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Circulating Dehydroepiandrosterone Sulfate Level and Cardiovascular Or All-Cause Mortality in the Elderly Population: a Meta-Analysis

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Circulating Dehydroepiandrosterone Sulfate Level and Cardiovascular Or All-Cause Mortality in the Elderly Population: a Meta-Analysis 3545 Review Article Circulating dehydroepiandrosterone sulfate level and cardiovascular or all-cause mortality in the elderly population: a meta-analysis Rui Li1, Lihua E2, Nashunbayaer Zha3 1Department of General Practice, 2Department of Stomatology, 3Department of Thoracic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China Contributions: (I) Conception and design: N Zha; (II) Administrative support: N Zha; (III) Provision of study materials or patients: R Li; (IV) Collection and assembly of data: R Li, L E; (V) Data analysis and interpretation: R Li, L E; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Doctor. Nashunbayaer Zha (ORCID: 0000-0002-9449-9871). Department of Thoracic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, No.1 Tongdao North Road, Hohhot, 010050, China. Email: [email protected]. Abstract: Studies have yielded contradictory results concerning the association between dehydroepiandrosterone sulfate (DHEAS) and mortality in the elderly population. This meta-analysis aimed to evaluate the association of low serum DHEAS level with cardiovascular or all-cause mortality in the elderly population. A comprehensive literature search was conducted in PubMed and Embase databases up to 4 February, 2019. Longitudinal observational studies reporting multivariate adjusted risk ratio (RR) and corresponding 95% confidence intervals (CI) for cardiovascular or all-cause mortality with respect to baseline low DHEAS level were included. Both fixed-effect and random effect model were used to pool the overall risk estimate. Methodological quality of the included studies was evaluated using a 9-point Newcastle-Ottawa Scale. Six prospective studies enrolling 6,744 individuals were identified. Five studies were graded as high methodological quality. When compared the lowest to the reference higher circulating DHEAS level, the pooled RR of all-cause and cardiovascular mortality was 1.46 (95% CI: 1.25–1.70) and 1.49 (95% CI: 1.11–1.99), respectively. Subgroup analysis indicated that the association of low DHEAS level with all-cause mortality risk was only found in men (RR 1.41;95% CI: 1.18–1.69) but not in women (RR 1.72; 95% CI: 0.99–2.99). This meta-analysis provides evidence that low circulating DHEAS level is associated with increased risk all-cause mortality in the elderly population. Keywords: Dehydroepiandrosterone sulfate (DHEAS); cardiovascular mortality; all-cause mortality; meta-analysis Submitted Feb 17, 2020. Accepted for publication Aug 07, 2020. doi: 10.21037/apm-20-441 View this article at: http://dx.doi.org/10.21037/apm-20-441 Introduction decreases with advancing age in both genders (4). Age- related decline in DHEAS level has been implicated in Dehydroepiandrosterone sulfate (DHEAS), also known as the aging process (5), which means DHEAS may play an androstenolone sulfate, is an endogenous androstane steroid that is present in both male and female. Almost all DHEAS important role in the longevity (6). is synthesized in the adrenal cortex and only minimal level Low level of serum/plasma DHEAS has been linked of DHEAS is produced by the testes (1). DHEAS can be to impaired survival prognosis in the patients with converted into testosterone, androstenedione, and estrogen (2). cardiovascular disease (7,8), hemodialysis (9), and chronic Men have higher circulating DHEAS level than women (3). obstructive pulmonary disease (10). There are several The production of DHEAS peaks in young adults and possible explanations for low circulating level of DHEAS © Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2020;9(5):3537-3545 | http://dx.doi.org/10.21037/apm-20-441 3538 Li et al. DHEAS and death being associated with cardiovascular mortality, including (per SD, per quartile or per log change in DHEAS); (IV) vascular inflammation (11), platelet aggregation (12), only provided unadjusted risk estimate of cardiovascular oxidative stress (13), and coronary atherosclerosis (14). or all-cause mortality. Two authors independently assess However, the association between baseline DHEAS level the eligibility of the retrieved articles based on the above and cardiovascular or all-cause mortality has yielded inclusion and exclusion criteria. conflicting findings in the general population (15). Differences in baseline age may partly contribute to the Data extraction and quality assessment contradictory finding of prior studies. To date, no previous meta-analysis has specially Data extraction and quality assessment were conducted performed to evaluate the association of low blood DHEAS by two independent authors. The following information level with cardiovascular or all-cause mortality risk in the were extracted from the eligible studies: surname of the general population. DHEAS exhibits a steady decline with first author, year of publication, geographic region, study age, reaching less than 20% of its maximal value (16). design, sample sizes, proportion of women, mean age or Considering age is an obvious heterogeneity when analyzing age range at baseline, comparison of DHEAS category, the predictive role of DHEAS level, this meta-analysis number of endpoints, follow-up duration, fully adjusted specially focused on the association of serum/plasma risk ratio (RR), hazard ratio (HR), odds ratio (OR) with DHEAS level with cardiovascular or all-cause mortality their corresponding 95% confidence intervals (CI), and risk in the elderly population. We presented the following adjustment for confounding factors. A 9-star Newcastle- article in accordance with the PRISMA reporting checklist Ottawa Scale (NOS) for cohort studies was applied (available at http://dx.doi.org/10.21037/apm-20-441). to assess the methodological quality of the included studies (17). Studies awarding a score of ≥7 stars were deemed as high-quality. Discrepancies in data extraction Methods and quality assessment were resolved by discussion with a Search strategy third author. Relevant studies were identified by a comprehensive search of PubMed and Embase databases from their inceptions to Statistical analyses 4 February, 2019. Literature search was performed using a If the studies reported the lower DHEAS level as the combination of the following keywords without language reference category, we recalculated risk estimate taking the restriction: “dehydroepiandrosterone sulfate” AND higher DHEAS as a reference group. HR and OR were “mortality” OR “death”. In addition, we also manually directly deemed as the same measure of RR in this meta- scanned the reference lists of pertinent articles for any analysis. Statistical heterogeneity across studies was checked possible missing studies. using the Cochran’s Q test (significance set at P<0.10) and I2 statistic (significance set at I2≥50%). Meta-analyses were conducted using a random effect model in the presence of Study selection statistical heterogeneity or a fixed-effect model without Inclusion criteria were the follows: (I) longitudinal statistical heterogeneity. Publication bias was scheduled observational studies that performed in the elderly for the Begg’s rank correlation (18) and Egger’s linear population; (II) baseline serum/plasma DHEAS level as regression test (19). Subgroup analyses were planned by exposure; (III) outcome of interests were cardiovascular or the sample sizes (>1,000 vs. <1,000), geographic region all-cause mortality; (IV) provided multivariable-adjusted (Europe vs. others), length of follow-up (>5 vs. ≤5 years), risk estimate of cardiovascular or all-cause mortality for gender (women vs. men), and cutoff value of DHEAS level categorical analysis of circulating DHEAS level. Studies (>2 categories vs. single). We performed leave-out one study were removed according to the following exclusion sensitivity analysis at each turn to investigate the impact of criteria: (I) participants not restricted in the elderly general individual studies on the overall pooled risk estimate. All population; (II) outcome measures were not of interest; statistical analyses were carried out using STATA 12.0 (Stata, (III) reporting risk estimate by continuous DHEAS level College Station, TX, USA). © Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2020;9(5):3537-3545 | http://dx.doi.org/10.21037/apm-20-441 Annals of Palliative Medicine, Vol 9, No 5 September 2020 3539 801 records identified by PubMed and 2 additional records identified through Embase databases searching manually search 376 records after duplicates removed Records screened Records removed after scanning (n=376) titles and abstracts (n=336) 34 full-text articles excluded with Full-text articles assessed various reasons: participants not for eligibility (n=40) in the general population (n=9); participant not restricted in the elderly population (n=3); outcome measure was not of interest (n=16); reported risk estimate by Studies included in continuous DHEAS level (n=4); meta-analysis (n=6) systematic review (n=1); unadjusted risk estimate (n=1) Figure 1 Flow diagram of study selection process. Results reference higher category of DHEAS level. There was no significant heterogeneity between studies (I2=41.6%; Literature search and study characteristics P=0.113). Publication bias was not observed based on the Our initial literature search yielded 803 records, of which results of Begg’s test (P=1.000) and Egger’s test (P=0.489). 376 were left after removal of duplicates. Of these, 40 full- Sequential exclusion of
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