Impact of DHEA supplementation on testosterone and estradiol levels in postmenopausal women: a meta-analysis of randomized controlled trials assessing dose and duration effects

Abstract

Background and aim

The effects of dehydroepiandrosterone (DHEA) supplementation on testosterone and estradiol concentrations in postmenopausal women have produced conflicting results. This meta-analysis of randomized controlled trials aimed to evaluate the impact of DHEA supplementation on serum testosterone and estradiol levels and to provide evidence regarding the optimal dosage and duration of supplementation.

Methods

A comprehensive literature search was conducted across PubMed/Medline, Embase, Web of Science, and Scopus to identify relevant studies published before June 11, 2024. Data were analyzed using a random-effects model and presented as weighted mean differences (WMDs) with 95% confidence intervals (CIs).

Results

The analysis included 21 studies, comprising 17 trial arms assessing estradiol and 20 assessing testosterone. DHEA supplementation significantly increased estradiol (WMD: 7.86 pg/mL; 95% CI 6.33–9.40; P ≤ 0.001) and testosterone levels (WMD: 24.31 ng/dL; 95% CI 15.22–33.40; P ≤ 0.001). Subgroup analyses showed greater increases in estradiol levels among studies using DHEA dosages ≥ 50 mg/day (WMD: 8.65 pg/mL) and those with participants aged ≥ 60 years (WMD: 8.92 pg/mL), although the differences were modest and 95% CIs overlapped. For testosterone, higher levels were observed with DHEA dosages ≥ 50 mg/day (WMD: 29.65 ng/dL).

Conclusion

DHEA supplementation at doses ≥ 50 mg/day significantly increases testosterone levels in postmenopausal women. Moreover, in women aged ≥ 60 years, supplementation at the same dosage significantly elevates estradiol levels.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13098-025-01770-0.

Introduction

In humans and other mammals, dehydroepiandrosterone (DHEA) is a vital prohormone primarily produced by the adrenal glands. It serves as a precursor to biologically active androgens and estrogens [1]. After being synthesized in the adrenal cortex, DHEA is taken up by various tissues, including the liver, gonads, kidneys, and brain, where it is metabolized into different steroid hormones depending on the specific tissue context [2–4]. In the bloodstream, DHEA is largely converted into its sulfated form, DHEA sulfate (DHEA-S), which circulates at much higher concentrations and can be further metabolized into active sex hormones as needed [5].

DHEA levels decline significantly with age, decreasing by approximately 70% between the ages of 20 and 60, primarily due to reduced adrenal production. DHEA supplementation has been explored as an adjunct therapy for postmenopausal women, alongside hormone replacement therapy (HRT), and has demonstrated potential benefits in improving metabolic and endocrine function, as well as sexual health [6]. DHEA exerts androgenic, estrogenic, and steroidal effects and has been associated with various biological functions, including antioxidant properties, neuroprotection, and anticancer activity [7]. Supplementation may help maintain hormonal balance, enhance mood, support brain function, and potentially mitigate age-related decline [8].

Estradiol, the most potent female sex hormone, fluctuates throughout a woman's life and menstrual cycle. It plays a critical role in regulating the hypothalamic-pituitary–gonadal axis by modulating the secretion of gonadotropin-releasing hormone (GnRH), with both positive and negative feedback effects [9]. In postmenopausal women, circulating levels of both testosterone and DHEA gradually decline, though a transient increase in hormone levels may occur during the menopausal transition [10].

Several studies have suggested that DHEA supplementation can influence the biosynthesis of estradiol and testosterone [11]. However, the relationship remains inconclusive due to conflicting results from randomized controlled trials (RCTs) [11–13]. While some evidence suggests potential benefits, a previous meta-analysis involving peri- and postmenopausal women reported that DHEA did not significantly improve quality of life or menopausal symptoms and had only modest effects on sexual function. It was also associated with androgenic side effects, such as skin changes [14].

Although prior meta-analyses have investigated the effects of DHEA on hormone levels, none have focused specifically on postmenopausal women. Therefore, this meta-analysis of randomized controlled trials was conducted to evaluate the effect of DHEA supplementation on serum testosterone and estradiol levels in postmenopausal women, with the goal of clarifying the impact of dosage and treatment duration.

Methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15].

Search strategy

A comprehensive literature search was performed to identify relevant studies published prior to June 11, 2024, using the PubMed/Medline, Embase, Web of Science, and Scopus databases. No restrictions were placed on publication year. The search strategy combined Medical Subject Headings (MeSH) and free-text terms, including the following keywords and Boolean combinations: ("DHEA"OR"Prasterone"OR"Dehydroepiandrosterone"OR"DHEAS") AND (Postmenopause OR Postmenopausal) AND ("clinical trials"OR"single-blind method"OR"double-blind method"OR"cross-over studies"OR"controlled trial"OR"RCT"OR"random allocation"OR"intervention studies"OR"intervention"OR"randomized"OR"randomised"OR"randomly"OR"random"OR"assignment"OR"placebo"). Additionally, the reference lists of all identified articles were manually screened by two independent reviewers to ensure a thorough search.

Eligibility criteria

Studies were included if they met the following criteria: (1) Participants were postmenopausal women; (2) The study included an intervention group receiving DHEA supplementation and a control group not receiving DHEA; (3) The study reported mean and standard deviation (SD) values for serum estradiol and/or testosterone concentrations.

Exclusion criteria were as follows: (1) Editorials, commentaries, letters, case reports, and family-based studies; (2) Studies for which relevant data could not be obtained; (3) Articles not published in English.

Data extraction

Two researchers independently extracted data from the eligible studies. Any disagreements were resolved through discussion with a third, supervising author. Extracted data included the first author’s name, year of publication, study design, population characteristics, sample size for both intervention and control groups, participants’ ages, DHEA treatment details (including dosage and duration), and the reported means and standard deviations of estradiol and testosterone concentrations.

Quality assessment

The methodological quality of the included studies was assessed using the Risk of Bias 2 (RoB 2) tool [16]. This tool evaluates five key domains: the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Each study was independently evaluated by two reviewers, and any disagreements were resolved through discussion or consultation with a third reviewer.

Statistical methods

All statistical analyses were performed using Stata software (StataCorp, College Station, TX, USA). Effect sizes were reported as weighted mean differences (WMDs) with 95% confidence intervals (CIs). A two-tailed P value of < 0.05 was considered statistically significant. Pooled estimates were calculated using the generic inverse variance method under a random-effects model to account for variability among studies.

Heterogeneity was assessed using the I² statistic and Chi-square test. An I² value greater than 50% or a P-value less than 0.10 was interpreted as indicating substantial heterogeneity. To explore potential sources of heterogeneity, subgroup analyses were conducted based on participants’ mean age, intervention duration, DHEA dosage, and population characteristics.

Sensitivity analysis was performed by sequentially excluding individual studies to evaluate the robustness of the overall findings. Potential publication bias was assessed using visual inspection of funnel plots and quantified by Egger’s regression test [17, 18].

Results

Study selection and characteristics of the eligible trials

The initial search yielded 7256 records. After removing 1872 duplicates, 5384 records were screened based on titles and abstracts, leading to the exclusion of studies that did not meet the inclusion criteria. The full texts of 61 potentially relevant articles were then reviewed in detail. Of these, 21 studies met the eligibility criteria and were included in the final meta-analysis. These studies comprised 17 trial arms reporting on estradiol outcomes and 20 trial arms reporting on testosterone outcomes (Fig. 1) [19–39].

Fig. 1.

Flow-chart of the systematic review and meta-analysis evaluating the impact of dehydroepiandrosterone supplementation on estradiol and testosterone in postmenopausal women

Characteristics of included RCTs

A total of 21 randomized controlled trials (RCTs) were included in this systematic review, with studies conducted across diverse geographic locations including the USA, Italy, Australia, Israel, Japan, Germany, Mexico, and Sweden. The studies were published between 1995 and 2019. Sample sizes varied from 14 to 280 participants, and participants were generally postmenopausal women with diverse profiles: healthy individuals, those with primary Sjogren’s syndrome, mild to moderate cognitive impairment, or classified as frail. The administered dose of dehydroepiandrosterone (DHEA) ranged from 10 to 100 mg/day, with intervention durations spanning from 2 weeks to 12 months. Most trials employed a double-blind, randomized, placebo-controlled design. Hormone concentration measurements typically included estradiol and testosterone, and methods varied across studies: common techniques included radioimmunoassay, mass spectrometry, chemiluminescence immunoassay, and enzyme-linked immunosorbent assay (ELISA). Nearly all studies defined postmenopausal status as at least one year of amenorrhea, with some also accepting surgical menopause (e.g., bilateral oophorectomy). A detailed summary of study characteristics, including participant age, country, study duration, and hormone measurement methods, is provided in Table 1. The risk of bias for each included study is detailed in Supplementary Table 1.

Table 1.

Characteristics of eligible studies

Author	Year	Country	Population	Participants’ age (years)	Sample size DHEA/Placebo	Duration	DHEA dosage (mg/d)	Outcomes	Methods used to measure hormone concentrations"	Definition of the post-menopausal status in each study	Types of studies	Placebo/control group
Jankowski, C. M	2019	USA	postmenopausal older women	69	135/145	12 months	50	Estradiol, testosterone	Radioimmunoassay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Bloch, M	2013	Israel	postmenopausal women	45	13/13	6 weeks	100	Estradiol, testosterone	Gas chromatography mass spectrometry	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Weiss, E. P	2012	USA	postmenopausal older women	70	20/22	12 months	50	Estradiol, testosterone	Testosterone, was measured using chemiluminescent assays; estradiol was measured using an ultra-sensitive radioimmunoassay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Merritt, P	2012	USA	postmenopausal older women	63.5	24/48	4 weeks	50	testosterone	Liquid chromatography tandem mass spectrometry relying on stable isotope dilution	One year’s absence of menses or bilateral ovariectomy	Double-blind placebo-controlled cross-over	Placebo
Genazzani, A. R	2011	Italy	postmenopausal women	54.5	12/12	12 months	10	Estradiol, testosterone	Radioimmunoassay	At least 1 year of amenorrhea	Randomised controlled clinical trial	Placebo
Yamada, S	2010	Japan	postmenopausal women with mild to moderate cognitive impairment	82	12/15	6 months	25	Estradiol, testosterone	Chemiluminescent immunoassays	At least 1 year of amenorrhea	Open, non-randomized controlled study	Control
Kenny, A. M	2010	USA	frail older postmenopausal women	76.59	43/44	6 months	50	Estradiol, testosterone	ELISA and estrone using radioimmune assay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Weiss, E. P	2009	USA	postmenopausal older women	70	58/58	12 months	50	Estradiol, testosterone	Testosterone, was measured by using chemiluminescent assays; estradiol was measured by using an ultrasensitive radioimmunoassay	At least 1 year of amenorrhea	Randomized, placebo-controlled trial	Placebo
Stanczyk, F. Z	2009	USA	postmenopausal women	55 to 65	7/7	6 months	25	Estradiol, testosterone	Radioimmunoassay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Panjari, M	2009	Australia	postmenopausal women	55.1	29/32	52 weeks	50	Estradiol, testosterone	Mass spectrometry methods	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Forsblad-d'Elia, H	2009	Sweden	postmenopausal women with primary Sjogrens syndrome	60.7	23/23	9 months	50	Estradiol, testosterone	HP5973 quadrupole mass spectrometer equipped with a chemical ionization source	Not reported	Double-blind placebo-controlled cross-over	Placebo
Jankowski, C. M	2008	USA	postmenopausal older women	69	25/33	12 months	50	Estradiol, testosterone	Radioimmunoassay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Igwebuike, A	2008	USA	postmenopausal women	64.59	17/17	12 weeks	50	Estradiol, testosterone	Chemiluminescence immunoassays	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Villareal, D. T	2006	USA	elderly postmenopausal women	72	29/27	10 months	50	Estradiol, testosterone	Levels of testosterone was measured by enzyme-linked immunosorbent assay; estradiol levels was measured by ultrasensitive radioimmunoassay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Williams, M. R	2004	Australia	healthy postmenopausal women	59.2	18/18	3 months	100	Estradiol, testosterone	Radioimmunoassay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Villareal, D. T.(b)	2004	USA	postmenopausal older women	71	13/14	6 months	50	Estradiol, testosterone	Levels of testosterone were measured by enzymelinked immunosorbent assay, estradiol levels were measured by ultrasensitive radioimmunoassay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Carranza-Lira, S	2002	Mexico	healthy postmenopausal women	53	10/10	1 month	35	Estradiol, testosterone	Radioimmunoassay	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Kudielka, B. M	1998	Germany	postmenopausal older women	67	18/18	2 weeks	50	Estradiol	Radioimmunoassay	At least 1 year of amenorrhea	Randomized, placebo-controlled trial	Placebo
Lasco, A	2001	Italy	postmenopausal women	57	10/10	12 months	25	Testosterone	Solid-phase immunoassays	At least 1 year of amenorrhea	Double-blind, randomized, placebo-controlled trial	Placebo
Morales, A. J	1998	USA	postmenopausal older women	54	10/10	6 months	100	Testosterone	Radioimmunoassay	At least 1 year of amenorrhea	Double-blind placebo-controlled cross-over	Placebo
Casson, P. R	1995	USA	postmenopausal women	56.1	11/11	3 Weeks	50	Testosterone	Radioimmunoassay	at least 1 year of amenorrhea	Double-blind placebo-controlled cross-over	Placebo

DHEA, dehydroepiandrosterone. mg/d, miligrams/day. USA, United States of America

Impact of DHEA administration on estradiol in postmenopausal women

Seventeen trial arms involving a total of 986 participants (482 in the intervention group and 504 in the control group) assessed the effect of DHEA supplementation on estradiol concentrations in postmenopausal women. The pooled analysis demonstrated a significant increase in estradiol levels following DHEA administration (WMD: 7.86 pg/mL; 95% CI 6.33–9.40; P ≤ 0.001), with substantial heterogeneity among studies (I² = 92%, P ≤ 0.001) (Fig. 2).

Fig. 2.

Forest plot of the randomized controlled trials investigating the effect of dehydroepiandrosterone (DHEA) supplementation on serum estradiol concentrations

When stratified by intervention duration, a slightly greater effect was observed in participants receiving DHEA for < 26 weeks (WMD: 7.93 pg/mL; 95% CI 2.94–12.92; P = 0.002) compared to those treated for ≥ 26 weeks (WMD: 7.50 pg/mL; 95% CI 6.50–8.51; P ≤ 0.001). However, the overlapping confidence intervals suggest no statistically significant difference between the subgroups.

Subgroup analysis by dosage showed that DHEA doses ≥ 50 mg/day significantly increased estradiol levels (WMD: 8.65 pg/mL; 95% CI 7.07–10.22; P ≤ 0.001), whereas doses < 50 mg/day did not result in a significant change (WMD: 0.64 pg/mL; 95% CI − 4.69 to 5.98; P = 0.813).

Additionally, studies involving participants aged ≥ 60 years demonstrated a more pronounced increase in estradiol levels (WMD: 8.92 pg/mL; 95% CI 7.33–10.51; P ≤ 0.001) compared to those with participants < 60 years (WMD: 3.04 pg/mL; 95% CI − 4.79 to 10.88; P = 0.446), though the overlapping CIs suggest the difference is not statistically significant.

Impact of DHEA Administration on Testosterone in Postmenopausal Women

Twenty trial arms including 1,084 participants (519 in the DHEA group and 565 in the control group) evaluated testosterone levels following DHEA supplementation. The meta-analysis revealed a significant increase in testosterone levels in the DHEA group (WMD: 24.31 ng/dL; 95% CI 15.22–33.40; P ≤ 0.001), accompanied by considerable heterogeneity (I² = 99%; P ≤ 0.001) (Fig. 3).

Fig. 3.

Forest plot of the randomized controlled trials investigating the effect of dehydroepiandrosterone (DHEA) supplementation on serum testosterone concentrations

Subgroup analysis by duration indicated that supplementation for ≥ 26 weeks led to a greater increase in testosterone levels (WMD: 24.77 ng/dL; 95% CI 16.59–32.96; P ≤ 0.001) compared to < 26 weeks (WMD: 19.04 ng/dL; 95% CI − 8.41 to 46.49; P = 0.174). However, the overlapping confidence intervals again suggest no statistically significant difference between durations.

In terms of dosage, DHEA ≥ 50 mg/day was associated with a significant increase in testosterone levels (WMD: 29.65 ng/dL; 95% CI 21.33–37.98; P ≤ 0.001), whereas < 50 mg/day did not yield a significant effect (WMD: 8.36 ng/dL; 95% CI − 1.91 to 18.64; P = 0.111).

Age-stratified analysis showed significant increases in testosterone in both age groups: participants < 60 years (WMD: 25.57 ng/dL; 95% CI 7.33–43.77; P = 0.006) and those ≥ 60 years (WMD: 24.87 ng/dL; 95% CI 14.56–35.18; P ≤ 0.001). The similarity in effect sizes suggests minimal age-related difference.

Sensitivity analysis and publication bias

Sensitivity analysis, conducted by sequentially omitting individual studies, confirmed the robustness of the pooled effect estimates (Supplementary Figure 2). Visual inspection of the funnel plot revealed no evidence of publication bias (Fig. 4), and this was further supported by the results of Egger’s regression test.

Fig. 4.

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

Discussion

This meta-analysis of randomized controlled trials (RCTs) evaluated the effects of dehydroepiandrosterone (DHEA) supplementation on testosterone and estradiol levels in postmenopausal women. Our analysis of 21 RCTs revealed that DHEA supplementation significantly increased both testosterone and estradiol concentrations, although substantial heterogeneity was observed across the included trials.

Our findings indicate that DHEA is particularly effective in elevating testosterone levels when administered at dosages ≥ 50 mg/day. Additionally, a marked increase in estradiol levels was noted among participants aged ≥ 60 years receiving the same dosage. These findings are consistent with a previous meta-analysis by Li et al., which reported increased testosterone levels in participants receiving > 50 mg/day of DHEA for ≤ 12 weeks, particularly among those under 60 years of age [40]. Similarly, Zhu et al. found that estradiol concentrations were significantly increased in participants aged ≥ 60 years who received ≥ 50 mg/day of DHEA for ≥ 26 weeks [41]. The variation in effective intervention duration may stem from differences in study populations. Our meta-analysis focused exclusively on postmenopausal women, which may have contributed to differing results compared to previous analyses involving broader populations.

Most of the included trials in our study had an intervention duration of 6 to 12 months; therefore, we used 26 weeks (approximately 6 months) as the stratification threshold. While the average increase in estradiol was 7.86 pg/mL, this change may be clinically minimal. Estradiol levels below 9 pg/mL have been associated with increased bone resorption, reduced hip bone density, and a higher risk of osteopenia and osteoporosis in postmenopausal women[42].

Preclinical studies suggest that DHEA exerts tissue-specific effects and acts by binding to estrogen and androgen receptors on cell membranes [43]. The primary benefit of DHEA supplementation in postmenopausal women is its potential to raise estrogen levels to physiologically functional ranges, thereby mimicking the effects of endogenous estrogen [22]. DHEA serves as a precursor for nearly all circulating estrogens and androgens in postmenopausal women [44].

Our findings align with previous research indicating that a 50 mg/day dose of DHEA significantly elevates both testosterone and estradiol levels [45–47]. A narrative review reported that supplementation with 50 mg of DHEA led to peak estradiol levels that may offer estrogenic benefits, such as improved bone health and protection against bone loss [47]. These results are further supported by other meta-analyses that reported similar hormonal increases following DHEA supplementation [40, 41].

Our review also observed a significant increase in testosterone levels with DHEA supplementation administered for ≥ 26 weeks. In line with this, the review conducted by Wierman et al. evaluated the effect of DHEA over a long period in older women and found that both estradiol and testosterone levels significantly increased [48]. A prospective clinical trial found that 50 mg/day of DHEA led to a higher estradiol concentration and testosterone levels after 6 months of treatment. These findings highlight the dynamic, time-dependent hormonal response to DHEA supplementation.

Biochemically, DHEA serves as a precursor to both estrogens and androgens. Once converted to DHEA sulfate in the liver, it undergoes further enzymatic transformation in peripheral tissues, where it contributes to the synthesis of active estrogens and androgens, including estradiol and testosterone [6].

It is important to note that elevated levels of estradiol can have adverse effects, such as stimulating the endometrium [27]. Consequently, prolonged high estradiol levels may increase the risk of developing endometrial carcinoma [49]. Therefore, it is crucial to use low doses of DHEA to raise estradiol levels without overstimulating the endometrium [50]. In our review, subgroup analysis based on DHEA dosage showed that doses of 50 mg/day or higher significantly increased estradiol levels. Given DHEA’s potential to influence estradiol concentrations and thereby promote tumorigenesis, chronic supplementation should be used with caution and accompanied by regular monitoring for hormone receptor–positive cancers. Similarly, DHEA intake at or above 50 mg/day also raises testosterone levels. It is important to emphasize that higher doses of DHEA may cause unwanted side effects, including androgenic effects such as skin changes, hirsutism, and acne [14].

Clinical implications

As a key precursor of androgens, DHEA is converted into estrogens and testosterone. Therefore, DHEA supplementation can be beneficial for postmenopausal women to alleviate menopausal symptoms and enhance overall well-being. However, potential adverse effects must be carefully considered when prescribing DHEA.

Strength and limitations

This meta-analysis provides a comprehensive overview and high-quality evidence on the effects of DHEA supplementation on testosterone and estradiol levels in postmenopausal women. Importantly, no evidence of bias was detected.

Nonetheless, our review has some limitations. The participants in the included randomized controlled trials (RCTs) represented a heterogeneous population, including healthy postmenopausal women, those with primary Sjögren’s syndrome, and individuals with mild to moderate cognitive impairment. This diversity may limit the generalizability of our findings. Additionally, significant heterogeneity was observed across studies, warranting cautious interpretation of the results. Although subgroup analyses were conducted to explore sources of heterogeneity, some factors, such as differences in types of DHEA supplementation, study settings, and population characteristics, were not fully addressed and could have influenced the outcomes. These variables should be carefully considered when recommending DHEA supplementation for increasing estradiol and testosterone levels in postmenopausal women.

Moreover, DHEA metabolism can be affected by conditions like hepatic impairment and other comorbidities, which were not consistently reported or controlled for in the included studies. One included study focused on postmenopausal women with primary Sjögren’s syndrome and had a matched control group, allowing its inclusion in the analysis. However, the potential influence of such metabolic factors on DHEA supplementation outcomes could introduce bias. Despite this, sensitivity analyses indicated that no single study disproportionately affected the overall results, supporting the robustness of our conclusions.

Our review did not account for these metabolic and comorbidity-related factors, which future research should control for or report in detail to minimize bias. Additionally, sensitivity analyses addressing these variables would be valuable in future meta-analyses.

Conclusion

This meta-analysis found that DHEA supplementation at doses of 50 mg/day or higher significantly increased testosterone levels, and in participants aged 60 years or older, significantly elevated estradiol levels. To our knowledge, this is the first meta-analysis to assess the effects of DHEA supplementation on both testosterone and estradiol levels in postmenopausal women, providing a foundation for future interventions and clinical practice. Understanding the optimal DHEA dosage based on specific health conditions is essential to guide rational therapy for postmenopausal women.

Author contributions

The authors’ responsibilities were as follows—S.Y.H, K.L, X.T, X.Z and L.Z conducted the research, analyzed the data, and performed statistical analysis. L.Z and H.C contributed to the writing, design of the manuscript. X.T, X.Z and S.Y.H contributed to the research design. All authors read and approved the final manuscript.

Funding

No funding was received for this study.

Data availability 

All data generated or analyzed during this study are included in this published article, and you can find these data in references [19–39].

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.