD. Notably, neurodegenerative diseases are associated with internal energy and material metabolism disorders, which are not limited to reproductive hormones. According to the latest epidemiological studies, neurodegenerative diseases were closely related to diabetes and non-alcoholic fatty liver disease (NAFLD) (Szmuilowicz et al., 2009; Martins, 2014; Slopien et al., 2018; Venetsanaki and Polyzos, 2019). They may have a common pathogenic mechanism, which involves the production of Aβ protein, insulin resistance, and mitochondrial dysfunction (Martins, 2015, 2018). Detection of these endocrine markers that associate with metabolic syndrome would help with timely diagnosis of the disease in the early or presymptomatic phase. Future studies need to determine how the induction or inhibition of endocrinal targets could be used for predictable neuroprotection in neurodegenerative disease therapies.

Data Availability Statement

All datasets generated for this study are included in the article/supplementary material.

Author Contributions

QL and YC conceived and designed the study. SL and YS collected the data. YS, XC, and XL analyzed and interpreted the data. YS drafted the manuscript with critical revisions from all the authors.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

Funding. This study was supported by the National Science Foundation of China (81774006 and 81703492), the Key Research and Development Projects of the Ministry of Science and Technology (2017YFC1704000), and the Fund of Xizang Minzu University (324011809906).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All datasets generated for this study are included in the article/supplementary material.

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